Low ALP Research Articles

Abstract 11652: What is the Relative Risk for Elevated Liver Function Tests of Single and Combined Statin and Alcohol Use and Implications for Management?

Introduction: Statins play a critical role in primary and secondary ASCVD prevention. Although uncommon, myalgias and abnormal liver function tests (LFTs) may limit statin use. Alcohol consumption also is a common cause of LFT elevations. It is unknown whether or to what extent concurrent alcohol and statin use may alter elevated LFT risk and impact management. Methods: Patients (pts) enrolled in the Intermountain INSPIRE registry who completed a health questionnaire for alcohol and other socioeconomic, dietary, and physical activity data were studied. Demographics, anthropometrics, cardiac risk factors, comorbidities, medication use, and laboratory results were obtained from electronic health records. Associations of alcohol and statin use with high ALT (females, >40 U/L; males, >55 U/L) were tested. Alcohol categories were: non-drinkers (ND; n=2797), moderate drinkers (MD; ≤7 drinks/week, n=980), and heavy drinkers (HD; >7 drinks/week, n=164). Results: High ALT was found in 18.9%, 12.6%, and 10.5% of HD, MD, and ND respectively (p=0.002) and in 11.3% of both statin (n=2154) and non-statin users (n=1787) (p=0.97). After adjustment, HD vs. ND had OR=2.19 (CI: 1.44, 3.33; p<0.001), and MD vs ND had OR=1.09 (CI: 0.86, 1.37; p=0.49). Pts not on statins had high ALT in 15.4% of HD (OR=1.47, CI: 0.73, 2.95; p=0.28) and 12.0% of MD (OR=1.10, CI: 0.79, 1.54; p=0.57) compared to 11.0% of ND. In parallel, pts on statins had high ALT in 21.2% of HD (OR=2.58, 95% CI: 1.52, 4.36; p<0.001) and 13.0% of MD (OR=1.16, CI: 0.85, 1.59; p=0.34) vs. 10.2% of ND. Despite these trends, no formal interaction was found between statin use with HD (p-interaction=0.27) or with MD (p-interaction=0.43). Results for high AST (>40 U/L) and low ALP (<40 U/L) were similar to the ALT findings. Conclusions: In this prospective database, statin use was not associated with abnormal LFT findings, whereas risk was higher with increasing alcohol consumption. Concurrent statin and alcohol use was associated with a modestly elevated risk of abnormal LFT, but the interaction was not significant. Reducing alcohol consumption rather than reducing or discontinuing statins may reverse abnormal LFT while preserving the preventive benefit of statins. This hypothesis deserves further prospective testing.

ODP629 A Case of Juvenile Onset Hypophosphatasia Diagnosed In An Elderly Patient With Recurrent Fractures.

Abstract Background Hypophosphatasia (HPP) is a rare genetic disorder characterized by defective bone mineralization. Here we report a case of juvenile onset HPP in an elderly man. CASE A 77-year-old man presented for management of osteoporosis. He complained of joint pains and trouble walking. He had recurrent non-traumatic fractures since his teenage years and he and his sister were diagnosed with childhood rickets. He sustained fractures of both forearms, right ankle, right hip and left femoral neck, and had undergone right hip replacement and left femoral neck internal fixation. In his 20's, following a MVA he had several tooth extractions and eventually required dentures. He was misdiagnosed with osteogenesis imperfecta, vitamin D deficient osteomalacia and pseudogout, and had been treated with cholecalciferol and alendronate in the past. On exam, we noted a waddling gait, short stature and bowing of his knees. Labs revealed normal vitamin D 25-OH 48 ng/mL (30-100), and PTH 18 pg/mL (14-64), borderline corrected calcium 10.5 mg/dL (8.4-10.6) and elevated phosphorous 4.4 mg/dL (2.2-4.3). ALP was notably low 30 U/L (40-150) and had ranged between 15-46 U/L since 2009. These findings caught our attention and we ordered Vitamin B6 levels which were elevated >250. 0 ng/mL (2.1-21.7). Genetic testing identified two ALPL gene variants, a rare C.340G>A variant and a c.571G>A variant which has been found to be causative of HPP. His DXA scan showed normal L-spine (T-score 3.3) and significantly decreased BMD of the proximal 1/3 of the left forearm (T-score -4.4). Hip and femur were not assessed due to presence of hardware. He is scheduled to start treatment with Asfotase alfa. Conclusion HPP is caused by ALPL gene mutations, which lead to loss of function of the enzyme tissue nonspecific alkaline phosphatase (TSNALP). Clinical manifestations such as seizures, recurrent fractures and premature dental loss are observed. Pseudogout may occur due to intraarticular calcium pyrophosphate deposition, as in our patient. Characteristic lab findings are elevated metabolites of TNSALP, including urine inorganic pyrophosphate (PPi) and serum pyridoxal 5'phosphate (PLP) (biologically active metabolite of vitamin B-6). A persistently low ALP is most suggestive and may be a clue for early referral. Genetic testing is confirmatory, but novel mutations may be missed. Delayed diagnosis in our patient led to increased morbidity, potentially avoidable surgeries and inappropriate treatment with bisphosphonate which are contraindicated as they may increase risk for atypical fractures. Asfotase alfa is a TNSALP enzyme replacement therapy designed to address the underlying cause of HPP and studies show improvement in bone mineralization, fracture healing, decreased concentration of PLP and PPi, and improved physical function and quality of life. Cost and availability remain a barrier to many patients. Presentation: No date and time listed

