Lithium-related neurotoxicity despite serum concentrations in the therapeutic range:risk factors and diagnosis

We would like to comment on the interesting case report of lithium intoxication reported by Jing Peng.[1]An 18-year old female with mania developed confusion,trembling extremities,slurred speech,increased muscle tension,and hyperactive tendon reflexes 20 days after initiating treatment with routine dosages of lithium bicarbonate.When admitted to the hospital due to her acute neurological condition,her serum lithium concentration was in the therapeutic range(0.57 mmol/L).Most of her symptoms spontaneously reversed one

Effects of Serum Concentration, Synchronization Time and Confluence on the Cell-Cycle Synchronization Efficiency of Goat Fibroblasts

This study aims to evaluate the effect of serum concentration, synchronization time, and confluence degree on the synchronisation efficiency of goat fibroblast cycle. The results indicated that there was no difference in the percentage of nucleated fibroblasts in the G0/G1 stage between serum concentrations of 0.3% and 0.4% (83.89% and 82.69%, respectively, P > 0.05) as well as between serum concentrations of 0.2% and 0.5% (76.95% and 75.46%, respectively, P > 0.05). The percentage of nucleated fibroblasts in the G0/G1 stage was highest at the concentration of 0.3% and lowest in the control group (83.89% vs. 62.67%, P 0.05). The beneficial effect of high confluence was confirmed by the large percentage of nucleated fibroblasts at the G0/G1 stage. The 60% confluency was significantly lower than the 80% and 100% confluency (73.44%, 86.63%, and 87.17%, respectively, P < 0.05). The results indicate that the goat fibroblast cycle synchronization is the most effective at the serum concentration of 0.3%, 72 hours of synchronization and 100% confluency.

Determination of Sulphonylurea Glimepiride in Dog Serum by RP-HPLC with Pre-column Derivatization

Aim A simple, sensitive and rapid RP HPLC method with pre column derivatization has been developed for the determination of sulphonylurea glimepiride in dog serum. Methods The sulphonylurea glimepiride was extracted from the dog serum using dichlromethane followed by derivatization with DNBF for 20 min at 100℃. The solvent was then evaporated at 60℃ under nitrogen, and the residue was taken up in 100 μL of mobile phase consisting of acetonitrile water (75∶30, v/v). The separation was performed on a Hypersil BDS C18 column with a flow rate of 0 8 mL·min -1 , and the ultraviolet detector wavelength was set at 350 nm. Results Extraction recovery ranged from 75.9% to 83.2%, and methodological recovery was between 96.5% and 109.3%. Within day RSD ranged from 1.5% to 6.3%, and inter day RSD was between 2 9% and 14.8%. The method showed good linearity (R=0.9998). Conclusion The method was simple, convenient and sensitive. The reaction of derivatization was reproducible.

Effect of serum concentration on adhesion of monocytic THP-1 cells onto cultured EC monolayer and EC-SMC co-culture

Background:The adhesion of monocytes to the endothelium following accumulation of low-density lipoprotein (LDL) in subendothelial spaces is an important step in the development of intimal hyperplasia in arterially implanted vein grafts and atherosclerosis in both animals and humans. However, it is not well known how serum factors affect the adhesion of monocytes. Methods: We have studied the effect of fetal calf serum (FCS), which we considered a source of LDL, on the adhesion of monocytes to endothelial cells (ECs) by using human monocytic THP-1 cells and both a monolayer of cultured bovine aortic endothelial cells (EC monoculture) and a co-culture with bovine aortic smooth muscle cells (EC-SMC co-culture). Results: It was found that the addition of FCS to the medium greatly affected the adhesion of THP-1 cells, and the higher the concentration of FCS in the medium, the greater the adhesion of THP-1 cells to endothelial cells. Adhesion of THP-1 cells to an EC-SMC co-culture was approximately twofold greater than that to an EC monoculture, and after adhering to endothelial cells, many THP-1 cells trans-migrated into the layer of smooth muscle cells. Conclusion: The results suggest that the elevation of the LDL (cholesterol) level in blood provides a favorable condition for the development of intimal hyperplasia and atherosclerosis by promoting the adhesion of monocytes to the endothelium and their subsequent migration into subendothelial spaces.

