Urinary concentrations of neonicotinoid insecticides were related to renal tubular dysfunction and neuropsychological complaints in Dry-zone of Sri Lanka.

Neonicotinoids are systemic insecticides used since the 1990's , that possess renal tubular toxicity. We conducted a field-based descriptive study in the North Central Dry-zone of Sri Lanka, where chronic kidney disease (CKD) of unknown etiology has been increasing since the 1990's. To elucidate the relationship between renal tubular dysfunctions and urinary neonicotinoids concentrations, we collected spot urine samples from15 CKD patients, 15 family members, and 62 neighbors in 2015, analyzed two renal tubular biomarkers, Cystatin-C and L-FABP, quantified seven neonicotinoids and a metabolite N-desmethyl-acetamiprid by LC-MS/MS; and we investigated their symptoms using a questionnaire. Cystatin-C and L-FABP had a positive correlation (p < 0.001). N-Desmethyl-acetamiprid was detected in 92.4% of the urine samples, followed by dinotefuran (17.4%), thiamethoxam (17.4%), clothianidin (9.8%), thiacloprid and imidacloprid. Dinotefuran and thiacloprid have never been registered in Sri Lanka. In High Cystatin-C group (> 70 µg/gCre, n = 7), higher urinary concentration of dinotefuran (p = 0.009), and in Zero Cystatin-C group (< LOQ, n = 7), higher N-desmethyl-acetamiprid (p = 0.013), dinotefuran (p = 0.049), and thiacloprid (p = 0.035), and more complaints of chest pains, stomachache, skin eruption and diarrhea (p < 0.05) were found than in Normal Cystatin-C group (n = 78). Urinary neonicotinoids may be one of the potential risk factors for renal tubular dysfunction in this area.

Trends in renal calculus composition and 24-hour urine analyses in patients with neurologically derived musculoskeletal deficiencies

ABSTRACT Purpose: To better characterize metabolic stone risk in patients with neurologically derived musculoskeletal deficiencies (NDMD) by determining how patient characteristics relate to renal calculus composition and 24-hour urine parameters. Materials and Methods: We performed a retrospective cohort study of adult patients with neurologically derived musculoskeletal deficiencies presenting to our multidisciplinary Kidney Stone Clinic. Patients with a diagnosis of NDMD, at least one 24-hour urine collection, and one chemical stone analysis were included in the analysis. Calculi were classified as primarily metabolic or elevated pH. We assessed in clinical factors, demographics, and urine metabolites for differences between patients who formed primarily metabolic or elevated pH stones. Results: Over a 16-year period, 100 patients with NDMD and nephrolithiasis were identified and 41 met inclusion criteria. Thirty percent (12 / 41) of patients had purely metabolic calculi. Patients with metabolic calculi were significantly more likely to be obese (median body mass index 30.3kg / m2 versus 25.9kg / m2), void spontaneously (75% vs. 6.9%), and have low urine volumes (100% vs. 69%). Patients who formed elevated pH stones were more likely to have positive preoperative urine cultures with urease splitting organisms (58.6% vs. 16.7%) and be hyperoxaluric and hypocitraturic on 24-hour urine analysis (37mg / day and 265mg / day versus 29mg / day and 523mg / day). Conclusions: Among patients with NDMD, metabolic factors may play a more significant role in renal calculus formation than previously believed. There is still a high incidence of carbonate apatite calculi, which could be attributed to bacteriuria. However, obesity, low urine volumes, hypocitraturia, and hyperoxaluria suggest an underrecognized metabolic contribution to stone formation in this population.

Clinical Guide and Update on Porphyrias.

Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An α-melanocyte-stimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or X-linked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.

Trends in renal calculus composition and 24-hour urine analyses in patients with neurologically derived musculoskeletal deficiencies.