Glymphatic system evaluation using diffusion tensor imaging in patients with traumatic brain injury.

Glymphatic system dysfunction has been reported in animal models of traumatic brain injury (TBI). This study aimed to evaluate the activity of the human glymphatic system using the non-invasive Diffusion Tensor Image-Analysis aLong the Perivascular Space (DTI-ALPS) method in patients with TBI. A total of 89 patients with TBI (June 2018 to May 2020) were retrospectively enrolled, and 34 healthy volunteers were included who had no previous medical or neurological disease. Magnetic resonance imaging (MRI) with DTI was performed, and the ALPS index was calculated to evaluate the glymphatic system's activity. Wilcoxon rank-sum test was used to compare the ALPS index between patients with TBI and healthy controls. ANOVA was done to compare the ALPS index among controls and patients with mild/moderate-to-severe TBI. Multivariate logistic regression analyses were used to identify independent clinical and radiological factors associated with the ALPS index. The correlation between Glasgow Coma Scale (GCS) score and the ALPS index was also assessed. The ALPS index was significantly lower in patients with TBI than in healthy controls (median, 1.317 vs. 1.456, P < 0.0001). There were significant differences in the ALPS index between healthy controls and patients with mild/moderate-to-severe TBI (ANOVA, P < 0.001). The presence of subarachnoid hemorrhage (P = 0.004) and diffuse axonal injury (P = 0.001) was correlated with a lower ALPS index in the multivariate analysis. There was a weak positive correlation between the ALPS index and GCS scores (r = 0.242, P = 0.023). The DTI-ALPS method is useful for evaluating glymphatic system impairment and quantifying its activity in patients with TBI.

Platelet-to-White Blood Cell Ratio: A Feasible Biomarker for Pyogenic Liver Abscess.

The platelet-to-white blood cell ratio (PWR) has been reported to predict the severity of patients with various diseases. However, no previous studies have assessed the use of the PWR as a prognostic marker for pyogenic liver abscesses (PLA). This observational retrospective study was performed between January 2008 and December 2017, including 833 patients with PLA from multiple centers. The enrolled patients, on average, had a PWR of 17.05, and 416 patients had a PWR lower than 17.05. A total of 260 patients (31.2%) with PLA showed complications of metastatic infection, pleural effusion and abscess rupture. A low PWR level was identified as a strong risk factor for metastatic infection and pleural effusion. The low PWR group also had a longer hospital stay. In the multivariate analysis, old age, anemia, albumin and CRP levels and unidentified pathogens were significant factors for low PWR levels. A low PWR, old age, male sex, abscess size, albumin, ALP and unidentified causative pathogens showed significant associations with a hospital stay longer than 28 days. As a result, PLA patients presenting with a low PWR were shown to have more complications and a poor prognosis. Considering its cost-effectiveness, PWR could be a novel biomarker used to predict a prognosis of PLA.

Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study.