Prognostic role of pretreatment serum ferritin concentration in lung cancer patients:A meta-analysis

BACKGROUND The association between pretreatment serum ferritin concentration(SFC)and long-term survival in lung cancer remains unclear now.AIM To identify the prognostic value of pretreatment SFC in lung cancer patients based on current evidence.METHODS The PubMed,EMBASE and Web of Science databases were searched from inception to May 29,2022 for relevant studies.The primary endpoint was overall survival(OS)and the hazard ratios(HRs)with corresponding 95%confidence intervals(CIs)were combined to assess the predictive role of pretreatment SFC for long-term survival of lung cancer patients.The data were then extracted and assessed on the basis of the Reference Citation Analysis(https://www.reference citationanalysis.com/).RESULTS Twelve retrospective studies involving 1654 patients were analyzed.The results manifested that increased pretreatment SFC was associated with worse OS(HR=1.09,95%CI:1.03-1.15,P=0.004).Subgroup analysis stratified by the country(China vs non-China)showed similar results.However,subgroup analysis stratified by tumor type revealed inconsistent results(lung cancer:HR=1.39,P=0.008;small cell lung cancer:HR=1.99,P=0.175;non-small cell lung cancer:HR=1.03,P=0.281).CONCLUSION Pretreatment SFC might serve as a promising prognostic indicator in lung cancer patients and elevated pretreatment SFC predicts worse prognosis.However,more high-quality studies with big sample sizes are still needed to further verify its prognostic value in lung cancer.

Concentration Changes of Medroxyprogesterone Acetate in Serum and Milk in Lactating Woman Who Used Depo Geston~

Objective To determine the concentration changes of medroxyprogesterone acetate （MPA） in serum and milk in the Chinese lactating women who used Depo Geston Methods Ten postpartum and breastfeeding women received an injectable contraceptive of Depo Geston （depo medroxyprogesterone acetate, DMPA, 150 mg/ampoule）. Serum and milk samples were collected in the 1^st, 2^st, 4^th, 6^th, 8^th 10^th and 12^th week after contraceptive injection. The concentrations of medroxyprogesterone acetate （MPA） in serum and milk were determined by radioimmunoassay. Results The highest MPA concentration in serum was observed at the 1^st week and then the level of serum MPA decreased obviously at the 2^na and 4^th week. After the 4^th week, the decline of serum MPA level slowed down. The concentration of milk MPA reached the highest level at 1^th week. But at the 2^nd week the average level of MPA in milk dropped by half The MPA concentration in the milk was changed in the range of 5.2-8.3 ng/mL in the following 10 weeks. During observation, the average ratios of concentration and area under curve （AUC） in milk/serum were both 0.55. There was a wide variation in MPA concentrations and ratios of milk/serum between subjects. Conclusion MPA concentrations maintained a certaim level at the 12^th week after DMPA injection. However, whether mather＇s intake of DMPA during feeding period has effect on children＇s growth, espcially pubertal growth, deserves further studies.

Determination of Polydatin in Rat Serum and Its Changes by UPLC Method

[Objectives]To establish a UPLC-UV method for the determination of polydatin in the serum of Wistar rats.[Methods]Acquity UPLC BEH shield RP18 column(1.7μm,2.1 mm×100 mm,Waters Corporation,USA)was used as the analytical column,acetonitrile-water(55∶45)was used as the mobile phase,the flow rate was 0.5 mL/min,and the column temperature was 30℃and the detection wavelength was 306 nm.[Results]The linear range of the established serum sample analysis method was 1.0-20.0μg/mL,and the correlation coefficient was r=0.9994;the intraday and interday RSD of Wistar rat serum was less than 3.0%,and the accuracy was higher than 90%.[Conclusions]This method is sensitive,accurate,and rapid.It is suitable for monitoring the concentration of polydatin in serum after intragastric administration,and can also be used for pharmacokinetics and bioavailability studies.

Risk Stratification with Serum Cardiac Troponin I in Acute Myocardial Infarction on Admission

Objective To assess the prognostic significance of serum cardiac troponin I (cTnI) concentration in patients with acute myocardial infarction on admission. Methods Serum samples of 108 patients with established AMI were collected on admission for measuring cTnI and were grouped according to the intervals between the onset of chest pain and admission. Results In each of these groups, the serum cTnI concentrations in patients died after admission were significantly higher than those who survived (all P<0.05). Conclusions A higher serum cTnI concentration on admission in patients with AMI was associated with an increased risk of subsequent cardiac death during hospitalization.

