Asymptomatic bacteriuria in candidates for active treatment of renal stones: results from an international multicentric study on more than 2600 patients.

The occurrence of asymptomatic bacteriuria concomitant to urolithiasis is an issue for patients undergoing renal stone treatment. Disposing of a preoperative urine culture is essential to reduce the risk of septic events. The endpoint of the study is to report which characteristics of candidates for renal stone treatment are frequently associated with positive urine culture. 2605 patients were retrospectively enrolled from 14 centers; inclusion criteria were age > 18 and presence of a single renal stone 1-2 cm in size. The variables collected included age, gender, previous renal surgery, comorbidities, skin-to-stone distance, stone size, location, density, presence of hydronephrosis. After a descriptive analysis, the association between continuous and categorical variables and the presence of positive urine culture was assessed using a logistic regression model. Overall, 240/2605 patients (9%) had preoperative bacteriuria. Positive urine culture was more frequent in females, patients with previous renal interventions, chronic kidney disease, congenital anomalies, larger stones, increased density. Multivariate analysis demonstrated that previous renal interventions (OR 2.6; 95% CI 1.9-3.4; p < 0.001), renal-related comorbidities (OR 1.31; 95% CI 1.19-1.4; p < 0.001), higher stone size (OR 1.06; 95% CI 1.02-1.1; p = 0.01) and density (OR 1.00; 95% CI 1.0-1.00; p = 0.02) were associated with bacteriuria; male gender and lower caliceal location were inversely related to it. Beyond expected risk factors, such as female gender, other parameters are seemingly favoring the presence of positive urine culture. The awareness of variables associated with bacteriuria allows to assess which individuals are at increased risk of presenting bacteriuria and reduce the rate of septic complications.

Bone marrow failure may be caused by chromosome anomalies exerting effects on RUNX1T1 gene.

BACKGROUND: The majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80-85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease. RESULTS: We report two further patients with non-hereditary BM failure, with diagnosis of severe aplastic anaemia and pancytopenia caused by two different constitutional structural anomalies involving chromosome 8, and possibly leading to the disorder due to effects on the RUNX1T1 gene, which was hypo-expressed and hyper-expressed, respectively, in the two patients. The chromosome change was unbalanced in one patient, and balanced in the other one. CONCLUSIONS: We analyzed the sequence of events in the pathogenesis of the disease in the two patients, including a number of non-haematological signs present in the one with the unbalanced anomaly. We demonstrated that in these two patients the primary event causing BMFS/AA was the constitutional chromosome anomaly. If we take into account the cohort of 219 patients with a similar diagnosis in whom we made cytogenetic studies in the years 2003-2017, we conclude that cytogenetic investigations were instrumental to reach a diagnosis in 52 of them. We postulate that a chromosome change is the primary cause of BMFS/AA in a not negligible proportion of cases, as it was ascertained in 6 of these patients.

Development and Evaluation of Buccal Films Based on Chitosan for the Potential Treatment of Oral Candidiasis.

In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.

Percutaneous ultrasound-guided radiofrequency ablation of an allograft renal cell carcinoma: a case report.

BACKGROUND: Renal cell carcinomas (RCCs) are rarely described in transplanted kidneys. Available therapeutic strategies range from allograft nephrectomy to nephron-sparing procedures such as partial nephrectomy or image-guided thermal ablation. Percutaneous radiofrequency ablation (RFA) is a minimally invasive technique which provides promising oncologic outcomes in small allograft RCCs while preserving allograft function. So far, only a few cases have been reported in the transplant setting. We describe a renal transplant RCC successfully approached by ultrasound-guided RFA. METHODS: A 42-year-old renal transplant recipient developed a small subcapsular allograft RCC at 11 years after transplantation. The decline in glomerular filtration rare prompted us to preserve as much parenchyma as possible. Ultrasound-guided RFA was performed under light sedation and local analgesia in a single session with a Starbust Talon needle. RESULTS: Postablation contrast-enhanced ultrasound displayed a 25×23 mm avascular area of complete necrosis. After 3 months gadolinium-enhanced magnetic resonance imaging confirmed the absence of viable tumor tissue and while the patient did not experience any graft function reduction (serum creatinine 2.6 mg/dL). CONCLUSIONS: Image-guided RFA represents a promising therapeutic modality for small allograft RCCs in recipients with mild graft dysfunction and/or elevated surgical risk. It is associated with low morbidity and parenchymal preservation.

