Healthy Referents Research Articles

CLSI Guided Reference Interval Limits for Cancer Biomarkers for Adults and Geriatrics

Reference interval limits for cancer biomarkers in geriatrics are rare because priority is given to the development of reference interval limits for those in the age range of 18–60 years, which are normally used for clinical trials study. The aim of this study was therefore to develop gender and age-specific reference interval limits for cancer markers CA19-9, CEA, CA 15-3, CA 125, and PSA for adults and geriatrics in Taita-Taveta County, Kenya, using the CLSI CA28-A3 guideline. This prospective cross-sectional study involved 244 healthy referents, including 124 females and 120 males of ages 50–95, between May 2015 and December 2017 at the Department of Clinical Chemistry of Moi Subcounty Hospital, Voi, Kenya. Serum CA 19-9, CEA, CA 15-3, CA 125, and PSA of the 244 referents were measured using a well-calibrated, quality controlled Clinical Chemistry AutoAnalyzer. Gender differences in the measured values of the biomarkers were assessed using the Mann-Whitney U test, while age differences were assessed using the Kruskal-Wallis H test followed by the Mann-Whitney U test with an adjusted significant ρ-value of less than 0.0167. Reference interval limits for the measured cancer biomarkers were expressed in terms of medians and ranged between 2.5 and 97.5 percentiles. The established 95% reference interval limits were: 0-58 U/mL males and 0-42.8 U/mL females for CA 19–9, 0–7 ng/mL for CEA, 0-56.9 U/mL for CA 15–3, 0–25 ng/mL for CA 125, and 0–6.8 ng/mL for PSA. Gender-related biomarker values were developed for CA 19-9 adults and geriatrics (60–70 years), CEA for geriatrics (60–70 years), and CA 15-3 for adults. Age-related biomarker values were developed for CA 19–9 males and not for females. In conclusion, gender-related 95% reference interval limits were developed for CA 19-9, CEA, CA 15-3, CA 125, and PSA, and age-related 95% reference interval limits were established for CA 19-9. CA 19-9 decreased from adulthood to the early elderly and increased in the more elderly population. These developed reference interval limits for these biomarkers, which differed from those reported in previous literature, could be adopted for use in Taita-Taveta County, Kenya, for better medical care. Doi: 10.28991/SciMedJ-2022-04-02-04 Full Text: PDF

Impaired CD8+ T Cell Proliferation to Alloantigens in Lung Transplant Recipients with Idiopathic Pulmonary Fibrosis is Associated with P53 Upregulation

<h3>Purpose</h3> Telomere dysfunction may persist in the immune system following lung transplantation for idiopathic pulmonary fibrosis (IPF) and impact responses to infections or donor antigens. Mechanistically, critically short telomeres can activate p53 and block cell proliferation. We hypothesized that p53 activation might be associated with the impaired proliferation to alloantigens for IPF lung transplant recipients. <h3>Methods</h3> We analyzed 5 IPF lung transplant recipients with telomere dysfunction and 6 age-matched non-IPF controls, 18 months after transplantation, and 4 healthy donors. We quantified CD8+ T cell proliferation to pooled, donor-derived, stimulated B cells (sBc) with or without treatment with KML001, a reagent that binds and erodes telomeres. Expression of p53 and proportions of Annexin V+ apoptotic cells were quantified by flow cytometry. Statistical comparisons were performed using 2-way ANOVA with Dunnett's post-test. <h3>Results</h3> IPF lung transplant recipients (Fig. A) demonstrated impaired CD8+ T cell proliferation relative to non-IPF patients (Fig. B) and healthy controls (Fig. C&D, P≤0.0002). This proliferation was further impaired by telomere erosion (Fig. C&E, P<0.0001). P53 expression was increased in cells responding to sBc stimulation (MFI change 183, 95% CI 159-207). Among T cells that did not proliferate to allo-stimulation (Fig. F), p53 expression was higher in IPF subjects versus non-IPF (P=0.049) or healthy referents (P=0.002). Apoptotic cells were not different between groups. <h3>Conclusion</h3> P53 upregulation is associated with impaired CD8+ T cell proliferation to alloantigens in lung transplant recipients with IPF and may mediate proliferative arrest in CD8+T cells for IPF lung transplant recipients. These findings may explain sensitivity of some recipients to p53 activators, such as mycophenolic acid, that may synergize with telomere dysfunction to drive cell cycle arrest and leukopenia.