PURPOSE: To better characterize metabolic stone risk in patients with neurologically derived musculoskeletal deficiencies (NDMD) by determining how patient characteristics relate to renal calculus composition and 24-hour urine parameters. MATERIALS AND METHODS: We performed a retrospective cohort study of adult patients with neurologically derived musculoskeletal deficiencies presenting to our multidisciplinary Kidney Stone Clinic. Patients with a diagnosis of NDMD, at least one 24-hour urine collection, and one chemical stone analysis were included in the analysis. Calculi were classified as primarily metabolic or elevated pH. We assessed in clinical factors, demographics, and urine metabolites for differences between patients who formed primarily metabolic or elevated pH stones. RESULTS: Over a 16-year period, 100 patients with NDMD and nephrolithiasis were identified and 41 met inclusion criteria. Thirty percent (12 / 41) of patients had purely metabolic calculi. Patients with metabolic calculi were significantly more likely to be obese (median body mass index 30.3kg / m2 versus 25.9kg / m2), void spontaneously (75% vs. 6.9%), and have low urine volumes (100% vs. 69%). Patients who formed elevated pH stones were more likely to have positive preoperative urine cultures with urease splitting organisms (58.6% vs. 16.7%) and be hyperoxaluric and hypocitraturic on 24-hour urine analysis (37mg / day and 265mg / day versus 29mg / day and 523mg / day). CONCLUSIONS: Among patients with NDMD, metabolic factors may play a more significant role in renal calculus formation than previously believed. There is still a high incidence of carbonate apatite calculi, which could be attributed to bacteriuria. However, obesity, low urine volumes, hypocitraturia, and hyperoxaluria suggest an underrecognized metabolic contribution to stone formation in this population.

Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.

Measurements of C-reactive protein (CRP) and nerve-growth-factor (NGF) concentrations in serum and urine samples of dogs with neurologic disorders.

BACKGROUND: The purpose of this study was to prove the hypothesis that C-reactive protein (CRP) and nerve growth factor (NGF) may be potential biomarkers for lower urinary tract disorders and may be able to distinguish between micturition dysfunctions of different origin in dogs with spinal cord diseases. NGF- and CRP- concentrations were measured in serum and urine samples using specific ELISA-Kits. Results in urine were standardized by urine-creatinine levels. RESULTS: CRP in serum was detectable in 32/76 and in urine samples in 40/76 patients. NGF could be measured in all serum and in 70/76 urine samples. Urinary CRP concentrations were significantly higher in dogs with micturition dysfunction (p = 0.0009) and in dogs with different neurological diseases (p = 0.0020) compared to the control group. However, comparing dogs with spinal cord disorders with and without associated micturition dysfunction no significant difference could be detected for NGF and CRP values in urine or serum samples. Additionally, levels did not decrease significantly, when measured at the time when the dogs regained the ability to urinate properly (urinary NGF p = 0.7962; urinary CRP p = 0.078). Urine samples with bacteria and/or leukocytes had no significant increase in urinary NGF (p = 0.1112) or CRP (p = 0.0534) concentrations, but higher CRP-levels in urine from dogs with cystitis were found compared to dogs without signs of cystitis. CONCLUSIONS: From these data we conclude that neither CRP nor NGF in urine or serum can be considered as reliable biomarkers for micturition disorders in dogs with spinal cord disorders in a clinical setting, but their production might be part of the pathogenesis of such disorders. Significantly higher levels of CRP could be found in the urine of dogs with micturition dysfunctions compared to control dogs. This phenomenon could potentially be explained by unspecific extrahepatic CRP production by smooth muscle cells in the dilated bladder.

Association of aryl hydrocarbon receptor gene polymorphism with the neurobehavioral function and autonomic nervous system function changes induced by benzo[a]pyrene exposure in coke oven workers.

