Specific mutations in the HEXA gene among Iraqi Jewish Tay-Sachs disease carriers: dating of founder ancestor

The incidence of Tay-Sachs disease (TSD) carriers, as defined by enzyme assay, is 1:29 among Ashkenazi Jews and 1:110 among Moroccan Jews. An elevated carrier frequency of 1:140 was also observed in the Iraqi Jews (IJ), while in other Israeli populations the worlds pan-ethnic frequency of approximately 1:280 has been found. Recently a novel mutation, G⁷⁴⁹T, has been reported in 38.7% of the IJ carriers (24/62). Here we report a second novel HEXA mutation specific to the IJ TDS carriers: a substitution of cytosine 1351 by guanosine (C¹³⁵¹G), resulting in the change of leucine to valine in position 451. This mutation was found in 33.9% (21/62) of the carriers and in none of 100 non-carrier IJ. In addition to the two specific mutations, 14.5% (9/62) of the IJ carriers bear a known Jewish mutation (Ashkenazi or Moroccan) and 11.3% (7/62) carry a known non-Jewish mutation. In 1 DNA sample no mutation has yet been detected. To investigate the genetic history of the IJ-specific mutations (C¹³⁵¹G and G⁷⁴⁹T), the allelic distribution of four polymorphic markers (D15S131, D15S1025, D15S981, D15S1050) was analyzed in IJ heterozygotes and ethnically matched controls. Based on linkage disequilibrium, recombination factor () between the markers and mutated loci, and the population growth correction, we deduced that G⁷⁴⁹T occurred in a founder ancestor 44.8±14.2 generations (g) ago [95% confidence interval (CI) 17.0–72.6 g] and C¹³⁵¹G arose 80.4±35.9 g ago (95% CI 44.5–116.3 g). Thus, the estimated dates for introduction of mutations are: 626±426 A.D. (200–1052 A.D.) for G⁷⁴⁹T and 442±1077 B.C. (1519 B.C. to 635 A.D.) for C¹³⁵¹G.     

N-methyl-2-pyridone-5-carboxamide: a novel uremic toxin?

BACKGROUND: N-methyl-2-pyridone-5-carboxamide (2PY) is one of the end products of nicotinamide-adenine dinucleotide (NAD) degradation. We recently found that serum 2PY concentrations in chronic renal failure (CRF) patients were enhanced to the values, which are potentially toxic. The aim of this study was to determine whether 2PY is an inhibitor of poly(ADP-ribose) polymerase, the nuclear enzyme that is highly involved in variety of physiologic events, including regulation of DNA replication and DNA repair. METHODS: High-performance liquid chromatography (HPLC) was used to determine 2PY and other NAD catabolite concentrations in serum of: nondialyzed patients; patients chronically hemodialyzed; patients after kidney transplantation; and healthy individuals (control group). Moreover, the effect of nicotinamide and 2PY on poly(ADP-ribose) polymerase (PARP-1) in vitro was studied. RESULTS: The serum nicotinamide, 2PY, and 4PY (N-methyl-4-pyridone-3-carboxamide) concentrations are many times elevated in nondialyzed CRF patients when compared with controls. The direct correlations were found between serum 2PY (as well as 4PY and nicotinamide) concentrations and serum creatinine concentration, and negative correlations between serum concentrations of these compounds and creatinine clearance. The concentration of 2PY decreases considerably after hemodialysis (HD) session, but elevates back 48 hours later. It permanently declines after kidney transplantation. Nicotinamide and 2PY significantly inhibit PARP-1 activity in vitro. CONCLUSIONS: Increased serum 2PY concentration, along with a deterioration of kidney function and its toxic properties (significant inhibition of PARP-1 by 2PY), suggest that it could be a novel uremic toxin.     

Pigmented villonodular synovitis of the temporomandibular joint: a report of two cases

Pigmented villonodular synovitis is a benign but locally destructive disease that originates in the synovial membranes of the joints. It is a proliferative disorder of unknown etiology, and it is usually monarthric. Approximately 80% of cases involve the knee; the hip, ankle, foot, hand, elbow, and shoulder account for most other cases. Pigmented villonodular synovitis in the temporomandibular joint is rare. When it does occur, its features include preauricular swelling, trismus, and symptoms of temporomandibular joint dysfunction. It can be diagnosed by a combination of the history, clinical examination, characteristic radiologic findings, and fine-needle aspiration or biopsy results. Wide local excision, including the involved bone, and a total synovectomy are advocated because the lesion can recur if it is not adequately excised. We report two new cases of pigmented villonodular synovitis of the temporomandibular joint, and we review the literature on this subject.     