MO208ASSOCIATION OF SERUM BETA-2 MICROGLOBULIN LEVEL WITH DIFFERENT CARDIAC AND METABOLIC RISK FACTORS IN CKD PATIENTS

Abstract Background and Aims Serum β M is a middle molecule uremic toxin that accumulates in serum and deposits at various tissues in chronic kidney disease (CKD), especially more in dialysis patients. The βâ M is generally considered as a predictor of cardiovascular morbidity and mortality and this is more investigated in dialysis group. However its relationship with several cardiac and metabolic risk factors in all stages of CKD is still under evaluation. This study was undertaken to evaluate the association of plasma βâ M level in different stages of chronic kidney disease patients with different cardiac, renal and metabolic risk factors that can predict future cardiovascular events Method This cross-sectional study was conducted by selecting consecutive 132 CKD subjects of stages 1-5D including both patients not requiring dialysis and those on maintenance hemodialysis. Their demographic, clinical and laboratory data were recorded in a data sheet. Fasting blood samples in dialysis non requiring subjects and predialysis samples in hemodialysis group (G5D) were taken for testin in laboratory for CBC, serum βâ M, hCRP, iPTH, lipid profile, creatinine, uric acid and serum albumin as cardiac, renal and metabolic risk markers. Urine sample was taken from predialysis patients for chemical test and ACR. The CKD staging were done by MDRD criteria. Additional 25 no CKD subject was taken as healthy referents. Results Primarily Beta-2 microglobulin was higher in CKD patients than in healthy group (13.53 ± 14.74 vs. 1.81 ± 0.47, mg/l; p&amp;lt;.001). The levels were gradually rising with the advancing stages of CKD (G1&amp;2-3.46 ± 2.39, G3-3.66 ± 1.08, G4-6.51 ± 2.20, G5-11.43 ± 2.98 and G5D-41.79 ± 8.58, mg/l). A Beta-2 microglobulin cut-off of &amp;gt;7.7 vs. &amp;lt; 7.7 mg/l showed significantly increased Systolic BP (136 ±22 vs. 123 ± 22, mmHg), diastolic BP (80 ± 12 vs. 75 ± 8.96, mmHg),( p&amp;lt;0.01); CRP (6.83 ± 6.03 vs. 4.39 ± 5.35, mg/l)( p&amp;lt;0.007); serum phosphate (4.84 ± 1.79 vs. 3.85 ±.92,mg/dl)( p&amp;lt;0.001); uric acid (5.89 ± 1.41 vs. 5.01 ± 1.57,mg/dl)( p&amp;lt;0.01); TG (189± 103 vs. 155 ± 88, mg/dl),( p&amp;lt;0.04); and PTH (239.83 ± 186.50 vs. 90.52 ± 81.77, pg/ml), ( p&amp;lt;0.001) indicating higher cardio metabolic risks in higher group. Similarly renal parameters were also more altered in high Beta-2 microalbumin group for serum creatinine (6.89 ± 3.54 vs. 1.58 ± .81, mg/dl) (p&amp;lt;0.001) and ACR (824 ± 917 vs. 320 ± 753, mg/g),( p&amp;lt;0.001). B-2 microglobulin also positively correlated with systolic blood pressure (r=.295, p&amp;lt;.001), serum creatinine (r=.879, p&amp;lt;.001), serum phosphate (r=.175, p =.047), serum iPTH (r=.403, p&amp;lt;.001) , hCRP ( r=.193, p =.050) , Triglycerides (r=.196, p =.023) and urine ACR in CKD patients. Conclusion Beta-2 microglobulin level was significantly higher in CKD with an increasing pattern towards advancing stages. The higher levels positively correlated with cardio renal and metabolic risk factors. Hence measuring Beta-2 microglobulin regularly can help to take preventive measures early to manage patients at risk.