We aimed to explore the heterogeneous treatment effects (HTEs) for spironolactone treatment in patients with Heart failure with preserved ejection fraction (HFpEF) and examine the efficacy and safety of spironolactone medication, ensuring a better individualized therapy. We used the causal forest algorithm to discover the heterogeneous treatment effects (HTEs) from patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Cox regressions were performed to assess the hazard ratios (HRs) of spironolactone medication for cardiovascular death and drug discontinuation in each group. The causal forest model revealed three representative covariates and participants were partitioned into four subgroups which were Group 1 (baseline BMI≤31.71kg/m2 and baseline ALP≤80U/L, n=759); Group 2 (BMI≤31.71kg/m2 and ALP>80U/L, n=1088); Group 3 (BMI>31.71kg/m2 , and WBC≤6.6 cells/μL, n=633); Group 4 (BMI>31.71kg/m2 and WBC>6.6 cells/μL, n=832), respectively. In the four subgroups, spironolactone therapy reduced the risk of cardiovascular death in high-risk group (Group 4) with both high BMI and WBC count (HR: 0.76; 95% CI 0.58 to 0.99; P=0.045) but increased the risk in low-risk group (Group 1) with both low BMI and ALP (HR: 1.45; 95% CI 1.02 to 2.07; P=0.041; P for interaction=0.020) but showed similar risk of drug discontinuation (P for interaction=0.498). Our study manifested the HTEs of spironolactone in patients with HFpEF. Spironolactone treatment in HFpEF patients is feasible and effective in patients with high BMI and WBC while harmful in patients with low BMI and ALP. Machine learning model could be meaningful for improved categorization of patients with HFpEF, ensuring a better individualized therapy in the clinical setting.

Association of MRI Indices of Glymphatic System With Amyloid Deposition and Cognition in Mild Cognitive Impairment and Alzheimer Disease.

The glymphatic system is a whole-brain perivascular network, which promotes CSF/interstitial fluid exchange. Alterations to this system may play a pivotal role in amyloid β (Aβ) accumulation. However, its involvement in Alzheimer disease (AD) pathogenesis is not fully understood. Here, we investigated the changes in noninvasive MRI measurements related to the perivascular network in patients with mild cognitive impairment (MCI) and AD. Additionally, we explored the associations of MRI measures with neuropsychological score, PET standardized uptake value ratio (SUVR), and Aβ deposition. MRI measures, including perivascular space (PVS) volume fraction (PVSVF), fractional volume of free water in white matter (FW-WM), and index of diffusivity along the perivascular space (ALPS index) of patients with MCI, those with AD, and healthy controls from the Alzheimer's Disease Neuroimaging Initiative database were compared. MRI measures were also correlated with the levels of CSF biomarkers, PET SUVR, and cognitive score in the combined subcohort of patients with MCI and AD. Statistical analyses were performed with age, sex, years of education, and APOE status as confounding factors. In total, 36 patients with AD, 44 patients with MCI, and 31 healthy controls were analyzed. Patients with AD had significantly higher total, WM, and basal ganglia PVSVF (Cohen d = 1.15-1.48; p < 0.001) and FW-WM (Cohen d = 0.73; p < 0.05) and a lower ALPS index (Cohen d = 0.63; p < 0.05) than healthy controls. Meanwhile, the MCI group only showed significantly higher total (Cohen d = 0.99; p < 0.05) and WM (Cohen d = 0.91; p < 0.05) PVSVF. Low ALPS index was associated with lower CSF Aβ42 (r s = 0.41, p fdr = 0.026), FDG-PET uptake (r s = 0.54, p fdr < 0.001), and worse multiple cognitive domain deficits. High FW-WM was also associated with lower CSF Aβ42 (r s = -0.47, p fdr = 0.021) and worse cognitive performances. Our study indicates that changes in PVS-related MRI parameters occur in MCI and AD, possibly due to impairment of the glymphatic system. We also report the associations between MRI parameters and Aβ deposition, neuronal change, and cognitive impairment in AD.

Prognostic Factors in Patients Treated with Pembrolizumab as a Second-Line Treatment for Advanced Biliary Tract Cancer.