OBJECTIVE: To analyze the association of aryl hydrocarbon receptor (AhR) gene polymorphism and the neurotoxicity induced by benzo[a]pyrene (B[a]P) in coke oven workers. METHODS: Subjects, 214 coke oven workers and 81 controls, were detected for neurobehavioral function and autonomic nervous system (ANS) function. Airborne B[a]P concentration, urinary 1-hydroxypyrene level, and AhR gene polymorphisms were determined and analyzed for their association with B[a]P neurotoxicity. RESULTS: Neurobehavioral function and ANS function were significantly decreased and dependent on B[a]P dose. The AhR GG, GA, and AA genotypes in G1661A fitted the Hardy-Weinberg equation, whereas C1549T and G1708A gene mutants were not detected. Indices indicating neurotoxicity showed no significant difference among individuals with AA, GG, or GA genotype except for the confusion-bewilderment (P > 0.05). CONCLUSION: The AhR gene polymorphism is not thought to correlate with B[a]P neurotoxicity among coke oven workers.

Noninvasive urine-derived cell lines derived from neurological genetic patients.

Many major inherited neurological disorders are characterized by early childhood onset, high lethality rate, and the absence of effective treatments. A poor understanding of the underlying mechanisms of such disorders is partly because of the scarcity of patient-specific samples. In this study, we cultured the urine sediments of such patients, aiming to explore the capacity of urine cell cultures to obtain specimens from patients suffering from rare inherited neurological diseases. We collected fresh urine from a variety of neurogenetic patients; cultured the specimens; generated different urine cell lines; and classified these cell lines through morphology, reverse transcription-PCR, and immunofluorescence. We then used these cell lines to detect the affected genes in spinal muscular atrophy and Duchenne muscular dystrophy. We successfully established cell lines from patients with spinal muscular atrophy, Duchenne muscular dystrophy, paroxysmal kinesigenic dyskinesia, and Wilson's disease. All established cell lines consisted of urinary tract epithelial cells and podocytes, and had the same gene defects as the blood specimens. Urine cell culture is thus a new, simple, and noninvasive avenue for getting patient-specific samples not only for genetic diagnosis, but also for storing the samples from patients with rare neurological inherited diseases.

Screening for primary creatine deficiencies in French patients with unexplained neurological symptoms.

A population of patients with unexplained neurological symptoms from six major French university hospitals was screened over a 28-month period for primary creatine disorder (PCD). Urine guanidinoacetate (GAA) and creatine:creatinine ratios were measured in a cohort of 6,353 subjects to identify PCD patients and compile their clinical, 1H-MRS, biochemical and molecular data. Six GAMT [N-guanidinoacetatemethyltransferase (EC 2.1.1.2)] and 10 X-linked creatine transporter (SLC6A8) but no AGAT (GATM) [L-arginine/glycine amidinotransferase (EC 2.1.4.1)] deficient patients were identified in this manner. Three additional affected sibs were further identified after familial inquiry (1 brother with GAMT deficiency and 2 brothers with SLC6A8 deficiency in two different families). The prevalence of PCD in this population was 0.25% (0.09% and 0.16% for GAMT and SLC6A8 deficiencies, respectively). Seven new PCD-causing mutations were discovered (2 nonsense [c.577C > T and c.289C > T] and 1 splicing [c.391 + 15G > T] mutations for the GAMT gene and, 2 missense [c.1208C > A and c.926C > A], 1 frameshift [c.930delG] and 1 splicing [c.1393-1G > A] mutations for the SLC6A8 gene). No hot spot mutations were observed in these genes, as all the mutations were distributed throughout the entire gene sequences and were essentially patient/family specific. Approximately one fifth of the mutations of SLC6A8, but not GAMT, were attributed to neo-mutation, germinal or somatic mosaicism events. The only SLC6A8-deficient female patient in our series presented with the severe phenotype usually characterizing affected male patients, an observation in agreement with recent evidence that is in support of the fact that this X-linked disorder might be more frequent than expected in the female population with intellectual disability.

A quantitative evaluation of brain dysfunction and body-burden of toxic metals.