MO101ASSESSING EARLY RENAL INVOLVEMENT IN ESSENTIAL HYPERTENSION BY MEASURING URINARY ALBUMIN AND UROMODULIN EXCRETION

Abstract Background and Aims Kidneys are target organs in hypertension. Hypertensive damage results in glomerular as well as tubular dysfunction. Albuminuria is a known marker of glomerular damage. Whereas, urinary uromodulin is increasingly considered as potential biomarker of early tubular dysfunction. The aim of this study was to identify the pattern of early renal involvement based on glomerular and tubular function assessment by measuring urinary albumin and uromodulin in hypertensive patients Method In this cross-sectional study 122 hypertensive subjects with age&amp;gt;30 years, duration of hypertension &amp;lt;5years, without accelerated or malignant BP, absence of dipstick proteinuria and eGFR&amp;gt;60ml/min. Subjects with possibility of secondary hypertension were excluded. There were also 33 normotensive volunteers included as healthy referents. Morning spot urine for albumin-creatinine ratio (ACR mg/g), urine uromodulin-creatinine ratio (urUMODµg/g), urinary sodium-creatinine ratio (mEq/g) and potassium-creatinine ratio (mEq/g) were measured in single urine sample. Urine uromodulin was measured by ELISA method. Results The hypertensive and healthy subjects were matched for age 48±11 vs. 47±11, years (P=NS). The systolic BP was 145±15 vs. 112±12 mmHg and diastolic BP 86±9 vs. 70±8 mmHg; (p&amp;lt;0.001) and the mean ACR was 29±65 vs. 5.6±2.7 mg/g, (p&amp;lt;0.001) respectively. Around 20% hypertensives had albuminuria. Urinary potassium excretion was lower in hypertensives (51±31 vs. 69±31, mEq/g; p&amp;lt;0.02). The median urUMOD in hypertensive subjects was 3.38 (1.73-9.06) and in normotensives 3.85(2.28-5.69) µg/g (P=NS).Multivariate analysis showed significant inverse association between diastolic blood pressure and urinary uromodulin excretion. An urURMOD cut-off of 2.9 (25th percentile in normotensives) showed eGFR, urinary sodium &amp; potassium excretions were significantly lower at low uromodulin cut-off and this was seen in38%subjects. Conclusion The glomerular involvement was found in 20% hypertensives as evidenced by albuminuria. In general urinary uromodulin level was not different between hypertensive and normotensive subjects. Association of low uromodulin cut-off with lower eGFR, Na+ and K+ excretion indicates simultaneous tubule glomerular involvement in 38%.

Health-Related Quality of Life in Children, Adolescents, and Adults With a Fontan Circulation: A Meta-Analysis.

BackgroundPeople with a Fontan circulation experience a range of physical, psychosocial and neurodevelopmental challenges alongside, or caused by, their cardiac condition, with significant consequences for health‐related quality of life (HRQOL). We meta‐analyzed HRQOL outcomes reported by people with a Fontan circulation or their proxies and evaluated predictors of poorer HRQOL.Methods and ResultsSix electronic databases were searched for peer‐reviewed, English‐language articles published before March 2019. Standardized mean differences (SMD) were calculated using fixed and random‐effects models. Fifty articles reporting on 29 unique studies capturing HRQOL outcomes for 2793 people with a Fontan circulation and 1437 parent‐proxies were analyzed. HRQOL was lower in individuals with a Fontan circulation compared with healthy referents or normative samples (SMD, −0.92; 95% CI, −1.36 to −0.48; P<0.001). Lower scores were reported across all HRQOL domains, with the largest differences found for physical (SMD, −0.90; 95% CI, −1.13 to −0.67; P<0.001) and school/work functioning (SMD, −0.71; 95% CI, −0.90 to −0.52; P<0.001). Meta‐regression analyses found no significant predictors of self‐reported physical functioning, but older age at Fontan operation was associated with poorer emotional functioning (β=−0.124; P=0.004), and diagnosis of hypoplastic left heart was associated with poorer social functioning (β=−0.007; P=0.048). Sensitivity analyses showed use of the PedsQL Core Module was associated with lower HRQOL scores compared with the Short‐Form Health Survey‐36.Conclusions HRQOL outcomes for people with a Fontan circulation are lower than the general population. Optimal care acknowledges the lifelong impact of the Fontan circulation on HRQOL and offers targeted strategies to improve outcomes for this growing population.

Subarachnoid Hemorrhage is Followed by Pituitary Gland Volume Loss: A Volumetric MRI Observational Study

BackgroundSubarachnoid hemorrhage (SAH) is a devastating disease associated with high mortality and morbidity. Besides neurological sequelae, neuropsychological deficits largely contribute to patients’ long-term quality of life. Little is known about the pituitary gland volume (PGV) after SAH compared to healthy referents and the association of PGV with long-term outcome including cognitive function.MethodsSixty consecutive non-traumatic SAH patients admitted to the neurological intensive care unit between 2010 and 2014 were enrolled. 3-Tesla magnetic resonance imagining was performed at baseline (16 days) and 12 months after SAH to measure PGV semi-automatically using the software iPlan Net 3.5.0. PGV was compared to age and sex matched healthy referents. The difference between baseline and 1-year-PGV was classified as increase (> 20 mm3 PGV increase), stable (± 20 mm3), or decrease (> 20 mm3 PGV decrease). In addition, total intracerebral volume was calculated. Neuropsychological testing was applied in 43 SAH patients at 1-year follow up encompassing several domains (executive, attention, memory) and self-assessment (questionnaire for self-perceived deficits in attention [German: FEDA]) of distractibility in mental processes, fatigue and decrease in motivation. Multivariable regression with multivariable generalized linear models was used for comparison of PGVs and for subgroup analysis to evaluate a potential association between PGV and neuropsychological outcome.ResultsPatients were 53 years old (IQR = 44–63) and presented with a median Hunt&Hess grade of 2 (IQR = 1–3). SAH patients had a significantly lower PGV both at baseline (360 ± 19 mm3, p < 0.001) and 1 year (367 ± 18 mm3p < 0.001) as compared to matched referents (mean 505 ± 18 mm3). PGV decreased by 75 ± 8 mm3 in 28 patients, increased by 120 ± 22 mm3 in 22 patients and remained stable in 10 patients at 1-year follow-up. PGV in patients with PGV increase at 12 months was not different to healthy referents (p = 0.062). Low baseline PGV was associated with impaired executive functions at 1 year (adjOR = 8.81, 95%-CI = 1.46–53.10, p = 0.018) and PGV decrease within 1 year was associated with self-perceived worse motivation (FEDA; Wald-statistic = 6.6, df = 1, p = 0.010).ConclusionsOur data indicate significantly lower PGVs following SAH. The association of sustained PGV decrease with impaired neuropsychological long-term outcome warrants further investigations including neuroendocrine hormone measurements.