Simple SummaryThe five-year survival rate for advanced biliary tract cancer (BTC) is still less than 10%. Moreover, there is no established second-line chemotherapy after the failure of the first-line chemotherapy. Pembrolizumab is known to be an effective treatment in advanced BTC, but the prognostic factors of pembrolizumab are unknown. The purpose of this study is to provide guidelines for selecting treatment alternatives for BTC patients with refractory to gemcitabine-based chemotherapy, by exploring the prognostic factors of pembrolizumab in BTC.Some BTC types respond to pembrolizumab, but there are no known prognostic factors to predict its treatment benefits. In this study, we attempted to identify the prognostic factors associated with pembrolizumab as a second-line treatment for gemcitabine-refractory BTC. This retrospective and single tertiary-center study involved all the consecutive patients (n = 80) with refractory advanced BTC, who were diagnosed as programmed cell death ligand 1-positive and treated with pembrolizumab between August 2017 and February 2021. The overall survival (OS) was analyzed using Cox regression analysis. The median OS was 6.0 months [95% confidence interval (CI): 3.87–8.20]; median progression-free survival was 1.9 months (95% CI: 1.82–1.98); and the response rate was 15.9%. In the multivariate Cox regression analysis, the TB [adjusted hazard ratio (HR) = 2.286; 95% CI: 1.177–4.440; p = 0.015), albumin levels (adjusted HR = 0.392; 95% CI: 0.211–0.725; p = 0.003), ALP levels (adjusted HR = 1.938; 95% CI: 1.105–3.400; p = 0.021), and LMR (adjusted HR = 0.325; 95% CI: 0.173–0.609; p < 0.001) were identified as significant variables associated with the OS. High albumin levels and LMR and low ALP levels and TB were significantly associated with better OS in patients treated with pembrolizumab.

Different mechanisms in periventricular and deep white matter hyperintensities in old subjects.

ObjectiveAlthough multiple pieces of evidence have suggested that there are different mechanisms in periventricular white matter hyperintensities (PWMHs) and deep white matter hyperintensities (DWMHs), the exact mechanism remains uncertain.MethodsWe reviewed clinical and imaging data of old participants from a local She Ethnic group. We assessed the cerebral blood flow of white matter (WM-CBF) on arterial spin-labeling, deep medullary veins (DMVs) visual score on susceptibility-weighted imaging, and index for diffusion tensor image analysis along the perivascular space (ALPS index), indicating glymphatic function on diffusion tensor imaging. Furthermore, we investigated their relationships with volumes of PWMHs and DWMHs.ResultsA total of 152 subjects were included, with an average age of 63 ± 8 years old. We found that higher age and history of hypertension were independently related to higher volumes of both PWMHs and DWMHs (all p < 0.05). Lower ALPS index was independently associated with higher PWMHs volumes (β = 0.305, p < 0.001), and this relationship was accounted for by the indirect pathway via DMVs score (β = 0.176, p = 0.017). Both lower ALPS index and WM-CBF were independent risk factors for higher DWMHs volumes (β = −0.146, p = 0.041; β = −0.147, p = 0.036).ConclusionsOur study indicated that there were different mechanisms in PWMHs and DWMHs. PWMHs were mainly attributed to the damage of veins due to the dysfunction of the glymphatic pathway, while DWMHs could be affected by both ischemia-hypoperfusion and dysfunction of the glymphatic pathway.Advances in knowledgeThe relationship between glymphatic dysfunction and PWMHs might be accounted for by the indirect pathway via venous abnormalities, a glymphatic dysfunction, and lower CBF in white matter were independent risk factors for DWMHs.

Do trace elements play a role in coronary artery calcification in hemodialysis patients?

Abnormalities of trace elements have previously been linked to inflammatory processes in hemodialysis (HD) patients. We aimed to establish the trace element status of maintenance HD patients, to investigate the relationship between coronary artery calcification scores (CACs) and whole blood levels of trace elements. Patients undergoing HD in three times a week for > 6months and age-and sex-matched controls were included from October 2015 to June 2016. Data were collected from patient files. All subjects' whole blood levels of trace elements were measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). CACs for patients were assessed by multi-detector computed tomography. The 35 patients (male, 60%) with a mean age of 45.7 ± 10.4years and 35 controls were included. HD patients showed significantly lower levels of selenium and uranium and higher cadmium (Cd), cobalt, lithium, manganese, nickel, lead, platinum, tin, strontium, and thallium levels compared to controls. Coronary artery calcification (CAC) was present in 21 patients (60%), and median CACs were 14.2 (IQR 0-149). Patients with CACs > median were significantly older, had a higher prevalence of hypertension and lower ALP levels than patients with CACs ≤ median. No significant differences in whole blood levels of trace elements were found between patients with CACs > median and patients with CACs ≤ median. A near significance was noted in median whole blood levels of Cd between these groups (P = 0.096). According to multivariate analysis, age was the only independent determinant for CAC development. Age is independently associated with coronary vascular calcification. High Cd levels might play a role in CAC development in HD patients.