OTX1 expression in breast cancer is regulated by p53.

The p53 transcription factor has a critical role in cell stress response and in tumor suppression. Wild-type p53 protein is a growth modulator and its inactivation is a critical event in malignant transformation. It has been recently demonstrated that wild-type p53 has developmental and differentiation functions. Indeed an over-expression of p53 in tumor cells induces asymmetrical division avoiding self-renewal of cancer stem cells (CSCs) and instead promoting their differentiation. In this study, 28 human breast carcinomas have been analyzed for expression of wild-type p53 and of a pool of non-clustered homeobox genes. We demonstrated that orthodenticle homolog 1 gene (OTX1) is transcribed in breast cancer. We established that the p53 protein directly induces OTX1 expression by acting on its promoter. OTX1 has been described as a critical molecule for axon refinement in the developing cerebral cortex of mice, and its activity in breast cancer suggests a synergistic function with p53 in CSC differentiation. Wild-type p53 may regulate cellular differentiation by an alternative pathway controlling OTX1 signaling only in breast cancer cells and not in physiological conditions.

Benzene metabolites inhibit the release of proinflammatory mediators and cytokines from human basophils.

Benzene and its metabolites have been involved in the pathogenesis of chronic lung inflammation and allergic disorders such as bronchial asthma. However, the effects of these xenobiotics on human basophils, key cells in the development of respiratory allergy, have not been investigated. We examined the effects of hydroquinone (HQ) and benzoquinone (BQ), two important chemicals implicated in benzene toxicity, on the release of preformed (histamine) and de novo synthesized mediators (cysteinyl leukotriene C4, LTC4, and IL-4) from human basophils. Preincubation of basophils purified from normal donors with HQ (3-100 microM) inhibited up to 30% histamine release induced by anti-IgE and up to 55% of that induced by the Ca2+ ionophore A23187. HQ had no effect on histamine release induced by formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). Preincubation of basophils with BQ (3-100 microM) resulted in the concentration-dependent inhibition of histamine release (up to 70%) induced by anti-IgE, A23187 and f-Met-Leu-Phe. HQ completely suppressed the de novo synthesis of LTC4 from basophils challenged with anti-IgE or f-Met-Leu-Phe and the production of IL-4 in cells stimulated with anti-IgE. These results indicate that two major benzene metabolites, HQ and BQ, inhibit the release of proinflammatory mediators and Th2-promoting cytokines from basophils activated by different stimuli. These results suggest that benzene metabolites interfere with multiple intracellular signals involved in the activation of human basophils.

[Percutaneous nephrolithotomy (PCNL) in a 9-year-old patient with horseshoe kidney]. / Paziente di nove anni con rene a ferro di cavallo.

INTRODUCTION: The horseshoe kidney is the most frequent renal anomaly, with a prevalence of 0.25% and a male to female ratio of 3:1. Although the pathogenesis remains controversial, the consequences of the impaired urinary drainage are well known: up to two third of patients present with urinary stasis, infection and urolithiasis. Percutaneous nephrolithotomy (PCNL) is a successful procedure for urolithiasis in horseshoe kidneys. MATERIALS AND METHODS: A 9-year-old patient with a 4-cm stone associated with horseshoe kidney underwent Percutaneous nephrolithotomy (PCNL). During the procedure, a flexible uretheroscopy was performed in order to obtain a complete vision and an optimal management of the procedure. RESULTS: At the end of the procedure, the patient was stone-free. We reported no hemorrhagic complications, no pain and no infection. The patient was discharged after 48 hours. CONCLUSIONS: The procedure is safe and effective, as long as the surgeon pays attention to the recommendations below.

[Endourological management of ureteral stenosis and vesicoureteral reflux after renal transplantation].