Comparative Analysis of Essential and Toxic Elements in Water and Blood Samples of Kidney Patients in Quetta, Pakistan

The current study based on the comparative analysis of essential elements such as sodium (Na), potassium (K), Calcium (Ca) and Magnesium (Mg) and toxic elements such as Al (Al) and lead (Pb), in drinking water, and biological sample of kidney disorder patients in Quetta capital city of Balochistan, Pakistan. In this study our main purpose was to compare the level of heavy metals (Pd & Al) and essential metals (Ca, Na, K & Mg) in blood samples of kidney disorder patients and in water samples of their respective areas. Level of these essential and toxic elements in blood samples as well as in water determined by atomic absorption spectrometer (AAS). It was evaluate that Ca and Mg in water might be related with patients of kidney disorders in Quetta Balochistan, Pakistan. The Ca and Mg contents in two types of drinking water, Ground Water (GW) and Munciple treated water (MTW) were found in the range of (510.7) mg/L and (319) mg/L respectively. In blood samples of kidney disorder patient’s concentration of essential elements were found in the range of Ca (118-140), Mg (20.1-43.2), Na (3156-4094) and K (211-299) mg/L while, the levels of Al and Pb were found in the range of (586-1380) and (278-645) μg/L, respectively. In the healthy referents concentration of electrolytes are lower than Kidney disorder patient (KDP), while the levels of toxic metals in blood samples of referents were three to six fold lower than kidney disorder patients. As water samples of Quetta area were not polluted with toxic elements (Pb and Al), but these elements were present in biological samples of KDPs due to the environmental exposure of Pb and Al to these individual. Eventually it is clear from present research work that only Ca is that element which is present in large amount in water samples of Quetta Area and contributed as one of the important factor for raising the Ca level in biological samples of KDPs and KDPs showing abnormal level of Ca element in their biological samples is due to the usage of unsafe water containing this element in excess amount.

Learning and Memory in Adolescents With Critical Biventricular Congenital Heart Disease.

Although evidence exists of broadly defined memory impairment among adolescents with critical congenital heart disease (CHD), nuanced investigations of declarative memory in this at-risk population have not been conducted. This study had two primary aims: (1) to conduct a fine-grained analysis of a range of relevant learning and memory processes in adolescents with critical biventricular CHD, and (2) to identify risk, odds, and predictors of memory impairment. Data were combined from two single-center studies of neurodevelopmental outcomes in critical CHD. Two-hundred seven adolescents (M age =15.61±1.0 years) with critical CHD (139 with dextro-transposition of the great arteries and 68 with tetralogy of Fallot without an identified genetic condition), as well as 61 healthy referents (M age =15.27±1.1 years) completed a neuropsychological evaluation which included the Children's Memory Scale. Whereas visual-spatial memory deficits were found in both CHD subgroups, verbal memory abilities were relatively preserved. Adolescents with CHD demonstrated stronger memory for Stories than Word Pairs, t (203)=2.63, p=.009, and for Dot Locations than Faces, t(204)=-2.57, p=.01. CHD subgroup, socioeconomic status, sex, and seizure history were among the most frequent significant predictors of memory impairment. Seizure history, in particular, was associated with a 2 to 3 times greater odds of impaired performance on learning and memory tasks. Adolescents with critical biventricular CHD are at risk for deficits in aspects of declarative memory. Independent risk factors for worse outcome include history of seizures. (JINS, 2017, 23, 627-639).

Forecasting Chronic Diseases Using Data Fusion.