Glymphatic dysfunction correlates with severity of small vessel disease and cognitive impairment in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by β-amyloid deposition in cortical and leptomeningeal arterioles, which might result from glymphatic dysfunction. The aim was to explore glymphatic function in CAA using the non-invasive diffusion tensor image analysis along the perivascular space method. Sixty-three patients with CAA were prospectively recruited together with seventyage- and sex-matched normal controls. The Mini-Mental State Examination and Montreal Cognitive Assessment were applied to screen global cognitive status. Magnetic resonance imaging scans were conducted to calculate the index for diffusivity along the perivascular space (ALPS index), and linear regression models were used to assess its relationships with cerebral small vessel disease (CSVD) markers, cognitive status and blood biomarkers. Cox proportional hazard models were applied to explore the role of the baseline ALPS index in disease recurrence. Patients with CAA exhibited a lower ALPS index than controls globally (p &lt; 0.001). In addition, a lower ALPS index was related to more enlarged perivascular space in basal ganglia (p=0.026), more lacunes (p &lt; 0.001), higher white matter hyperintensity Fazekas score (p=0.049), elevated total magnetic resonance imaging burden of CSVD (p=0.034) and lower Mini-Mental State Examination (p=0.001) as well as Montreal Cognitive Assessment (p &lt; 0.001) in CAA. During a median follow-up of 4.1 years, a higher ALPS index was associated with lower disease recurrence (p=0.022). The ALPS index was also negatively correlated with serum soluble intercellular adhesion molecule-1, neurofilament light and chitinase-3-like protein 1 in CAA. Patients with CAA showed impaired glymphatic function. The ALPS index was significantly related to CSVD severity, cognitive impairment and disease recurrence in CAA.

Bone microstructure evaluated by TBS and HR-pQCT in Chinese adults with X-linked hypophosphatemia

X-linked hypophosphatemia (XLH) is the most common form of heritable hypophosphatemic rickets. Although generalized mineralization defects have been observed, elevated areal bone mineral density (aBMD) in the lumbar spine measured by dual-energy X-ray absorptiometry (DXA) has also been found in XLH. In contrast, high-resolution peripheral quantitative computed tomography (HR-pQCT) revealed lower volumetric BMD (vBMD) and damaged bone microstructure in the peripheral bone in XLH. Trabecular bone score (TBS), which can assess the trabecular microstructure in the lumbar spine, has not been explored in XLH. This study aimed to explore TBS and its correlations with biochemical indices and HR-pQCT parameters in adult XLH patients. A total of 66 patients with XLH (26 men and 40 women) aged 29.6±9.6years and 66 age- and sex-matched healthy controls were included. Z score of lumbar spine aBMD was relatively high [2.0 (0.6, 3.7)], with normal TBS (1.475±0.129) in the XLH patients. HR-pQCT revealed larger total and trabecular area in the peripheral bone in the XLH group compared with the control group. In addition, lower trabecular and cortical vBMD, lower trabecular number with greater separation, and lower bone strength at both the radius and tibia were found in the XLH group compared with the control group. Smaller cortical area, lower thickness and higher porosity in the XLH group compared with controls were only found at the radius. TBS was not associated with any biochemical indices, while better HR-pQCT parameters correlated with higher serum phosphate and lower ALP levels. TBS was positively related with aBMD but not HR-pQCT parameters. In conclusion, adult patients with XLH had high bone mass and normal TBS in the lumbar spine but compromised microarchitecture and bone strength in the peripheral bone. This finding indicated a site-specific effect of the disease on the skeleton in the XLH patients.

Cardioprotective Effect of Rumex vesicarius Linn. Leaf Extract against Catecholamine-Induced Cardiotoxicity.

Rumex vesicarius (L.) is a folklore medicinal herb that has been used for centuries to cure cardiovascular diseases. The present work was carefully designed to ascertain the pharmacological basis for R. vesicarius’s therapeutic efficacy in cardiovascular diseases, as well as the underlying mechanism. In the ex vivo investigation, the aqueous-methanolic leaf extract of R. vesicarius was shown to have endothelium-dependent vasorelaxant effects in rabbit aorta tissue preparations, and its hypotensive responses were quantified by pressure and force transducers coupled to the Power Lab Data Acquisition System. Furthermore, when rabbits were subjected to adrenaline-induced myocardial infarction, R. vesicarius demonstrated cardioprotective characteristics. In contrast to the intoxicated group, the myocardial infarction model showed lower ALP, CK-MB, CRP, LDH, ALT, troponin, and AST levels (p > 0.005–0.000), as well as edema, necrosis, apoptosis, inflammatory cell enrolment, and necrosis. R. vesicarius exhibited significant antioxidant activity and delayed noradrenaline-induced platelet aggregation. Its cardioprotective, anticoagulant, and vasorelaxant properties in both investigations (in vivo and ex vivo) are mediated through partial endothelium-dependent, NO and calcium channel blockade mediated vasorelaxation. The minimizing of adrenaline, oxidative stress, and tissue damage demonstrate its therapeutic efficacy in cardiovascular diseases.

