The Use of Brain Natriuretic Peptide as a Decision-supporting Tool in Hospitalized Patients.

BACKGROUND: Most dyspneic patients in internal medicine departments have co-morbidities that interfere with the clinical diagnosis. The role of brain natriuretic peptide (BNP) levels is well-established in the acute setting but not in hospitalized patients. OBJECTIVES: To evaluate the additive value of BNP tests in patients with dyspnea admitted to medical wards who did not respond to initial treatment. METHODS: We searched the records of patients who were hospitalized in the department of internal medicine D at Sheba Medical Center during 2012 and were tested for BNP in the ward. Data collected included co-morbidity, medical treatments, diagnosis at presentation and discharge, lab results including BNP, re-hospitalization, and mortality at one year following hospitalization. RESULTS: BNP results were found for 169 patients. BNP was taken 1.7 ± 2.7 days after hospitalization. According to BNP levels, dividing the patients into tertiles revealed three equally distributed groups with a distinctive character. The higher tertile was associated with higher rates of cardiac co-morbidities, including heart failure, but not chronic obstructive pulmonary disease. Higher BNP levels were related to one-year re-hospitalization and mortality. In addition, higher BNP levels were associated with higher rates of in-admission diagnosis change. CONCLUSIONS: BNP levels during hospitalization in internal medicine wards are significantly related to cardiac illness, the existence of heart failure, and patient prognosis. Thus, BNP can be a useful tool in managing dyspneic patients in this setting.

Cardiovascular health among two ethnic groups living in the same region: A population-based study.

BACKGROUND: Poor cardiovascular health (CVH) among ethnic/racial minorities, studied primarily in the USA, may reflect lower access to healthcare. We examined factors associated with minority CVH in a setting of universal access to healthcare. METHODS AND RESULTS: CVH behaviors and factors were evaluated in a random population sample (551 Arabs, 553 Jews) stratified by sex, ethnicity and age. More Jews (10%) than Arabs (3%) had 3 ideal health behaviors. Only one participant had all four. Although ideal diet was rare (≤1.5%) across groups, Arabs were more likely to meet intake recommendations for whole grains, but less likely to meet intake recommendations for fruits/vegetables and fish. Arabs had lower odds of attaining ideal levels for body mass index and physical activity. Smoking prevalence was 57% among Arab men and 6% among Arab women. Having four ideal health factors (cholesterol, blood pressure, glucose, smoking) was observed in 2% and 8% of Arab and Jewish men, respectively, and 13% of Arab and Jewish women. Higher prevalence of ideal total-cholesterol corresponded to lower high-density lipoprotein cholesterol among Arabs. No participant met ideal levels for all 7 metrics and only 1.8% presented with 6. Accounting for age and lower socioeconomic status, Arabs were less likely to meet a greater number of metric goals (odds ratio (95% confidence interval): 0.62 (0.42-0.92) for men, and 0.73 (0.48-1.12) for women). CONCLUSIONS: Ideal CVH, rare altogether, was less prevalent among the Arab minority albeit universal access to healthcare. Health behaviors were the main contributors to the CVH disparity.

[Low ALT activity amongst patients hospitalized in internal medicine wards is a widespread phenomenon associated with low vitamin B6 levels in their blood].

BACKGROUND: Monitoring the activity of ALT (SGPT) in the blood is part of the routine, clinical-laboratory follow-up in hospitalized patients. In most cases, activity levels which are above the normal range are considered pathology, mostly related to lysis of hepatocytes, as in cases of hepatitis. Little has been investigated and published in regard to cases in which the ALT activity level is lower than normal. PATIENTS AND METHODS: Since normal ALT activity is regarded essential for normal metabolism and homeostasis, we decided to evaluate the extent to which low ALT levels are found in healthy and hospitalized patient populations and to characterize its circumstances and etiology. Furthermore, we measured the blood concentration of vitamin B6 (being the source for the ALT co-factor, Pyridoxal-5-Phosphate) in a random sample of patients with lower than normal ALT activity level. RESULTS AND CONCLUSIONS: The results of the current study showed a high prevalence, exceeding a third of hospitalized patients in internal medicine departments have low levels of ALT in the serum, and that a linear correlation (p = 0.0004, r = 0.47) exists between lower than normal ALT activity and low concentrations of vitamin B6 in the serum. The authors attribute these findings to a high prevalence of frailty amongst hospitalized patients. We aim to conduct further investigations intended to better characterize quantifiable parameters of frailty amongst our patient population.

Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia - preliminary study.

BACKGROUND: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N- methylglycine and inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia. METHODS: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients. RESULTS: Significant improvement was observed after one week of treatment on PANSS sub-scale of 'positive symptoms' (Z= -2.68; P=0.007) and 'general psychopathology' (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t½ of ~1½- 2½ hr and ~1hr, respectively. LIMITATIONS: This was a short period, open label pilot study with small sample size per dosage group. CONCLUSIONS: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia.

Effects of antihypertensive and triglyceride-lowering agents on hepatic copper concentrations in rats with fatty liver disease.

Copper deficiency had been suggested to link between fructose-enriched diet (FED) and the development of non-alcoholic fatty liver disease (NAFLD). In this study, we characterized changes in hepatic copper concentrations and hepatic oxidative milieu, in rats with the metabolic syndrome and NAFLD as a result of FED with pharmacological manipulations to reduce blood pressure or plasma triglycerides. Changes in plasma and hepatic copper concentrations were correlated with changes observed in the immunohistochemical hepatic expression of copper-zinc-superoxide dismutase (CuZnSOD; SOD1), metallothionein (MT) and nitrotyrosine (NITT). FED administration was associated with a 2.2-fold reduction in hepatic copper concentrations, a decrease in the hepatic SOD1 expression, disappearance of the hepatic MT expression and increase in the hepatic NITT expression. Bezafibrate administration restored the hepatic copper concentrations and the hepatic SOD1 expression to levels that were observed in the control rats. A significant positive correlation between hepatic copper concentrations and the values of hepatic SOD1 expression of each animal included in this study was found. Administration of either captopril or bezafibrate increased hepatic MT expression, however, to levels that were lower than those observed in the control group. Administration of either amlodipine, or captopril or bezafibrate to the FED rats, had no effect on hepatic NITT expression. NAFLD development in FED rats is associated with a decrease in hepatic copper concentrations that is associated with a decrease in the hepatic SOD1 expression. Bezafibrate administration increases hepatic copper concentrations and restores the hepatic SOD1 expression.

Titin mutation in familial restrictive cardiomyopathy.

BACKGROUND: Familial restrictive cardiomyopathy (RCM) caused by a single gene mutation is the least common of the inherited cardiomyopathies. Only a few RCM-causing mutations have been described. Most mutations causing RCM are located in sarcomere protein genes which also cause hypertrophic cardiomyopathy (HCM). Other genes associated with RCM include the desmin and familial amyloidosis genes. In the present study we describe familial RCM with severe heart failure triggered by a de novo mutation in TTN, encoding the huge muscle filament protein titin. METHODS AND RESULTS: Family members underwent physical examination, ECG and Doppler echocardiogram studies. The family comprised 6 affected individuals aged 12-35 years. Linkage to candidate loci was performed, followed by gene sequencing. Candidate loci/gene analysis excluded 18 candidate genes but showed segregation with a common haplotype surrounding the TTN locus. Sequence analysis identified a de novo mutation within exon 266 of the TTN gene, resulting in the replacement of tyrosine by cysteine. p.Y7621C affects a highly conserved region in the protein within a fibronectin-3 domain, belonging to the A/I junction region of titin. No other disease-causing mutation was identified in cardiomyopathy genes by whole exome sequencing. CONCLUSIONS: Our study shows, for the first time, that mutations in TTN can cause restrictive cardiomyopathy. The giant filament titin is considered to be a determinant of a resting tension of the sarcomere and this report provides genetic evidence of its crucial role in diastolic function.