BACKGROUND: Toxic metal exposure (e.g. Hg, Pb, As) exposure is known to induce significant adverse effects on human brain function. The aim this study was to assess toxic metal body-burden in relation to potential brain dysfunction in patients diagnosed with neurological disorders (NDs). MATERIAL/METHODS: The Liberty Institutional Review Board (Deland, FL) approved the present study. Quantitative, fractionated, random urinary porphyrin testing (µg/L) from the Clinical Laboratory Improvement Act/Amendment (CLIA)-approved Laboratory Corporation of America (LabCorp) and cortical perfusion index (CPi) values from single-photon-emission-computed-tomography (SPECT) brain scans were employed to evaluate a prospective cohort of qualifying patients with diagnosed NDs (n=52) presenting for medical care at an endocrinology practice in the Cincinnati, OH area. RESULTS: Patients with more severe in comparison to mild brain dysfunction had significant increases in the mean urinary concentration of uroporphyrins (uP), coproporphyrins I (cP I), and total cP (cP I + III), as well as a trend towards significantly increased mean urinary concentration of pentacarboxyporphyins (5cxP) and cP III. A significant positive correlation between Hg body-burden associated porphyrins (5cxP + cP I + cP III) and increased brain dysfunction was observed. CONCLUSIONS: The present study associated brain dysfunction with Hg body-burden in a cohort of patients diagnosed with NDs, but the contributions of other heavy metals or genetic factors cannot be ruled-out. Additional studies should be conducted to evaluate the consistency of the present findings with examinations of other populations.

Psychiatric patients in the pediatric emergency department undergoing routine urine toxicology screens for medical clearance: results and use.

OBJECTIVE: We sought to determine the use and results of urine toxicology screens (UTS) in psychiatric patients undergoing a UTS test for medical clearance in a pediatric emergency department. METHODS: A structured retrospective study was conducted over a 6-month period. All emergency department (ED) charts were reviewed of patients 8 to 17 years who had a UTS. Urine toxicology screens were identified as medically indicated or routine-driven. Medically indicated UTS were patients who presented with seizures, syncope, headache, altered mental status, ingestion, chest pain/palpitation, shortness of breath, sexual assault, or those who were brought in for motor vehicle accident (MVA). Routine-driven UTS were uncomplicated psychiatric patients who presented with aggressive or out of control behavior, intentional self-inflicted wounds, or symptoms of depression, all of whom presented without any evidence of drug or alcohol ingestion or altered mental status. Routine-driven UTS were quantified for positive tests. In addition, we determined the change in management and disposition of those patients. We also determined the concordance of provided drug use history with UTS result. RESULTS: Of the 652 charts reviewed, 267 UTS were medically indicated; 385 were routine-driven. Of the routine-driven UTS group, 254/267 (95%) patients with negative screens and 115/118 (97%) with positive screens were referred for psychiatric treatment after psychiatric evaluation. Fisher exact test of the comparison of the disposition after psychiatric assessment with the UTS result was nonsignificant. The UTS result also had no effect on the type of psychiatric disposition (ie, outpatient therapy, partial hospitalization, inpatient hospitalization). Concordance with provided history of illicit drug use was significant. CONCLUSIONS: Routine-driven UTS in uncomplicated pediatric psychiatric patients being evaluated in the ED offered little additional information, did not influence management, and potentially increased both ED cost and time. Patients with straightforward psychiatric complaints may be medically cleared without a UTS.

Urinary nerve growth factor level is correlated with the severity of neurological impairment in patients with cerebrovascular accident.

OBJECTIVE: To measure urinary nerve growth factor (uNGF, essential in nerve growth and regeneration) levels in patients with a cerebrovascular accident (CVA), to determine whether uNGF could be a biomarker for predicting the neurological deficits in CVA, as the level of uNGF increases in patients with idiopathic detrusor overactivity (DO) and incontinence. PATIENTS, SUBJECTS AND METHODS: uNGF levels were measured using an enzyme-linked immunosorbent assay in normal subjects and patients with CVA and different severities of neurological impairment. Total uNGF levels were normalized to the concentration of urinary creatinine (uNGF/Cr). RESULTS: The median (interquartile range) uNGF/Cr levels were significantly higher in patients, at 0.13 (0-1.04), than in normal subjects (undetectable). The uNGF/Cr levels correlated well with the severity of neurological impairment. Patients with none/minimal neurological impairment had no detectable uNGF/Cr level, like the controls. Patients with mild/moderate impairment had levels of 0.27 (0.09-0.8) and with severe impairment level of 1.53 (0.5-3.0) (both P < 0.001), significantly greater than that of none/minimal impairment or controls. However, uNGF/Cr levels were not correlated with age, location of CVA, multiplicity of CVA, duration of CVA, urodynamic findings or the presence of urge urinary incontinence. CONCLUSIONS: The uNGF level is correlated with the severity of neurological impairment in patients with CVA but not with urge symptoms or urodynamic findings, suggesting elevated uNGF might be a result of the neurological lesion rather than lower urinary tract dysfunction in CVA.