The Predictive Value of Serum Alkaline Phosphatase Level on the Degree of Neurological Impairment in Patients with Acute Cerebral Infarction

Objective: To analyze the correlation between the changes of ALP level and the degree of neurological impairment in patients with acute cerebral infarction. Methods: A total of 267 patients with acute cerebral infarction were selected as the cerebral infarction group, 181 elderly patients who were matched age and gender in the same period with the cerebral infarction group were selected as the control group by the physical examination. All the selected patients were tested for serum ALP, ALT, AST, Cr, BUN,TG, TC, LDL - C and HDL - C after eight hours on an empty stomach. In the 72nd hour of the patient's course of cerebral infarction, the degree of neurological impairment was assessed using NIHSS score. The relationship between serum ALP level and NIHSS score was analyzed. Results: According to NIHSS score, the patients with score of 5~15 were Group A , patients with score of 15~20 were Group B and score of 21~42 were Group C. Pearson correlation analysis showed that the serum ALP level of the three groups was positively correlated with NIHSS score. Multivariate regression analysis results showed that the high serum ALP level of the risk of cerebral infarction is a low serum ALP level 1.58 times. Conclusions Serum ALP level was increased in patients with acute cerebral infarction and was closely related to the degree of neurological impairment. Perhaps the serum ALP level may be used as a serum marker to predict the degree of neurological impairment in patients.

Neuroimaging evidence of glymphatic system dysfunction in possible REM sleep behavior disorder and Parkinson\u2019s disease

Alpha-synucleinopathy is postulated to be central to both idiopathic rapid eye movement sleep behaviour disorder (iRBD) and Parkinson’s disease (PD). Growing evidence suggests an association between the diminished clearance of α-synuclein and glymphatic system dysfunction. However, evidence accumulating primarily based on clinical data to support glymphatic system dysfunction in patients with iRBD and PD is currently insufficient. This study aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship to clinical scores of disease severity in patients with possible iRBD (piRBDs) and those with PD. Further, we validated the correlation between the ALPS index and the prognosis of PD longitudinally. Overall, 168 patients with PD, 119 piRBDs, and 129 healthy controls were enroled. Among them, 50 patients with PD had been longitudinally reexamined. Patients with PD exhibited a lower ALPS index than those with piRBDs (P = 0.036), and both patient groups showed a lower ALPS index than healthy controls (P < 0.001 and P = 0.001). The ALPS index and elevated disease severity were negatively correlated in the piRBD and PD subgroups. Moreover, the ALPS index was correlated with cognitive decline in patients with PD in the longitudinal analyses. In conclusion, DTI-ALPS provided neuroimaging evidence of glymphatic system dysfunction in piRBDs and patients with PD; however, the potential of assessing the pathological progress of α-synucleinopathies as an indicator is worth verifying. Further development of imaging methods for glymphatic system function is also warranted.

Taurine is an effective therapy against thiram induced tibial dyschondroplasia via HIF-1α/VEGFA and β-catenin/ GSK-3β pathways in broilers

Thiram causes tibial dyschondroplasia in broilers, leading to a significant economic loss in the poultry industry. Our study explored the effects of taurine in thiram induced tibial dyschondroplasia (TD) through in vivo and in vitro approches. In in vivo study, thiram resulted in lameness disorder, low production parameters ALP, ACP, and a high level of NOS. While, the taurine exhibited promising effect by reducing lameness, increasing ALP, ACP levels, and significantly lowering NOS level with the restoration of the growth plate. In in vitro study, thiram caused distortion and disintegration of chondrocytes. The CCK-8 technique revealed the lower cell activity in TD as compared with the treatment group. Even, the treatment and taurine groups had higher cell activity than control group. Also, the chondrocyte morphology progressively reverted to normal after taurine treatment. It might effectively decreased the symptoms of TD in broilers and their production performance. Further research found that the taurine effectively improved chondrocytes' cell viability and recovered lameness disorder by regulation of HIF-1α, VEGFA, and Wnt/β-catenin signaling pathways. In summary, these results indicate that taurine has a protective effect on thiram-induced broilers and it can enhance the growth activity by directly affecting the development of chondrocytes and blood vessels.