Elevated homocysteine level in siblings of patients with schizophrenia.

Increased homocysteine plasma levels were reported in patients with schizophrenia and Levine et al. (2002) suggested that such increase characterizes mainly males. In the following study we examined whether such increased levels also characterize male siblings of schizophrenia patients. Forty-four pairs of schizophrenia patients and their corresponding healthy male siblings were recruited and sampled for homocysteine. We also had age-matched controls for each of the sibling. The median homocysteine plasma level for patients was 13.0 µMol/L and 11.7 µMol/L for their male siblings compared with a median of 10.9 µMol/L for the siblings' controls. There was no significant difference between homocysteine plasma level in patients and their siblings. Significant difference was found for homocysteine plasma level between the siblings' group and their matched controls. A partial correlation of Ln plasma homocysteine level between patients and their siblings was found to be close to a zero correlation of -0.089, p=0.57 for the whole study group and -0.15, p=0.38 in the male-male patient-sibling pairs. Our results show that elevated homocysteine plasma level may characterize schizophrenia patients' male siblings, a finding that seems to agree with previous studies suggesting elevated homocysteine level as a risk factor for developing schizophrenia.

Subependymal mass lesions and peripheral polyneuropathy in adult-onset glutaric aciduria type I.

Glutaric aciduria type I (GA-I) is an autosomal recessive disease caused by a deficiency of the mitochondrial enzyme glutaryl CoA dehydrogenase (GCDH). This metabolic block causes increased urinary concentrations of glutaric and 3-hydroxyglutaric acids. The accumulation and excretion of glutarylcarnitine esters leads to secondary carnitine deficiency. GA-I has an incidence of 1:30,000. The clinical hallmark of GA-I is an acute encephalopathic crisis, with bilateral striatal necrosis presented by severe dystonic dyskinetic disorder. Most patients have their first symptoms during infancy, but some have a less severe form of the disease and some may even remain asymptomatic.

Effects of antihypertensive and triglyceride lowering agents on splenocyte apoptosis in rats with fatty liver.

Individuals with the metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) have an increased incidence of infection and infection-related mortality. Rats given fructose-enriched diet (FED) develop the MS including NAFLD. In this study, we characterized changes in splenocyte apoptosis in FED rats given medications to treat various components of the MS. Apoptosis of splenocytes may induce immunosuppression. Splenocyte apoptosis was evaluated by activated caspase-3 immunohistochemistry in the periarterial sheath (PALS), (a T cell area), follicles (B cell area), marginal (B cell area) and in the red pulp zones. FED administration caused an enormous increase in splenocyte apoptosis in all of the spleen zones: PALS (+2966%), follicles (+3025%), marginal (+5228%) and red pulp (+7000%). Administration of captopril to the FED rats was associated with a further increase in the splenocyte apoptosis only in the marginal (150%), PALS (+105%) and red pulp (+67%) zones. Bezafibrate administration to the FED rats was associated with no further increase in apoptosis rates. Amlodipine administration to the FED rats was associated with almost complete amelioration of the splenocyte apoptosis that was induced by the FED diet. These pharmacological manipulations were also associated with changes in the hepatic lipids composition, and oxidative milieu that did not correlate to the changes in splenocyte apoptosis. NAFLD in FED rats is associated with an increase in splenic apoptosis. Agents administered to treat components of the MS in FED rats may lead to divergent changes in the splenic histology and splenocyte apoptosis.

Free light chain monomer-dimer patterns in the diagnosis of multiple sclerosis.