Data fusion, that is, extracting information through the fusion of complementary data sets, is a topic of great interest in metabolomics because analytical platforms such as liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy commonly used for chemical profiling of biofluids provide complementary information. In this study, with a goal of forecasting acute coronary syndrome (ACS), breast cancer, and colon cancer, we jointly analyzed LC-MS, NMR measurements of plasma samples, and the metadata corresponding to the lifestyle of participants. We used supervised data fusion based on multiple kernel learning and exploited the linearity of the models to identify significant metabolites/features for the separation of healthy referents and the cases developing a disease. We demonstrated that (i) fusing LC-MS, NMR, and metadata provided better separation of ACS cases and referents compared with individual data sets, (ii) NMR data performed the best in terms of forecasting breast cancer, while fusion degraded the performance, and (iii) neither the individual data sets nor their fusion performed well for colon cancer. Furthermore, we showed the strengths and limitations of the fusion models by discussing their performance in terms of capturing known biomarkers for smoking and coffee. While fusion may improve performance in terms of separating certain conditions by jointly analyzing metabolomics and metadata sets, it is not necessarily always the best approach as in the case of breast cancer.

Psychiatric Disorders and Function in Adolescents with Tetralogy of Fallot

To assess psychiatric disorders and function in adolescents with repaired tetralogy of Fallot (TOF) without and with a genetic diagnosis and to evaluate associations of functioning with medical factors, IQ, and demographics. Adolescents with TOF (n = 91) and 87 healthy referents completed a clinician-rated structured psychiatric interview, parent-/self-report measures of psychopathology, and brain magnetic resonance imaging. Twenty-three of the adolescents with TOF had a known genetic diagnosis. The prevalence of anxiety disorders did not differ significantly between adolescents with TOF without genetic diagnosis (n = 68) and referents. Adolescents with TOF and a genetic diagnosis showed an increased lifetime prevalence of anxiety disorder (43%) and lower global psychosocial functioning (median, 70; IQR, 63-75) compared with adolescents with TOF without genetic diagnosis (15% and 83; IQR, 79-87, respectively; P = .04 and <.001, respectively) and referents (6% and 85; IQR, 76-90, respectively; P = .001 and <.001, respectively). Adolescents with TOF without and with a genetic diagnosis had a higher lifetime prevalence of attention deficit-hyperactivity disorder (ADHD) than referents (19% and 39%, respectively, vs 5%; P = .04 and .002, respectively) and worse outcomes on parent-/self-report ratings of anxiety and disruptive behavior compared with referents. Risk factors for anxiety, ADHD, and lower psychosocial functioning for adolescents with TOF without a genetic diagnosis included older age, male sex, and low IQ. Medical variables were not predictive of psychiatric outcomes. Adolescents with TOF, particularly those with a genetic diagnosis, show increased rates of psychiatric disorder and dysfunction. Continued mental health screening and surveillance into young adulthood is warranted for adolescents with TOF.

Psychiatric Disorders in Adolescents With Single Ventricle Congenital Heart Disease.

Mental health outcomes for survivors of critical congenital heart disease (CHD) remain under-investigated. We sought to examine psychiatric disorders and psychosocial functioning in adolescents with single ventricle CHD and to explore whether patient-related risk factors predict dysfunction. This cohort study recruited 156 adolescents with single ventricle CHD who underwent the Fontan procedure and 111 healthy referents. Participants underwent comprehensive psychiatric evaluation including a clinician-rated psychiatric interview and parent- and self-report ratings of anxiety, disruptive behavior, including attention-deficit/hyperactivity disorder (ADHD), and depressive symptoms. Risk factors for dysfunction included IQ, medical characteristics, and concurrent brain abnormalities. Adolescents with single ventricle CHD had higher rates of lifetime psychiatric diagnosis compared with referents (CHD: 65%, referent: 22%; P < .001). Specifically, they had higher rates of lifetime anxiety disorder and ADHD (P < .001 each). The CHD group scored lower on the primary psychosocial functioning measure, the Children's Global Assessment Scale, than referents (CHD median [interquartile range]: 62 [54-66], referent: 85 [73-90]; P < .001). The CHD group scored worse on measures of anxiety, disruptive behavior, and depressive symptoms. Genetic comorbidity did not impact most psychiatric outcomes. Risk factors for anxiety disorder, ADHD, and lower psychosocial functioning included lower birth weight, longer duration of deep hypothermic circulatory arrest, lower intellectual functioning, and male gender. Adolescents with single ventricle CHD display a high risk of psychiatric morbidity, particularly anxiety disorders and ADHD. Early identification of psychiatric symptoms is critical to the management of patients with CHD.

Health-related quality of life in patients with Barrett's esophagus.