Prevalence of low alkaline phosphatase activity in laboratory assessment: Is hypophosphatasia an underdiagnosed disease?

BackgroundTissue-nonspecific alkaline phosphatase (TNSALP) encoded by the ALPL gene is of particular importance for bone mineralization. Mutation in the ALPL gene can lead to persistent low ALP activity resulting in the rare disease Hypophosphatasia (HPP) that is characterized by disturbed bone and dental mineralization. While severe forms are extremely rare with an estimated prevalence of 1/100.000, recent studies suggest that moderate form caused by heterozygous mutations are much more frequent with an estimated prevalence of 1/508. The purpose of this study was to estimate the prevalence of low AP levels in the population based on laboratory measurements.MethodsIn this study, the prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6.918.126 measurements from 2011 to 2016 at a single laboratory in northern Germany. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included, all repeated values were excluded.ResultsIn total, 8.46% of the measurements of a total of 6.918.126 values showed a value < 30 U/L. 0.59% of the subjects with an ALP activity below 30 U/L had an additional PLP measurement. Here, 6.09% showed elevated pyridoxal-5-phosphate (PLP) levels. This suggest that 0.52% (1:194) of subjects show laboratory signs of HPP.ConclusionThese data support the genetic estimation that the prevalence of moderate forms of HPP may be significantly higher than expected. Based on these data, we recommend automatically measurement of PLP in the case of low ALP activity and a notification to the ordering physician that HPP should be included in the differential diagnosis and further exploration is recommended.

Factors Associated With Dysfunction of Glymphatic System in Patients With Glioma.

ObjectivesRodent experiments have provided some insights into the changes of glymphatic function associated with glioma growth. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method offers an opportunity for the noninvasive investigation of the glymphatic system in patients with glioma. We aimed to investigate the factors associated with glymphatic function changes in patients with glioma.Materials and MethodsA total of 201 glioma patients (mean age = 47.4 years, 116 men; 86 grade II, 52 grade III, and 63 grade IV) who had preoperative diffusion tensor imaging for calculation of the ALPS index were retrospectively included. Information collected from each patient included sex, age, tumor grade, isocitrate dehydrogenase 1 (IDH1) mutation status, peritumoral brain edema volume, tumor volume, and ALPS index. Group differences in the ALPS index according to sex, tumor grade, and IDH1 mutation status were assessed using analysis of covariance with age adjustment. Linear regression analyses were performed to identify the factors associated with the ALPS index.ResultsGroup comparisons revealed that the ALPS index of grade II/III gliomas was significantly higher than that of grade IV gliomas (p < 0.001). The ALPS index of IDH1 mutant gliomas was significantly higher than that of IDH1 wild-type gliomas (p < 0.001). On multivariable linear regression analysis, IDH1 mutation (β = 0.308, p < 0.001) and peritumoral brain edema volume (β = −0.353, p < 0.001) were the two independent factors associated with the ALPS index.Conclusion IDH1 wild-type gliomas and gliomas with larger peritumoral brain edema volumes were associated with a lower ALPS index, which may reflect impaired glymphatic function.

The Influence of Demographics and Vascular Risk Factors on Glymphatic Function Measured by Diffusion Along Perivascular Space.

Assessing glymphatic function using in-vivo imaging method is of great value for understanding its contribution to major brain diseases. In the present study, we aim to validate the association between a variety of risk factors and a potential index of glymphatic function—Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS index). We enrolled 142 subjects from communities and performed multi-modality magnetic resonance imaging scans. The ALPS index was calculated from diffusion tensor imaging data, and its associations with demographic factors, vascular factors were investigated using regression analyses. We found that the ALPS index was negatively associated with age (β = −0.284, p < 0.001). Compared to males, females had significantly higher ALPS index (β = −0.243, p = 0.001). Hypertensive subjects had significantly lower ALPS index compared to non-hypertensive subjects (β = −0.189, p = 0.013). Furthermore, venous disruption could decrease ALPS index (β = −0.215, p = 0.003). In general, our results are in consistent with previous conceptions and results from animal studies about the pathophysiology of glymphatic dysfunction. Future studies utilizing this method should consider introducing the above-mentioned factors as important covariates.