New biomarkers of occupational exposure to polycyclic aromatic hydrocarbons

Polycyclic aromatic hydrocarbons (PAH) are metabolized in a complex manner. Although biological activity is associated with diol-epoxide formation, phenolic metabolites have predominantly been used in human biomonitoring. In this study monohydroxylated and new metabolites were characterized as biomarkers for occupational PAH exposure. In 97 male workers, personal exposure to 16 airborne PAH compounds was measured during shift. In postshift urine, 1-hydroxypyrene and 1,6- and 1,8-dihydroxypyrene (1-OHP, DiOHP) were determined as metabolites of pyrene (P), and the sum of 1-, 2-, 3-, 4-, and 9-hydroxyphenanthrenes (OHPHE), and PHE-dihydrodiols (PHED) as metabolites of phenanthrene (PHE). The referent group comprised 21 nonsmoking construction workers. Median (interquartile range) shift concentrations of airborne P and PHE were 1.46 (0.62-4.05 microg/m(3)) and 10.9 (3.69-23.77 microg/m(3)), respectively. The corresponding parameters were 3.86 (2.08-7.44) microg/g creatinine (crn) for 1-OHP, 0.66 (0.17-1.65) microg/g crn for DiOHP, 11.44 (5.21-34.76) microg/g crn for OHPHE, and 12.28 (3.3-97.76) microg/g crn for PHED in PAH-exposed workers. The median levels of 1-OHP and OHPHE were 0.09 (0.08-0.17 microg/m(3)) and 0.59 (0.45-1.39 microg/m(3)), respectively, in the referents. PHE correlated significantly with OHPHE and PHED, and P with 1-OHP but not with DiOHP. Under a doubling of PHE, OHPHE increased by a factor of 1.56 and PHED by 1.57. With a doubling of P, 1-OHP rose by 1.31 and DiOHP by 1.27. P is predominantly metabolized into 1-OHP, whereas PHE is metabolized equally into OHPHE and PHED. Thus metabolites of PHE were found as reliable biomarkers for PAH exposure.     

Short-term effects of angiotensin II receptor blockade in patients with primary glomerulonephritis: pilot study.

OBJECTIVE: There is evidence that angiotensin II, the main effector of renin-angiotensin system, plays a crucial role in the pathogenesis of chronic renal injury. Angiotensin II type 1 (AT-1) receptor blockers reduce renin-angiotensin system activity by blocking the receptor, the activation of which is responsible for the majority of deleterious angiotensin II effects. The aim of the present study was to investigate renal and metabolic effects of specific AT-1 receptor blocker-losartan in patients with primary glomerulonephritis. DESIGN: Pilot clinical study. SETTING: Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland. PARTICIPANTS: Fifteen patients aged 43.3 +/- 11.3 years with primary glomerulonephritis confirmed by renal biopsy were studied. INTERVENTION: Creatinine clearance, urinary excretion of protein and uric acid, urinary activity of N-acetyl-beta-D-glucosaminidase, and serum concentrations of lipids, protein, and uric acid were evaluated before and after 3 months of losartan (Cozaar; Merck Sharp & Dohme, Harlow, Essex, United Kingdom) treatment at a dose of 25 mg daily. RESULTS: We found a significant reduction of urinary excretion of protein (P <.008; average, 32%). Results also revealed a decrease of serum uric acid level (P <.01), probably as a consequence of elevated uric acid urinary excretion (P <.09). No significant changes in creatinine clearance, N-acetyl-beta-D-glucosaminidase activity, protein, or lipid levels were observed. CONCLUSION: We concluded that losartan treatment at a small dose of 25 mg daily produces antiproteinuric effect without adverse effects, notably with no decrease of glomerular filtration, and simultaneously induces beneficial changes in purine metabolism.     

Recombinant Human Erythropoietin Treatment of Chronic Renal Failure Patients Normalizes Altered Phenotype and Proliferation of CD4‐positive T Lymphocytes

Patients with chronic renal failure (CRF) receive recombinant human erythropoietin (rhEPO) for the correction of anemia. However, rhEPO also has an immunomodulatory effect. Detailed changes of phenotype and function of CD4⁺ T lymphocytes in CRF patients receiving rhEPO have not been reported yet; their study may bring insight into understanding of this immunomodulatory action of rhEPO. Two groups of CRF patients were included into the study: those treated; and those not receiving rhEPO. The expression of activation markers on CD4⁺ lymphocytes was measured with flow cytometry, both ex vivo and in vitro. The kinetics of CD4⁺ T lymphocytes proliferation was calculated using a dividing cells tracing method and numerical approach. Significantly higher percentages of CD4⁺CD95⁺, CD4⁺HLA‐DR⁺ cells, and lower percentages of CD4⁺CD69⁺ and CD4⁺CD28⁺ cells were observed in both rhEPO‐treated and untreated patients when compared with healthy controls. Changes in the proportions of CD4⁺CD28⁺ and CD4⁺HLA‐DR⁺ subpopulations were dependent on the type of rhEPO, being more pronounced for rhEPOβ. CD4⁺ lymphocytes from untreated patients exhibited decreased expression of CD28 and CD69 after stimulation in vitro, whereas the expression of these antigens on lymphocytes of rhEPO‐treated patients was similar to that observed in healthy controls. Fewer CD4⁺CD28⁺ T lymphocytes of untreated patients proliferated in vitro; these cells had longer G0→G1 time, which negatively correlated with surface expression of CD28. Our study confirms that rhEPO treatment normalizes activation parameters of CD4⁺ T lymphocytes and their proliferative capacity, which could explain earlier described immunomodulatory effects of rhEPO in patients suffering from CRF.