Effect of thyroid hormone on serum NO concentration and iNOS activity of intestinal mucosa in septic rats

Objective To investigate the effect of exogenous thyroid hormone on serum NO and iNOS activity of intestinal mucosa in septic rats. Methods Septic model was established by cecal ligation puncture (CLP) in male SD rats. Triiodothyronine ( T3 ) was administered intraperitoneally to correct the low T3 syndrome of septic rats. Blood was collected to examine serum NO and thyroid hormone concentration. Intestinal mucosa iNOS activity was assayed using immunochemical stain. Results Mortality rate in the prevention group was significantly lower than the septic group (Log rank = 3. 85, P 【 0.05). Serum NO concentration was significantly lower in the prevention group (F=19.6,F【0.01). The degree of inflammatory injury of intestinal mucosa was much milder in the prevention group than in the septic group (x2 = 5.303,P【0. 05). Mucosa iNOS activity was also significantly lower in the prevention group (x2 = 4. 876, P【0. 01). Conclusion Thyroid hormone protects the intestinal mucosa barrier inhibiting the expression of

Study of concentration of vancomycin in serum during continuous intravenous infusion

Objective Pharmacokinetics/pharmacodynamics of vancomycin in serum were studied after continuous infusion. Methods Twelve neurosurgical postoperative patients with ventricular drainage were enrolled in this study. In each patient,a loading dose of vancomycin of 0. 5 g was administered for 1 h followed

Two New Species of Freshwater Shrimps from Hunan Province,China (Decapoda:Atyidae:Caridina)

Two new freshwater atyid shrimps, Caridina angustipes sp nov.and C clavipes sp nov.from Hunan Province,China are described. C angustipes sp nov.is similar to C baojingensis Guo,He et Bai,1992,but with longer rostrum,15-27 dorsal teeth,3-6 ventral teeth,and straighter inner margin of endopods in male 1st pleopods. C clavipes sp nov.is similar to C angustipes ,but with narrower distal and fewer spines on inner margin of endopds in male 1st pleopods,and shorter and thinner appendix masculina in male 2nd pleopods with only 1 spine on inner lateral margin and 4 spines in apex.The holotypes are deposited in Shanghai Fisheries University.Some representative paratypes are deposited in Foshan Science and Technology College.

MicroRNA expression profile and lipid metabolism characteristics in liver of rat undergoing high-fat diet

This study aimed to investigate the microRNA expression profile and the characteristics of lipid metabolism in the livers of rats undergoing a high-fat diet.Fifty male Sprague-Dawley(SD)rats were divided into a standard chow group(C group,N=10)and a high-fat diet group(H group,N=40).After 12 weeks,the rat body weight,body length,fat mass,and serum lipid concentration were measured.The expression profile of microRNAs and the gene and protein expression levels involved in lipid metabolism in rat liver were detected.Body fat and serum lipid concentrations were all significantly higher in the H group than those in the C group(p<0.05 or p<0.01).The expression of 10 microRNAs showed significant differences in the liver(p<0.05).In particular,the let-7 family expression levels significantly increased(p<0.05)in the H group compared with those in the C group.Compared with the C group,the high-fat diet resulted in low FAS,CPT1A,and ApoAI mRNA expression levels(p<0.05 or p<0.01)and high PPARαand FAT/CD36 mRNA expression levels in the H group rat liver(p<0.01).Meanwhile,the protein PPARα,FAS,CPT1A,FAT/CD36,and ApoAI expression levels were all significantly lower in the H group than those in the C group(p<0.05 or p<0.01).In conclusion,the high-fat diet increased the body fat and serum lipid levels and altered the 10 microRNA expression levels in the liver.The high-fat diet may affect hepatic carbohydrate metabolism and increase ectopic fat accumulation through let-7 family overexpression.The high-fat diet for 12 weeks decreased lipid metabolism level in the liver,thereby decreasing fatty acid synthesis,oxidation,and transport by down-regulating the PPARα,FAS,CPT1A,FAT/CD36,and ApoAI protein levels.