MO216PRELIMINARY STUDY OF THE GLYMPHATIC SYSTEM IN CKD

Abstract Background and Aims The glymphatic system is a network of extracellular spaces between neurons, glial cells, and capillaries that promotes the elimination of soluble molecules from the brain. Its dysfunction is probably relevant for neurodegenerative diseases such as Alzheimer's disease (AD). It is widely accepted that cognitive impairment accompanies chronic kidney disease (CKD). CKD is also a risk factor for dementia. However, the role of the glymphatic system in this process is unknown. A recent method to study the glymphatic system in human subjects has been proposed based on Diffusion Tensor Imaging (DTI) data and water diffusion calculation along with perivascular spaces. This approach is based on calculating a diffusion index named ALPS and showed that the glymphatic flow is reduced in MCI. Method To analyze the role of glymphatic system in CKD patients, we took advantage of the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI is a longitudinal multicenter study helping researchers to monitor Alzheimer's disease and Mild Cognitive Impairment (MCI) progression. This database has a cohort of control patients and MCI patients, among which several patients with CKD stage II-III were identifiable from the creatinine values. Patients with Alzheimer's disease were excluded for this study. Among the control and MCI patients, we identified 12 CKD patients and pair-matched 12 non-CKD patients comparable for age, gender, and MoCA score. Magnetic resonance data with DTI sequences were retrieved for all patients, and the glymphatic system was characterized by the ALPS index. Tensor values were calculated using the FSL software; the diffusion values were calculated on tensor images using the ImageJ software. Differences in ALPS between CKD and non-CKD patients with and without MCI were tested. Results Analysis of DTI data confirmed that control patients without CKD had lower ALPS values when MCI was present compared to the non-MCI patients, suggesting a reduction of water diffusion in the glymphatic system. However, the presence of CKD had a different effect: in the absence of MCI, CKD did not modify ALPS values compared to non-CKD patients. At variance, in patients with MCI, CKD resulted in a significant increase of water diffusion in the glymphatic system compared to the controls. Conclusion In this preliminary study, MCI and CKD exerted opposite effects on the diffusion of water within the glymphatic system: MCI was accompanied by a reduction of water diffusion whereas CKD by an increased diffusion in the glymphatic spaces. It is possible that small modification of water balance in CKD may be responsible for the increased diffusion of water in glymphatics in CKD. Further studies are needed to verify whether this unexpected phenomenon may modify cognitive function with a mechanism rather different from Alzheimer's disease.

The Prevalence and Burden of Hypophosphatasia in an Ambulatory Endocrinology Practice

Introduction: Hypophosphatasia (HPP) is an autosomal disease resulting from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The presentation and severity of the disease is highly variable ranging from perinatal-onset HPP with mortality rates as high as 100%, to adult onset with little mortality but with high disease-burden. Overall estimated prevalence of HPP in the general population is 1:100,000 though it may be significantly higher in specific populations. Hypophosphatasia is a heterogeneous disease that can reveal itself at any age, presenting within a wide range of symptoms. Adult HPP typically presents during middle age and is often misdiagnosed or missed in practice. The objective of this study was to determine the prevalence and burden of hypophosphatasia in an ambulatory care endocrinology practice. Methods: Potential subjects were identified via a computerized text search of the laboratory fields of patient electronic medical records (EMR). Search terms included serum ALP levels of less than or equal to 40 mg/dL. Records of patients with at least two low ALP levels were reviewed manually to identify potential patients with a history consistent with HPP. Results: A total of 315 patients with ALP levels < 40 mg/dL were identified via text search from an estimated 20,000 patient records. Fifty-six patients with a single low level were not considered for further review. The remaining 259 patients were reviewed for histories consistent with hypophosphatasia. These patients were predominantly white (64.9%), with an average age of 55 (+ 15) years, and an average BMI of 28 (+ 7) kg/m2. Ten of these patients had histories consistent with hypophosphatasia including musculoskeletal pain requiring scheduled use of pain medications, polyarthropathy, chondrocalcinosis, deformity secondary to fractures, low BMD, a history of nontraumatic fracture, delayed or incomplete fracture healing, a history of multiple orthopedic surgeries, fatigue, impaired mobility, impaired gait, impairment of daily activities, a history of renal stones or nephrocalcinosis, and/or high serum B6 levels. None of the identified ten patients were currently being treated or had previously been treated for hypophosphatasia and have subsequently been recommended for genetic testing. Conclusions: Hypophosphatasia is an uncommon condition with a highly variable presentation often resulting in a missed diagnosis. Surveillance of practices by identifying patients with low ALP levels is a reasonable screening approach to identifying potential patients with hypophosphatasia.