BackgroundGastroesophageal reflux disease (GERD) has become a major health problem globally, affecting patients’ health-related quality of life (HRQOL). Barrett’s esophagus (BE) is a precancerous lesion associated with GERD. BE patients might not only suffer from HRQOL losses by GERD but also face psychological distress due to the increased risk of developing cancer. However, the majority of patients in Asia have shorter BE segment which is different from the West. This study aimed to determine whether the HRQOL in BE patients were worse than in healthy referents in Taiwan.MethodsPatients who received referral esophagogastroduodenoscopy for various symptoms were evaluated for the existence of BE. Lesions were judged as endoscopically suspected esophageal metaplasia (ESEM) if they showed morphological resemblances to BE by endoscopy. The diagnosis of BE was confirmed by histology with intestinal metaplasia or gastric metaplasia based on the Montreal definition. The World Health Organization Quality of Life (WHOQOL-BREF) was administered to BE patients before treatment. For each BE patient, we selected 2 age-, sex-, educational background and municipality-matched healthy referents, sampled by simple randomization method from a national survey in Taiwan. Multiple linear regression models were constructed to control the potential confounders.ResultsA total of 84 patients diagnosed with BE were enrolled as BE group and then compared with 168 healthy referents. The BE group had significantly lower WHOQOL-BREF scores than those of healthy referents in the physical domain (P < 0.05) but higher scores in the environment domain (P < 0.05). In the physical domain, the BE group had significantly lower scores in various facets, including pain, discomfort, sleep and rest and dependence on medications or treatments. There was no significant difference in social and psychological domains between the BE group and healthy referents.ConclusionsBE patients suffer from poor sleep and rest and high dependence on medications, which significantly reduce their quality of life. Individual facets of each domain warrants a better clinical healthcare to improve quality of life of BE patients.

Peripheral Brain-Derived Neurotrophic Factor Levels in Alzheimer's Disease and Mild Cognitive Impairment: a Comprehensive Systematic Review and Meta-analysis.

Alzheimer's disease (AD) is becoming a growing global problem, and there is an urgent need to identify reliable blood biomarkers of the risk and progression of this condition. A potential candidate is the brain-derived neurotrophic factor (BDNF), which modulates major trophic effects in the brain. However, findings are apparently inconsistent regarding peripheral blood BDNF levels in AD patients vs. healthy people. We thus performed a systematic review and meta-analysis of the studies that have examined peripheral BDNF levels in patients with AD or mild cognitive impairment (MCI) and healthy controls. We searched articles through PubMed, EMBASE, and hand searching. Over a total pool of 2061 potential articles, 26 met all inclusion criteria (including a total of 1584 AD patients, 556 MCI patients, and 1294 controls). A meta-analysis of BDNF levels between early AD and controls showed statistically significantly higher levels (SMD [95% CI]: 0.72 [0.31, 1.13]) with no heterogeneity. AD patients with a low (<20) mini-mental state examination (MMSE) score had lower peripheral BDNF levels compared with controls (SMD [95% CI]: -0.33 [-0.60, -0.05]). However, we found no statistically significant difference in blood (serum/plasma) BDNF levels between all AD patients and controls (standard mean difference, SMD [95% CI]: -0.16 [-0.4, 0.07]), and there was heterogeneity among studies (P<0.0001, I 2=85.8%). There were no differences in blood BDNF levels among AD or MCI patients vs. controls by subgroup analyses according to age, sex, and drug use. In conclusion, this meta-analysis shows that peripheral blood BDNF levels seem to be increased in early AD and decreased in AD patients with low MMSE scores respectively compared with their age- and sex-matched healthy referents. At present, however, this could not be concluded from individual studies.

Is mercury in Tibetan Medicine toxic? Clinical, neurocognitive and biochemical results of an initial cross-sectional study.

Mercury an important therapeutic substance in Tibetan Medicine undergoes complex "detoxification" prior to inclusion in multi-ingredient formulas. In an initial cross-sectional study, patients taking Tibetan Medicine for various conditions were evaluated for mercury toxicity. Two groups were identified: Group 1, patients taking " Tsothel" the most important detoxified mercury preparation and Group 2, patients taking other mercury preparations or mercury free Tibetan Medicine. Atomic fluorescence spectrometry of Tibetan Medicine showed mercury consumption 130 µg/kg/day (Group 1) and 30 µg/kg/day (Group 2) ( P ≤ 0.001), levels above EPA (RfDs) suggested threshold (0.3 µg/kg /day) for oral chronic exposure. Mean duration of Tibetan Medicine treatment was 9 ± 17 months (range 3-116) (Group 1) and 5 ± 1.96 months (range 1-114) (Group 2) (NS) with cumulative days of mercury containing Tibetan Medicine, 764 days ± 1214 (range 135-7330) vs. 103 days ± 111 (range 0-426), respectively ( P ≤ 0.001). Comparison of treatment groups with healthy referents (Group 3) not taking Tibetan Medicine showed no significant differences in prevalence of 23 non-specific symptoms of mercury toxicity, abnormal neurological, cardiovascular and dental findings and no correlation with mercury exposure variables; consumption, cumulative treatment days, blood/ urine Hg. Liver and renal function tests in treatment groups were not significantly increased compared to referents, with mean urine Beta2 Microglobulin within the normal range and not significantly associated with Hg exposure variables after correcting for confounding variables. Neurocognitive testing showed no significant intergroup differences for Wechsler Memory Scale, Grooved Pegboard, Visual Retention, but Group1 scores were better for Mini-Mental, Brief Word Learning, Verbal Fluency after correcting for confounding variables. These results suggest mercury containing Tibetan Medicine does not have appreciable adverse effects and may exert a possible beneficial effect on neurocognitive function. Since evidence of mercury as a toxic heavy metal, however, is well known, further analysis of literature on mercury use in other Asian traditional systems is highly suggested prior to further studies.