Comparisons of drug efficacy and time-effect among magnesium valproate,sustained-release magnesium valproate tablet and depakine chrono for epilepsy An experiment of determining cortical convulsive threshold in rats undergoing electrical stimulation

BACKGROUND： Scholars have investigated the differences in drug metabolism and pharmacodynamics between valproate and its sustained-release tablets only from the angle of pharmaceutical sciences or clinical practice. Whether the fact that differences in drug efficacy and time-effect of different doses of valproate and different types of sustained-release valproate tablets at the same concentration can be quantitatively reflected by determining the changes in convulsive threshold pre- and post-administration in rat models of determining the convulsive threshold developed by direct cortical electrical stimulation remains unclear. OBJECTIVE： This study aimed to compare the drug efficacy and time-effect among magnesium valproate, sustained-release magnesium valproate tablet and depakine chrono in the treatment of epilepsy by determining the convulsive threshold of rat models created by direct cortical electrical stimulation, and human serum drug concentration before and after administration. DESIGN： A controlled observational experiment. SETTING： Research Institute of Epilepsy, Shanxi Medical University. MATERIALS： Adult health male SD rats of clean grade, weighing 200 - 220 g, provided by the Laboratory Animal Center of Shanxi Medical University. The protocol was carried out in accordance with requests from Animal Ethics Committees for guidance. Magnesium valproate （Lot No. 041004） and sustained-release magnesium valproate tablet （Lot No. 050501） were produced in Hunan Xiangzhong Pharmaceutical Co., Ltd. METHODS： This study was carried out in the Laboratory for Epilepsy, Shanxi Medical University between June and August 2005. （1）All the SD rats were created into models for determining cortical convulsive threshold. They were randomly divided into 4 groups with 20 rats in each： magnesium valproate tablet group, sustained-release magnesium valproate tablet group, depakine chrono group and control group. After being modeled, the rats in the first 3 groups were intragastrically administrated with magnesium valproate, sustained-release magnesium valproate tablet and depakine chrono, respectively, while the control group were intragastrically administrated with the same volume of normal saline. （2）Convulsive threshold of each fasting rat was determined 0.5 hour before, and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 and 24 hours after single administration, separately. （3） Convulsive threshold was determined repeatedly 2 weeks after single administration. Each rat was administrated two times daily successively. Convulsive threshold was determined 0.5 hour before, and 0.5, 2.5, 7 and 12 hours after administration, separately. （4）Hepatic and renal tissues were harvested for pathological examination after 1 month of administration. （5）Nine healthy voluntary medical stuffs were recruited in this study. Written informed consents of experiment were obtained each involved subject. The study was given an approval by the Ethics Committee of Shanxi Medical University. According to the scheme, the 9 volunteers were randomly assigned into 3 groups, in which, volunteers were asked to take magnesium valproate 500 g, sustained-release magnesium valproate tablet 500 g and depakine chrono 500 g, respectively, in the morning under the condition of fasting. Serum drug concentration of each drug was determined by fluorescence polarization immunoassay at different time points. MAIN OUTCOME MEASURES： （2） Rat convulsive threshold after single and repeated administrations. （2）Hepatic and renal pathological examination results. （3） Serum drug concentration in vivo. RESULTS：（4）Rat convulsive threshold after single and repeated administrations： Drug efficacy in the magnesium valproate tablet group reached to a peak level 1 to 2 hours after single administration, and was obviously higher than that in the other groups 1 hour after administration （P 〈 0.05）. Drug efficacy in the sustained-release magnesium valproate tablet group and depakine chrono group both reached to a peak level 7 hours after administration, and was significantly higher than that in the control group （P 〈 0.05）. After repeated administrations, the average peak valley deviation of the convulsive threshold in the magnesium valproate tablet group was 120- 150 μ A, which was 2 and 2.5 times as that in the sustained-release magnesium valproate tablet group and depakine chrono group, respectively. After repeated administrations for 10 times, convulsive threshold was increased by 440 μ A in the sustained-release magnesium valproate tablet group, and by 230 μ A in the depakine chrono group in comparison with before administration. （2） Hepatic and renal pathological examination results： No obvious differences in hepatic and renal impairment were found among the 4 groups after I month of administration successively. （3） Serum drug concentration in vivo： Serum-drug concentration of magnesium valproate was increased fast and reached to a peak level 0.5 - 2 hours after administration, remained at a relatively stable level 2 - 4 hours after administration, and then was slowly decreased. The drug efficacy of sustained-release magnesium valproate tablet and depakine chrono was slowly released 1 - 6 hours after administration, reached to a peak level at about 7 hours, and could last for about 16 hours. CONCLUSION： Magnesium valproate has a rapid onset and offset of action. Sustained-release magnesium valproate tablet has a slow onset but long duration of drug efficacy. Depakine chrono can be easier to be absorbed than sustained-release magnesium valproate tablet, but its long-term effect on improving the convulsive threshold is inferior to sustained-release magnesium valproate tablet.