Discerning the Mauve factor, Part 2.

"Mauve Factor" was once mistaken for kryptopyrrole but is the hydroxylactam of hemopyrrole, hydroxyhemopyrrolin-2-one (HPL). Treatment with nutrients--particularly vitamin B6 and zinc--reduces urinary excretion of HPL and improves diverse neurobehavioral symptoms in subjects with elevated urinary HPL. Heightened HPL excretion classically associates with emotional stress, which in turn is known to associate with oxidative stress. For this review, markers for nutritional status and for oxidative stress were examined in relationship to urinary HPL. In cohorts with mixed diagnoses, 24-hour urinary HPL correlated negatively with vitamin B6 activity and zinc concentration in red cells (P < .0001). Above-normal HPL excretion corresponded to subnormal vitamin B6 activity and subnormal zinc with remarkable consistency. HPL correlated inversely with plasma GSH and red-cell catalase, and correlated directly with plasma nitric oxide (P < .0001). Thus, besides implying proportionate needs for vitamin B6 and zinc, HPL is a promising biomarker for oxidative stress. HPL is known to cause non-erythroid heme depression, which lowers zinc, increases nitric oxide, and increases oxidative stress. Administration of prednisone reportedly provoked HPL excretion in animals. Since adrenocorticoid (and catecholamine) stress hormones mediate intestinal permeability, urinary HPL was examined in relationship to urinary indicans, presumptive marker for intestinal permeability. Urinary HPL associated with higher levels ofindicans (P < .0001). Antibiotics reportedly reduce HPL in urine, suggesting an enterobic role in production. Potentially, gut is reservoir for HPL or its precursor, and stress-related changes in intestinal permeability mediate systemic and urinary concentrations.

Discerning the Mauve Factor, Part 1.

"Mauve Factor" was once mistaken for kryptopyrrole but is the hydroxylactam of hemopyrrole, hydroxyhemopyrrolin-2-one (HPL). Treatment with nutrients--particularly vitamin B6 and zinc--reduces urinary excretion of HPL and improves diverse neurobehavioral symptoms in subjects with elevated urinary HPL. Heightened HPL excretion classically associates with emotional stress, which in turn is known to associate with oxidative stress. For this review, markers for nutritional status and for oxidative stress were examined in relationship to urinary HPL. In cohorts with mixed diagnoses, 24-hour urinary HPL correlated negatively with vitamin B6 activity and zinc concentration in red cells (P < .0001). Above-normal HPL excretion corresponded to subnormal vitamin B6 activity and subnormal zinc with remarkable consistency. HPL correlated inversely with plasma glutathione and red-cell catalase, and correlated directly with plasma nitric oxide (P < .0001). Thus, besides implying proportionate needs for vitamin B6 and zinc, HPL is a promising biomarker for oxidative stress. HPL is known to cause non-erythroid heme depression, which lowers zinc, increases nitric oxide, and increases oxidative stress. Administration of prednisone reportedly provoked HPL excretion in animals. Since adrenocorticoid (and catecholamine) stress hormones mediate intestinal permeability, urinary HPL examined in relationship to urinary indicans, presumptive marker for intestinal permeability. Urinary HPL associated with higher levels of indicans (P < .0001). Antibiotics reportedly reduce HPL in urine, suggesting an enterobic role in production. Potentially, gut is a reservoir for HPL or its precursor, and stress-related changes in intestinal permeability mediate systemic and urinary concentrations.