Organizational topology of brain and its relationship to ADHD in adolescents with d‐transposition of the great arteries

ObjectiveLittle is currently known about the impact of congenital heart disease (CHD) on the organization of large‐scale brain networks in relation to neurobehavioral outcome. We investigated whether CHD might impact ADHD symptoms via changes in brain structural network topology in a cohort of adolescents with d‐transposition of the great arteries (d‐TGA) repaired with the arterial switch operation in early infancy and referent subjects. We also explored whether these effects might be modified by apolipoprotein E (APOE) genotype, as the APOE ε2 allele has been associated with worse neurodevelopmental outcomes after repair of d‐TGA in infancy.MethodsWe applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 47 d‐TGA adolescents and 29 healthy referents to construct measures of structural topology at the global and regional levels. We developed statistical mediation models revealing the respective contributions of d‐TGA, APOE genotype, and structural network topology on ADHD outcome as measured by the Connors ADHD/DSM‐IV Scales (CADS).ResultsChanges in overall network connectivity, integration, and segregation mediated worse ADHD outcomes in d‐TGA patients compared to healthy referents; these changes were predominantly in the left and right intrahemispheric regional subnetworks. Exploratory analysis revealed that network topology also mediated detrimental effects of the APOE ε4 allele but improved neurobehavioral outcomes for the APOE ε2 allele.ConclusionOur results suggest that disruption of organization of large‐scale networks may contribute to neurobehavioral dysfunction in adolescents with CHD and that this effect may interact with APOE genotype.

Evolution of Mitral Valve Prolapse: Insights From the Framingham Heart Study.

Longitudinal studies of mitral valve prolapse (MVP) progression among unselected individuals in the community, including those with nondiagnostic MVP morphologies (NDMs), are lacking. We measured longitudinal changes in annular diameter, leaflet displacement, thickness, anterior/posterior leaflet projections onto the annulus, coaptation height, and mitral regurgitation jet height in 261 Framingham Offspring participants at examination 5 who had available follow-up imaging 3 to 16 years later. Study participants included MVP (n=63); NDMs, minimal systolic displacement (n=50) and the abnormal anterior coaptation phenotype (n=10, with coaptation height >40% of the annulus similar to posterior MVP); plus 138 healthy referents without MVP or NDMs. At follow-up, individuals with MVP (52% women, 57±11 years) had greater increases of leaflet displacement, thickness, and jet height than referents (all P<0.05). Eleven participants with MVP (17%) had moderate or more severe mitral regurgitation (jet height ≥5 mm) and 5 others (8%) underwent mitral valve repair. Of the individuals with NDM, 8 (80%) participants with abnormal anterior coaptation progressed to posterior MVP; 17 (34%) subjects with minimal systolic displacement were reclassified as either posterior MVP (12) or abnormal anterior coaptation (5). In comparison with the 33 participants with minimal systolic displacement who did not progress, the 17 who progressed had greater leaflet displacement, thickness, coaptation height, and mitral regurgitation jet height (all P<0.05). NDM may evolve into MVP, highlighting the clinical significance of mild MVP expression. MVP progresses to significant mitral regurgitation over a period of 3 to 16 years in one-fourth of individuals in the community. Changes in mitral leaflet morphology are associated with both NDM and MVP progression.

Lead Assessment in Biological Samples of Children with Different Gastrointestinal Disorders.

Lead (Pb) levels have been evaluated in the biological samples of children with different gastrointestinal disorders. Blood, scalp hair, and urine samples of children (of age 4-10years) complaining about different gastrointestinal disorders were analyzed. For comparison, age matched healthy subjects were also included in this study. Biological samples were digested in a microwave oven prior to Pb determination by graphite furnace atomic absorption spectrometry. Significant differences in Pb profile were found between the diseased and referent children. Elevated Pb contents were observed in case of diseased children than WHO permissible limit, while normal results were obtained for healthy referents. The results were compared with those of healthy children having the same age, socioeconomic status, and residential areas.