INTRODUCTION AND OBJECTIVES. Ureteral stenosis and vesicocoureteral reflux after renal transplantation represent a key concern because of their incidence and the associated morbidity. Prompt diagnosis and minimally invasive treatment are mandatory in immunosuppressed patients with single kidney. The aim of this study is to evaluate the success rate of the endourological techniques in the management of such complications. MATERIALS AND METHODS. Between January 1996 and December 2006, 647 kidney transplants were performed. Urinary tract continuity was re-established by ureteroneocystostomy according to Gregoir-Lich technique. We observed 13 cases of ureteral stenosis (2%) and 11 cases of symptomatic vesicoureteric reflux (1.7%). The endourogical procedure was performed in 13 patients: 5 cases of II-III grade vesicoureteric reflux, 4 early ureteral stenosis and 4 late ureteral stenosis. Patients with vesicoureteric reflux underwent endoscopic injection of macroplastique in 4 cases and Durasphere in 1. Early ureteral stenoses were treated using balloon dilation in 2 cases, balloon dilation and laser endoureterotomy in 3, ureteral stent placement in the other. Recipients with late stenosis underwent laser incision and balloon dilation in 2 cases, balloon dilation in 1 and a laser incision only in the last case. Combined antegrade and retrograde endoscopic approach was performed in 7 patients, whereas retrograde access in 1. RESULTS. Endourologic treatment was successful in 9 cases (69.2%); 2 patients required open reconstructive surgery due to endourological technique failure (early ureteropelvic junction stricture, late ureterovesical anastomotic stricture). Vesicoureteric reflux was corrected in 3 patients (60%), 2 patients underwent uretero-ureterostomy for recurrent reflux. No technique-related morbidity was observed. With a mean follow- up of 81.6 months, 8 patients show normal renal function, 5 patients have returned to haemodialysis (4 for chronic rejection, 1 for carcinoma in the graft). CONCLUSIONS. Considering their low morbidity and the satisfactory success rate, we claim that endourological procedures should be considered the preferred treatment for ureteral stenosis and vesicoureteric reflux in selected patients.

Sister chromatid exchange and oxidative DNA damage in paving workers exposed to PAHs.

Paving workers are exposed during road paving to several polycyclic aromatic hydrocarbons (PAHs) contained in asphalt fumes. In this study early genotoxic and oxidative effects of exposure to bitumen fumes were evaluated in 19 paving workers and 22 controls. Environmental and biological monitoring of exposure was carried out, measuring, on personal air samples from exposed workers collected during three working days, the concentration of 14 PAHs and urinary OH-pyrene at the end of each of the three working days. Genotoxic effect was evaluated analysing sister chromatid exchange (SCE) frequency and direct-oxidative DNA damage by formamido-pyrimidine-glycosylase (Fpg)-modified comet assay on lymphocytes. Tail moment values from Fpg-enzyme treated cells (TMenz) and from untreated cells (TM) were used as parameters of direct and oxidative DNA damage, respectively. For each subject, the TMenz/TM ratio >2.0 was used to indicate the presence of oxidative damage. DNA damage was also evaluated analysing comet percentage. Personal air samples showed low level of total PAHs (2.843 microg m(-3)) with prevalence of 2-3 ring PAHs (2.693 microg m(-3)). Urinary OH-pyrene after work-shift of the three working days was significantly higher than that found at the beginning of the working week. SCE analysis did not show any difference between two groups while an oxidative DNA damage was found in 37% of exposed with respect to the absence in controls. Comet percentage was significantly higher (P = 0.000 ANOVA) in the exposed than in controls. The results demonstrate the high sensitivity of comet assay to assess early oxidative effects induced by exposure to bitumen fumes at low doses and confirm the suitability of urinary OH-pyrene as a biomarker of PAH exposure. In conclusion the study suggests the use of Fpg-modified comet test as a biomarker of early genotoxic effects and that of urinary OH-pyrene as a biomarker of PAH exposure to furnish indications in terms of characterization, prevention and management of risk in occupational exposure to mixtures of potentially carcinogenic substances.

[Study of genotoxic and oxidative effects induced by PAH exposure in paving workers]. / Studio degli effetti genotossici ed ossidativi indotti dall'esposizione ad IPA in lavoratori addetti alla pavimentazione stradale.

Paving workers are exposed during road paving to several PAHs contained in asphalt fumes. We aimed to evaluate early genotoxic and oxidative effects in 19 paving workers and 22 controls. We analysed sister chromatide exchange (SCE) frequency as marker of genotoxicity. Moreover we assessed oxidative DNA damage by Fpg-modified comet assay on lymphocytes calculating tail moment values from fpg-enzyme treated cells (TMenz) and from untreated cells (TM). For each subject the TMenz/TM ratio higher than 2.0 was used to indicate the presence of oxidative damage. We also evaluated DNA damage analysing comet percentage. SCE analysis didn't show any difference between exposed and control groups. We found oxidative DNA damage in 37% of exposed in respect to the absence in controls. Comet percentage was significantly higher in the exposed than in controls. The results demonstrate the high sensitivity of comet assay to assess early oxidative effects induced by exposure to PAH mixtures at low doses and suggest the use of this biomarker in the characterization, prevention and management of risk induced by occupational exposure to mixtures of potentially carcinogenic substances.