Vitamin d deficiency and metabolic syndrome:The joint effect on cardiovascular and all-cause mortality in the United States adults

BACKGROUND The long-term impact of vitamin D deficiency and metabolic syndrome(MetS)on cardiovascular disease(CVD)and all-cause mortality are still a matter of debate.AIM To test the hypotheses that lower serum 25 hydroxyvitamin D[25(OH)D]concentrations(a marker of vitamin D level)and MetS have a long-term impact on the risk of CVD and all-cause mortality,and individuals with vitamin D deficiency can be identified by multiple factors.METHODS A sample of 9094 adults,20 to 90 years of age,who participated in the Third National Health and Nutrition Examination Survey(NHANES III,1988 to 1994)were followed through December 2015 was analyzed.The associations of serum 25(OH)D concentrations and MetS with CVD and all-cause mortality were analyzed longitudinally using Cox regression models.Classification and regression tree(CART)for machine learning was applied to classify individuals with vitamin D deficiency.RESULTS Of 9094 participants,30%had serum 25(OH)D concentrations<20 ng/mL(defined as vitamin D deficiency),39%had serum 25(OH)D concentrations between 20 to 29 ng/mL(insufficiency),and 31%had serum 25(OH)D concentrations≥30 ng/mL(sufficiency).Prevalence of MetS was 28.4%.During a mean of 18 years follow-up,vitamin D deficiency and MetS were significantly associated with increased risk of CVD and all-cause mortality.Subjects with both vitamin D deficiency and MetS had the highest risk of CVD mortality(HR=1.77,95%CI:1.22-2.58)and all-cause mortality(HR=1.62,95%CI:1.26-2.09),followed by those with both vitamin D insufficiency and MetS for CVD mortality(HR=1.59,95%CI:1.12-2.24),and all-cause mortality(HR=1.41,95%CI:1.08-1.85).Meanwhile,vitamin D sufficiency significantly decreased the risk of CVD and all-cause mortality for those who even had MetS.Among the total study sample,CART analysis suggests that being non-Hispanic Black,having lower serum folate level,and being female were the first three predictors for those with serum 25(OH)D deficiency.CONCLUSION Vitamin D deficiency and MetS were significantly associated with increased risk of CVD and allcause mortality.There was a significant joint effect of vitamin D deficiency and MetS on the risk of mortality.Findings of the CART analysis may be useful to identify individuals positioned to benefit from interventions to reduce the risk of CVD and all-cause mortality.

Effect of Socio-Demographic Factors on Zinc Status of Infants and Preschool Children in East Gojjam, Amhara Region of Ethiopia

Zinc deficiency is a public health concern and is the most prevalent micronutrient deficiencies in developing countries. The main objective of this study was to assess the prevalence and risk factors of zinc deficiency among infants and preschool children. Based on a community, the cross-sectional study was conducted in East Gojjam between October 2011 and April 2012. Two hundred and forty infants and preschool children were randomly selected in the study. Data on potential determinants of zinc deficiency were collected using a structured questionnaire. Serum zinc concentration was measured using atomic absorption spectrometer. Statistical analysis was done using ANOVA, independent sample student＇s t-test and linear regression model. The mean serum zinc concentration of infants and preschool children was 62.98 （±13.03） μg/dL in 95% confidence interval （CI） between 61.32 and 64.63 （i.e., 95% CI： 61.32, 64.63）. About 57,1% of the subjects were zinc deficient. The main determinants of low serum zinc status of infants and preschool children were age and number of family members living on the same land. Zinc status of older children was 3.67 μg/dL （95% CI： -5.58, -1.77） lower than children who were aged 6-10 months. Serum zinc status of infants and preschool children is decreased by 0.83 p.g/dL （95% CI： -1.36, -0.30） with each additional family member. Food insecurity, dietary diversity, sex, child health, anthropometric indices, maternal education and wealth index were not associated with serum zinc status. Zinc deficiency among infants and preschool children is highly prevalent. Such potential deficiencies require urgent attention, including complementary food preparation education, traditional phytate reduction method and family planning implementation recommended in the study area.