The nervous system effects of occupational exposure on workers in a South African manganese smelter.

Five hundred and nine production workers at a manganese (Mn) smelting works comprising eight production facilities and 67 external controls were studied cross-sectionally for Mn related neuroehavioural effects. Exposure measures from personal sampling included Mn in inhalable dust as cumulative exposure indices (CEI) and average intensity (INT). Biological exposure and biological effect measures included blood (MnB), urine (MnU) manganese and serum prolactin. Endpoints included items from the Swedish nervous system questionnaire (Q16), World Health Organisation neurobehavioural core test battery (WHO NCTB), Swedish performance evaluation system (SPES), Luria-Nebraska (LN), and Danish product development (DPD) test batteries, and a brief clinical examination. Potential confounders and effect modifiers included age, educational level, alcohol and tobacco consumption, neurotoxic exposures in previous work, past medical history, previous head injury and home language. Associations were evaluated by multiple linear and logistic regression modelling. Modelling assumptions were tested. Average exposure intensity across all jobs ranged from near 0 (0.06 microg/m3) for external controls to 5.08 mg/m3 for inhalable Mn, and was greater than the ACGIH TLV for 69% of subjects. Results from the large number of tests performed resolved into three groups. Group 1 shows differences between external unexposed referents and all the exposed and/or differences between internal low exposed referents and the rest of the exposed but no further exposure-response relationships. It includes the Santa Ana, Benton and digit-span tests from the WHO NCTB; the hand tapping and endurance tapping tests from the SPES; Luria-Nebraska item 2L; questionnaire items tired, depressed, irritated, having to take notes in order to remember things, and subjects' perception that they had sex less often than normal; a test of clinical abnormality; and increased sway under two conditions (eyes open without foot insulation, eyes open with foot insulation). Group 2 shows the presence of a more substantive exposure-response relationship. It consists of only two tests: and includes the WHO digit-symbol test (although the major impact is at low exposure and therefore counterintuitive, arguably placing this test in group 3) and the LN item 1R which has a step to a poorer score at high exposure. Group 3 contains the overwhelming majority of test results (almost all the questionnaire items, almost all the DPD tests including tremor, sway and diadochokinesia, and serum prolactin) which were either null or counterintuitive (did not make sense). The CEI was the strongest predictor of test abnormalities, except for the clinical test which was more strongly associated with blood manganese. Despite a comprehensive range of endpoints, and levels of exposure ranging from environmental to industrial, this large study of Mn workers found little convincing evidence for a continuum of effects, contributing further questions to current debates about the adequacy of the current ACGIH TLV.

Familial ATTR amyloidosis: microalbuminuria as a predictor of symptomatic disease and clinical nephropathy.

BACKGROUND: Portuguese type familial amyloid polyneuropathy (FAP) is a neuropathic amyloidosis caused by a mutant transthyretin (TTR). Varying degrees of renal involvement have been reported. Our aim was to assess the value of microalbuminuria (MA) for predicting clinical neurological disease and overt nephropathy in TTR-related amyloidosis. METHODS: All subjects had the TTR Val30Met mutation, and were recruited between 1993 and 1999. We have prospectively evaluated 22 asymptomatic gene carriers (7 male, 15 female; mean age 41.6+/-9.6 years) and 32 patients with neuropathy (14 male, 18 female; 36.8+/-8.8 years, on average, 33.0+/-9.3 years at the onset of neuropathy). We measured urinary albumin excretion every year, if asymptomatic, or every 6 months if already affected. Kidney biopsies were performed in patients with normal urinary albumin excretion, MA, and overt nephropathy, respectively. RESULTS: In asymptomatic carriers, persistent MA was detected in eight (36%) subjects. The presence of MA in asymptomatic gene carriers, compared with those having normal urinary albumin excretion, conferred a 4.8-fold risk of developing neuropathy, usually within the subsequent 3 years. Once neurological signs appeared, nephropathy, manifested as MA, progressed to overt nephropathy in one-half of subjects. In patients with neuropathy, 24 (75%) had MA during follow-up: evolution towards clinical renal disease occurred in 14 (58%) and renal failure occurred in five (21%), always after a course of MA. Proteinuria or renal failure without prior persistent MA were never observed in the present patient cohort. Histopathological evaluation did not reveal glomerular lesions other than amyloid deposits to explain abnormal urinary albumin excretion. The amount of mesangial and vascular-pole amyloid deposits was correlated with the degree of albuminuria. CONCLUSIONS: Microalbuminuria represents the first stage of clinical TTR amyloid nephropathy and is premonitory of neuropathy. Its presence identifies a subgroup of patients who are more prone to develop overt nephropathy. Screening of MA may be important to assess disease onset and to recommend liver transplantation in individuals at risk.