Association between a polymorphism affecting an AP1 binding site in the promoter of the TCIRG1 gene and bone mass in women.

The TCIRG1 gene encodes a component of the osteoclast vacuolar proton pump and previous work has shown that inactivating mutations of the TCIRG1 cause autosomal recessive osteopetrosis. In order to determine whether allelic variation in TCIRG1 contributes to the regulation of bone mineral density (BMD) in normal individuals, we studied the relationship between polymorphisms of TCIRG1 and BMD in a population-based cohort of 739 perimenopausal women. Five common polymorphisms were identified: two in the promoter, a conservative change within exon 4, one within intron 4 and one within intron 11. One of the promoter polymorphisms (G-1102A) lay within a consensus recognition site for the AP1 transcription factor. There was a significant association between the G-1102A genotype and BMD at the lumbar spine ( P = 0.01) and femoral neck ( P = 0.03). The association remained significant after correcting for age, weight, height, menopausal status/HRT use and smoking ( P = 0.008 for spine BMD and P = 0.03 for hip BMD), and homozygotes for the -1100 "G" allele had BMD values significantly higher than individuals who carried the -1100 "A" allele at both spine ( P = 0.007) and hip ( P = 0.047). Subgroup analysis showed that the association between G-1102A and BMD was restricted to premenopausal women who comprised 50.6% of the study group. None of the other polymorphisms or haplotypes were significantly associated with BMD in the study group as a whole or in any subgroup. Functional studies will need to be performed to determine the mechanisms that underlie this association, but we conclude that, in this relatively large population, allelic variation at the G-1102A site of TCIRG1 accounts for part of the heritable component of BMD in Scottish women, possibly by affecting peak bone mass.

The mutational spectrum of human malignant autosomal recessive osteopetrosis.

Human malignant infantile osteopetrosis (arOP; MIM 259700) is a genetically heterogeneous autosomal recessive disorder of bone metabolism, which, if untreated, has a fatal outcome. Our group, as well as others, have recently identified mutations in the ATP6i (TCIRG1) gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, are responsible for a subset of this condition. By sequencing the ATP6i gene in arOP patients from 44 unrelated families with a worldwide distribution we have now established that ATP6i mutations are responsible for approximately 50% of patients affected by this disease. The vast majority of these mutations (40 out of 42 alleles, including seven deletions, two insertions, 10 nonsense substitutions and 21 mutations in splice sites) are predicted to cause severe abnormalities in the protein product and are likely to represent null alleles. In addition, we have also analysed nine unrelated arOP patients from Costa Rica, where this disease is apparently much more frequent than elsewhere. All nine Costa Rican patients bore either or both of two missense mutations (G405R and R444L) in amino acid residues which are evolutionarily conserved from yeast to humans. The identification of ATP6i gene mutations in two families allowed us for the first time to perform prenatal diagnosis: both fetuses were predicted not to be affected and two healthy babies were born. This study contributes to the determination of genetic heterogeneity of arOP and allows further delineation of the other genetic defects causing this severe condition.

Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family.

Inhibitor of apoptosis protein (IAP)-like protein-1 (ILP-1) (also known as X-linked IAP [XIAP] and mammalian IAP homolog A [MIHA]) is a potent inhibitor of apoptosis and exerts its effects, at least in part, by the direct association with and inhibition of specific caspases. Here, we describe the molecular cloning and characterization of a human gene related to ILP-1, termed ILP-2. Despite high homology to ILP-1, ILP-2 is encoded by a distinct gene, which in normal tissues is expressed solely in testis. In contrast to ILP-1, overexpression of ILP-2 had no protective effect on apoptosis mediated by Fas (also known as CD95) or tumor necrosis factor. However, ILP-2 potently inhibited apoptosis induced by overexpression of Bax or by coexpression of caspase 9 with Apaf-1, and preincubation of cytosolic extracts with ILP-2 abrogated caspase activation in vitro. A processed form of caspase 9 could be coprecipitated with ILP-2 from cells, suggesting a physical interaction between ILP-2 and caspase 9. Thus, ILP-2 is a novel IAP family member with restricted specificity for caspase 9.