APPLICATION OF NONIONIC TEMPERATURE SENSITIVE HYDROGEL FOR CONCENTRATION OF PROTEIN AQUEOUS SOLUTION

Six different N-alkyl substituted acrylarnide nonionic hydrogels were prepared and their swelling characteristics were measured. Poly N-isopropyl acrylamide (PNIPA) and poly N-n-propyl-acrylamide (PNNPA) temperature sensitive hydrogels were chosen as the nonionic temperature sensitive hydrogels for concentration of very dilute aqueous protein solution. The separation properties of PNIPA and PNNPA hydr0gels with different network dimensions were studied and the modification of the hydrogels was surveyed in order to decrease their surface adsorption of protein molecules. The experimental results of the concentration of BSA (Bovin serum albumin) dilute aqueous solution by hydroxylpropyl methacrylate (HPMA) copolymerized PNIPA hydrogel were given. The value and the limitation of concentration of dilute aqueous protein solution by this method was evaluated.

Association between serum bilirubin concentration and Parkinson’s disease: a meta-analysis

Background: The antioxidant effects of bilirubin in Parkinson’s disease (PD) have recently gained much attention from the research community. However, results from these studies have been conflicting. This meta-analysis is conducted to assess the relationship between the serum bilirubin concentration and the risk of PD.Methods: Two reviewers performed a systematic literature search across five databases (MEDLINE, PubMed, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials). The case-control studies regarding bilirubin levels in PD patients published up to April 2020 were included. These studies were subjected to rigorous scrutiny and data extraction to determine the standard mean difference (SMD) and the 95% confidence interval (CI), which were analyzed using the Stata V.12.0 statistical software.Results: A total of eight studies which included 1463 PD cases and 1490 controls were incorporated into our meta-analysis. SMD analysis showed that there was a higher total bilirubin (TBIL) and direct bilirubin (DBIL) levels in PD patients compared with controls (for TBIL, SMD: 0.300, 95% CI: 0.050-0.549,P = 0.018;for DBIL, SMD: 0.395, 95% CI: 0.102-0.688,P = 0.008). However, no significant relationship was found between the serum indirect bilirubin and PD patients (SMD: -0.223, 95% CI: -0.952-0.505,P = 0.548). A subgroup analysis based on ethnicity indicated that the serum TBIL was higher in PD patients of Caucasian descent in contrast to matched healthy controls (SMD: 0.511, 95% CI: 0.324-0.698,P = 0.000,I2 = 58.0%).Conclusion: Higher serum bilirubin levels in PD patients suggest that bilirubin might play a role in the pathogenesis of PD and have the potential to be utilized as a biochemical marker for PD diagnosis and treatment.

The relationship between concentration of growth hormone in serum and microangiopathy in patients with diabetes mellitus.

Objective To study the relationship between growth hormone (GH) and microangiopathy in patients with diabetes mellitus in order to elucidate pathogenesis on microangiopathy in diabetics. Methods GH and insulin (INS) were detected by radioimmunoassay, and blood sugar (BS) was detected by oxydase method. Results 138 NIDDM diabetics were examined. The concentration of serum GH in diabetics without microangiopathy (2.3±1.2 μg/L) was higher than in normal people (1.0±1.2 μg/L) and GH in diabetics with microangiopathy (5.74±1.94 μg/L) was higher than in diabetics without microangiopathy. The differences were significant ( P <0.01). As the history of diabetes went on, the level of GH in serum increased, and the incidence of microangiopathy increased too. The correlation of GH in serum with BS was parallel. The correlation of GH in serum with INS was not apparent. 27 IDDM diabetics were examined, their level of GH in serum (6.8±3.4 μg/L) was higher than that of NIDDM diabetics (4.6±1.8 μg/L). They were all patients with microangiopathy. Conclusion The rise of GH in serum may be an important pathogeny that causes microangiopathy in diabetics.