A survey of urinary hippuric acid and subjective symptoms among occupational low toluene exposed workers.

Biological monitoring of toluene exposure by urinary hippuric acid determination and a subjective symptom survey by self-administered questionnaire were performed in 20 workers at low toluene exposure in factories to evaluate the health hazard including dysfunction of nervous system. Environmental monitoring was carried out using toluene gas detection tubes. Urine samples were collected three times a day in order to measure hippuric acid: first before the commencement of work, then at the end of forenoon work, and lastly at the end of afternoon work. Toluene vapor concentrations of throughout the workday ranged from 15.3 to 31.4 ppm. The urinary hippuric acid concentrations correlated with the toluene concentrations of ambient air (r = 0.58, p = 0.01). The subjective symptoms increased in close association with the exposure to toluene; the prevalence rate of subjective symptoms "during work" in the exposed group was 15 times higher than the rate of the non-exposed group (p < 0.0001). The prevalence rate of subjective symptoms "off-work" in the exposed group was 2.4 times higher than the rate of the non-exposed group (p < 0.0001), and also the prevalence rate of "nineteen symptoms off-work which are apparently related to central nervous system (CNS) and autonomic nervous system (ANS)" in the exposed group was 1.8 times higher than the rate of the non-exposed group (p < 0.05). From these results, these subjective symptoms, which have been believed to be complained in high organic solvent exposure should be reassessed and reconsidered in evaluating the nervous system dysfunction and local irritation in relatively low toluene exposed workers.

Adult onset glutaric aciduria type I presenting with a leukoencephalopathy.

Glutaric aciduria type I usually presents with an acute metabolic crisis during infancy. The authors report a previously healthy 19-year-old woman who presented with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy on MRI. The diagnosis was made by urinary organic acid analysis and confirmed by enzyme studies. Genetic analysis revealed compound heterozygosity with a deletion c.219delC in exon 3 and a novel missense mutation R132G in exon 5 of the glutaryl CoA dehydrogenase (GCDH) gene.

Clinical study of a urinary competitve ELISA for neural thread protein in Alzheimer disease.

AD7C-NTP (neural thread protein) is a approximately 41-kD brain protein that is selectively elevated in Alzheimer disease (AD). AD7C-NTP is associated with the pathologic changes of AD, and overexpression of the AD7C-NTP gene is associated with cell death similar to that found in the AD brain. A newly developed competitive ELISA (enzyme-linked immunosorbent assay) was tested in urine samples from patients with AD, patients with non-AD dementia, and healthy normal individuals. Mean assay measurement in the AD group (30.1 +/- 10.8) was significantly higher than in the non-AD dementia control group (13.4 +/- 3.4) and in the nondementia control group (14.8 +/- 5.2) (P <.001). Mean assay measurement in early-AD cases (25.3 +/- 7.6) was significantly lower than in other AD cases (33.9 +/- 11.4). Levels of more than 18 units were found in 89% of overall AD cases and in 10% of overall controls. The results further validate urinary AD7C-NTP as a biochemical marker for AD and indicate that the competitive ELISA-format AD7C-NTP test in urine is an accurate method for determining AD7C-NTP levels in AD.