Estimation of lead in biological samples of oral cancer patients chewing smokeless tobacco products by ionic liquid-based microextraction in a single syringe system.

Several studies have reported that the chewing habit of smokeless tobacco (SLT) has been associated with oral cancer. The aim of the present study was to evaluate the trace levels of lead (Pb) in biological samples (blood, scalp hair) of oral cancer patients and referents of the same age group (range 30-60 years). As the concentrations of Pb are very low in biological samples, so a simple and efficient ionic liquid-based microextraction in a single syringe system has been developed, as a prior step to determination by flame atomic absorption spectrometry. In this procedure, the hydrophobic chelates of Pb with ammonium pyrrolidinedithiocarbamate (APDC) were extracted into fine droplets of 1-butyl-3-methylimidazolium hexafluorophosphate [C4MIM][PF6] within a syringe while using Triton X-114 as a dispersant. Factors influencing the microextraction efficiency and determination, such as pH of the sample, volume of [C4MIM][PF6] and Triton X-114, ligand concentration, and incubation time, were studied. To validate the proposed method, certified reference materials were analyzed and the results of Pb(2+) were in good agreement with certified values. At optimum experimental values of significant variables, detection limit and enhancement factor were found to be 0.412 μg/L and 80, respectively. The coexisting ions showed no obvious negative outcome on Pb preconcentration. The proposed method was applied satisfactorily for the preconcentration of Pb(2+) in acid-digested SLT and biological samples of the study population. It was observed that oral cancer patients who consumed different SLT products have 2-3-fold higher levels of Pb in scalp hair and blood samples as compared to healthy referents (p < 0.001). While 31.4-50.8% higher levels of Pb were observed in referents chewing different SLT products as compared to nonconsumers (p < 0.01).

Comparative evaluation of essential and toxic elements in the blood of kidney failure patients and healthy referents.

The aim of the present study was to evaluate the comparative distribution, correlation, and apportionment of selected elements-aluminum (Al), calcium (Ca), cadmium (Cd), potassium (K), magnesium (Mg), sodium (Na), and lead (Pb)-in the blood samples of male kidney failure patients (KFP) and healthy subjects of age ranged 30-60 years. The blood samples were digested with nitric acid and perchloric acid mixture (2:1), followed by the quantification of elements by atomic absorption spectrometry. The concentration of essential elements in blood samples of KFP were found in the range of Ca (97-125), Mg (18-36), Na (2971-3685), and K (177-270) mg/L while, the levels of Al, Cd, and Pb were found in the range of (475-1275), (0.9-9.9), and (211-623) μg/L, respectively. In the healthy referents, concentration of electrolytes in blood samples was lower than KFP, but difference was not significant (p > 0.05). While the levels of toxic elements in blood samples of referents were three- to sixfold lower than KFP (p < 0.01). Principal component analysis (PCA) and cluster analysis (CA) of the element data manifested diverse apportionment of the selected elements in the blood sample of the KFP compared with the healthy counterparts.

Predictors of Health-Related Quality of Life in Adolescents with Tetralogy of Fallot

To assess health-related quality of life (HRQoL) of adolescents with repaired tetralogy of Fallot (TOF) and whether impairments in HRQoL domains are associated with neurocognitive and medical factors. Parents of subjects with TOF and healthy referents 13-16 years of age completed the Child Health Questionnaire-Parent Form 50, generating psychosocial (PsS) and physical (PhS) health summary scores. Adolescents completed the Child Health Questionnaire-Child Form 87 and concurrent in-person neurocognitive testing. We analyzed relationships of PsS and PhS scores with neurocognitive performance and medical factors. Compared with referents (n = 85), adolescents with TOF without a genetic diagnosis (n = 66) had lower PsS (50.9 ± 9.4 vs 57.2 ± 4.2, P < .001) and PhS scores (49.4 ± 9.5 vs 55.8 ± 4.9; P < .001). Compared with a normative sample, these adolescents with TOF had similar PsS scores (P = .52) but significantly lower PhS scores (P = .01). Within adolescents with TOF without genetic disorders, lower PsS scores were highly associated with worse neurocognitive measures, particularly the parent-reported Behavior Rating Inventory of Executive Function composite (r = -0.66, P < .001) and Parent Conners' attention deficit-hyperactivity disorder Index T score (r = -0.54, P < .001), whereas associations of PhS scores with neurocognitive measures were weaker. Psychosocial health status in adolescents with TOF without genetic disorders was worse than in healthy referents without risk factors for brain injury but similar to a normative sample; physical health status was worse in these adolescents than in either comparison group. Within these subjects with TOF, worse psychosocial health status was most highly associated with concurrent executive dysfunction and attention deficit-hyperactivity disorder. Optimizing HRQoL constitutes another indication for attention to neurodevelopment in children with congenital heart disease.