In our search of new biomarkers for multiple sclerosis (MS), we aimed to characterize the immunoglobulin (Ig) free light chains (FLC) in patients' cerebrospinal fluid (CSF) and serum, and to evaluate the diagnostic utility of FLC monomer-dimer patterns for MS. FLC were analyzed by Western blotting and mass spectroscopy. CSF and serum samples were examined for the presence of oligoclonal Ig bands by a conventional laboratory test for MS. Three distinct pathological FLC monomer-dimer patterns, typical of MS but not of other neurological diseases, were revealed. In 31 out 56 MS patients the highly increased CSF levels of κ monomers and dimers were demonstrated. In 18 MS patients, the increased κ-FLC levels were accompanied by highly elevated λ dimers. Five MS cases showed no significant elevation in κ-FLC, but they displayed abnormally high λ dimer levels. The intensity of the immunoreactive FLC bands was measured to account for κ and λ monomer and dimer levels and their ratios in the CSF and serum. Combined usage of different FLC parameters allowed the determination of the appropriate FLC threshold values to diagnose MS. The developed method showed higher sensitivity and specificity (96% and 90%, respectively), as compared to those of the conventional OCB test (82% and 70%, respectively). Our study highlights the role of the differential analysis of monomeric and dimeric κ- and λ-FLC for the precise diagnosis of MS.

The impact of refeeding on blood fatty acids and amino acid profiles in elderly patients: a metabolomic analysis.

BACKGROUND: Refeeding of elderly frail patients after food deprivation is commonly associated with a high mortality rate. OBJECTIVE: To evaluate the effect of refeeding on metabolite fluctuation of blood carnitine fatty acids (15 compounds) and free amino acids (14 compounds). METHODS: Metabolite fluctuation was followed up in an exploratory, cohort, and noninterventional study in elderly and frail patients (84.5 ± 5 years) after a long period of food deprivation. Patients in the study group were refed by enteral nutrition (EN) and were followed up during 7 days for blood metabolites (n = 27). Patients in the control group (n = 26) had been fed by EN for more than 3 months. Refeeding was initiated with 10 kcal/kg/d and gradual increases of 200 kcal/d for 3 days afterwards. Blood metabolites were assayed in a sample of 25 µL. RESULTS: On food deprivation, the concentrations of all even monocarboxylic carnitine fatty acids were much higher in the study group than in the EN control group (P < .01). Upon refeeding, a remarkable decrease in all carnitine fatty acids was observed. In addition, significant daily fluctuations were observed for most metabolites in the study group of the refed patients as compared with the EN control group (P < .01). The highest fluctuations were observed following refeeding in the 7 patients who later died. CONCLUSION: A significant metabolic instability is observed on refeeding even with a slow refeeding schedule of 10 kcal/kg/d. Measurement of metabolomics parameters may be used for the evaluation of malnutrition, refeeding status, and optimization of the enteral formula.

The impact of genetic and environmental factors on homocysteine levels in preterm neonates.

BACKGROUND: Hyperhomocysteinemia may be associated with vascular complications in adults. Whereas pediatric thrombosis risk peaks in neonates, data on homocysteine (Hcy) levels assessed in term and preterm infants during the perinatal period are scarce. In the present study, we aimed to establish Hcy reference values for preterm infants and study their potential associations with the early post-natal health status. Plasma Hcy and hematocrit levels and MTHFR polymorphisms (C677T and A1298C substitution) were studied in a large cohort of preterm infants in a tertiary referral medical center during an 18-month period. Data were collected on maternal history and delivery as well as on post-natal complications. RESULTS: The study cohort included 167 infants whose mean gestational age was 30.98 ± 2.34 weeks (range: 26-36 weeks), mean birth weight 1327.6 ± 327 g, and mean Hcy level 7.99 ± 3.27 (range: 2.2-21.2) µmol/L. Maternal intake of folic acid was inversely associated with the babies' Hcy levels (P = 0.0001). Increased Hcy levels positively correlated with birth weight, gestational age (P < 0.005), total number of pregnancies (P = 0.012), and presence of MTHFR polymorphism. Higher Hcy levels were associated with feeding (P = 0.008), especially total parenteral nutrition (P = 0.0001). There was no correlation between Hcy levels and any vascular post-natal complications. CONCLUSIONS: During their post-natal hospitalization, preterm infants may have relatively high, that is, within the adult normal range, Hcy levels which are influenced by genetic and environmental factors. Despite the fact that no correlation was found between Hcy levels and post-natal complications, these associations should be further studied.

Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2.

BACKGROUND: Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2). METHODS: Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations. RESULTS: Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions. CONCLUSIONS: This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.

[proPSA: a precursor of prostate-specific antigen, may improve the early diagnosis of prostate cancer].

Since its introduction as a mass-screen parameter for early detection of prostate cancer, PSA was credited for a significant revolution in the management of prostate disease. But over 2 decades of global experience with this marker have emphasized that the recommended threshold value of 4.0 ng/ml may not be valid in distinguishing tumor growth from benign proliferation of the prostate in over 30% of the cases. Hence, more advanced tools of PSA evaluation have been introduced such as "PSA velocity", "PSA density" or age-related PSA". Recently, precursor molecules of PSA were identified, which are assumed to be zymogen structures devoid of proteolytic activity. These precursor species known as pro-PSAs possess an additional "tail" ranging in size from 2 to 7 extra amino acids at the N terminus of PSA, and represent a fraction of the non-complex or "free PSA", that has usually been identified as a marker for non-cancerous proliferation of the prostate. Interestingly, one of these proPSA structures in particular, [-2]proPSA, has demonstrated to be more specifically indicative of prostate tumor growth in numerous clinical studies. Lately, a chemiluminescence kit has been approved by the European Health Agency as a more specific marker for diagnosis of prostate malignancy, mostly in men with PSA levels ranging from 2-10 ng/ml.

Immunoglobulin free light chain dimers in human diseases.

Immunoglobulin free light chain (FLC) kappa (κ) and lambda (λ) isotypes exist mainly in monomeric and dimeric forms. Under pathological conditions, the level of FLCs as well as the structure of monomeric and dimeric FLCs and their dimerization properties might be significantly altered. The abnormally high fractions of dimeric FLCs were demonstrated in the serum of patients with multiple myeloma (MM) and primary systemic amyloidosis (AL), as well as in the serum of anephric patients. The presence of tetra- and trimolecular complexes formed due to dimer-dimer and dimer-monomer interactions was detected in the myeloma serum. Analysis of the amyloidogenic light chains demonstrated mutations within the dimer interface, thus raising the possibility that these mutations are responsible for amyloidogenicity. Increased κ monomer and dimer levels, as well as a high κ/λ monomer ratio, were typically found in the cerebrospinal fluid from patients with multiple sclerosis (MS). In many MS cases, the elevation of κ FLCs was accompanied by an abnormally high proportion of λ dimers. This review focuses on the disease-related changes of the structure and level of dimeric FLCs, and raises the questions regarding their formation, function, and role in the pathogenesis and diagnosis of human diseases.

Impact of acute caffeine ingestion on endothelial function in subjects with and without coronary artery disease.

Although coffee is a widely used, pharmacologically active beverage, its impact on the cardiovascular system is controversial. To explore the effect of acute caffeine ingestion on brachial artery flow-mediated dilation (FMD) in subjects without coronary artery disease (CAD; controls) and patients with CAD, we prospectively assessed brachial artery FMD in 40 controls and 40 age- and gender-matched patients with documented stable CAD on 2 separate mornings 1 week to 2 weeks apart. After overnight fasting, discontinuation of all medications for ≥12 hours, and absence of caffeine for >48 hours, participants received capsules with caffeine 200 mg or placebo. One hour after drug ingestion, participants underwent brachial artery FMD and nitroglycerin-mediated dilation (NTG) using high-resolution ultrasound. As expected, patients with CAD were more often diabetic, hypertensive, obese, dyslipidemic, and smoked more than controls (p <0.01 for all comparisons). Aspirin, Clopidogrel, angiotensin-converting enzyme inhibitors, ß blockers, and statins were significantly more common in patients with CAD than in controls (p <0.01 for all comparisons). At baseline, FMD, but not NTG, was significantly lower in patients with CAD compared to controls. Acute caffeine ingestion significantly increased FMD (patients with CAD 5.6 ± 5.0% vs 14.6 ± 5.0%, controls 8.4 ± 2.9% vs 18.6 ± 6.8%, p <0.001 for all comparisons) but not NTG (patients with CAD 13.0 ± 5.2% vs 13.8 ± 6.1%, controls 12.9 ± 3.9% vs 13.9 ± 5.8%, p = NS for all comparisons) and significantly decreased high-sensitivity C-reactive protein (patients with CAD 2.6 ± 1.4 vs 1.4 ± 1.2 mg/L, controls 3.4 ± 3.0 vs 1.2 ± 1.0 mg/L, p <0.001 for all comparisons) in the 2 groups compared to placebo. In conclusion, acute caffeine ingestion significantly improved endothelial function assessed by brachial artery FMD in subjects with and without CAD and was associated with lower plasma markers of inflammation.

Is C-reactive protein level a marker of advanced motor and neuropsychiatric complications in Parkinson's disease?

C-reactive protein (CRP) is a plasma protein involved in inflammation. While its levels have been associated with stroke, cognitive impairment and depression, the association with clinical characteristics of Parkinson's disease (PD) is unknown. A total of 73 consecutive patients with PD (46 males, age 68.8 ± 11.5 years) were evaluated regarding motor as well as cognitive and psychiatric features of PD. Plasma CRP levels were determined and tests for associations with disease parameters were performed. The average level of CRP was 3.9 ± 4.1 µmol/L, and 45.2% of the patients (n = 33) had a level above 3.0 µmol/L. Patients in the high CRP group tended to be older (71.4 ± 9.2 vs. 66.7 ± 12.9 years; p = 0.08) and coronary artery disease (CAD) was more common (36 vs. 10%, p < 0.05) in the high CRP group, but no differences were found between the groups regarding gender, disease duration, levodopa dose, motor scores or most of the neuropsychiatric complications such as severity of depression, psychosis, dementia, cognitive decline or frontal lobe dysfunction. Reported depression (at present or in the past) was more common in the high CRP group (54.5 vs. 25%, p = 0.01). CRP levels in patients with PD are associated with a higher prevalence of CAD, but are not associated with PD duration or severity, or with neuropsychiatric complications other than reported depression.

URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews.

BACKGROUND: Hereditary renal hypouricemia may be complicated by nephrolithiasis or exercise-induced acute renal failure. Most patients described so far are of Japanese origin and carry the truncating mutation W258X in the uric acid transporter URAT1 encoded by SLC22A12. Recently, we described severe renal hypouricemia in Israeli patients with uric acid transporter GLUT9 (SLC2A9) loss-of-function mutations. Renal hypouricemia in Iraqi Jews has been previously reported, but its molecular basis has not been ascertained. METHODS: Three Jewish Israeli families of Iraqi origin with hereditary hypouricemia and hyperuricosuria were clinically characterized. DNA was extracted and the URAT1 gene was sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of URAT1 mutants found. RESULTS: A missense URAT1 mutation, R406C, was detected in all three families. Two affected siblings were found to carry in addition a homozygous missense URAT1 mutation, G444R. Both mutations dramatically impaired urate uptake into X. laevis oocytes. Moreover, we demonstrate for the first time that URAT1 facilitates urate efflux, which was abolished in the mutants, indicating also a secretion defect. Homozygous patients had serum uric acid concentrations of 0.5-0.8 mg% and a fractional excretion of uric acid of 50-85%. Most individuals studied were asymptomatic, two had nephrolithiasis and none developed exercise-induced acute renal failure. CONCLUSIONS: The URAT1 R406C mutation detected in all three families is likely to be the founder mutation in Iraqi Jews. Our findings contribute to a better definition of the different types of hereditary renal hypouricemia and suggest that the phenotype of this disorder depends mainly on the degree of inhibition of uric acid transport.