[Unusual case of inverted papilloma in a fibro-epithelial polyp of the ureter]. / Raro caso di papilloma invertito in polipo fibroepiteliale dell'uretere.

Inverted papilloma of the upper urinary tract is a rare lesion and the differential diagnosis with transitional cell carcinoma is really hard. A case of 49 year-old male with recurrent right flank pain is reported. Excretory urogram suggested a filling defect involving the right mid ureter and bilateral retrograde pyelogram that confirmed a solitary filling defect in the right mid-ureter, while selective urinary cytology was positive for transitional cell carcinoma G1. Conservative therapy was carried out and 2 years follow-up with several excretory urograms and ultrasound studies revealed no recurrence.

An atypical presentation of upper urothelial tumor.

In some cases of primary transitional cell carcinoma (TCC), there may be some uncertainty in clinical decision making. We present a case in which a pT1-N0 urothelial tumor was found in the renal pelvis after an open nephrectomy for urolithiasis. Because incomplete excision of the ureter can lead to recurrence of the TCC, we deemed it necessary to remove the residual ureter. Therefore, a combined endoscopic-transvescical laparoscopic ureterectomy was performed. The transabdominal approach was chosen for the procedure, because the patient had already undergone open nephrectomy with retroperitoneal access and was thus likely to have adhesions and inflammation in the region. For the endoscopic phase of surgery, a technique of ureteral intussusception was combined with transurethral resection. The choice of the endoscopic transurethral procedure was prompted by the fact that transurethral resection of the ureteral orifice and invagination ureterectomy has already been proposed as the first step of nephroureterectomy. The combined endoscopic laparoscopic procedure was not technically demanding; the ureterectomy took no longer than an open procedure. The surgery was uneventful, and the patient resumed normal activities the day after surgery. The broader issue of whether this technique should be adopted by the urological community at large as a routine practice requires longer follow-up outcome data.

One shot: a novel method to dilate the nephrostomy access for percutaneous lithotripsy.

BACKGROUND AND PURPOSE: The creation of the nephrostomy access is a fundamental step of percutaneous nephrolithotripsy (PCNL). Dilation of the track is usually achieved with multiple incremental flexible exchange dilators of the Amplatz type, metal telescoping dilators of the Alken type, or a balloon. Currently, balloon dilation is regarded as the most modern and safest system, though it has the disadvantage of relatively high cost. The aim of this study was to demonstrate that a procedure that we named "one shot," which consists of a single dilation of the track with a 25F or 30F Amplatz dilator, compares favorably in terms of efficacy, costs, and length with the other techniques of track dilation, without a significant increase in morbidity. PATIENTS AND METHODS: Seventy-eight consecutive patients who underwent PCNL for stone disease from June 1998 to July 1999 were considered and divided into three groups according to the type of tract dilation used: A (Alken telescoping dilators), B (balloon), or C (one shot). Radiologic exposure, blood loss, and costs were evaluated. RESULTS: The one-shot procedure compared favorably with both of the other dilation techniques without an increase in morbidity and with significant reductions in X-ray exposure and costs. Indeed, significant differences in estimated blood loss were observed between groups B and C and the minor bleeding for group C. CONCLUSION: Our experience indicates that one-shot dilation is feasible in the majority of patients. It is as safe and effective as the technique regarded today as the gold standard but less time consuming and less expensive. These encouraging results should be confirmed by further studies.

Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.

Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction. Although molecular defects have been described for many animal models of osteopetrosis, the gene responsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is unknown. Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life. Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis, suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts. Some of the mouse mutants have a decreased number of osteoclasts, which suggests that the defect directly interferes with osteoclast differentiation. In other mutants, it is the function of the osteoclast that seems to be affected, as they show normal or elevated numbers of non-functioning osteoclasts. Here we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans.

Liposome-delivered angiostatin strongly inhibits tumor growth and metastatization in a transgenic model of spontaneous breast cancer.

The possibility to inhibit tumor growth by interfering with the formation of new vessels, which most neoplasias depend on, has recently raised considerable interest. An angiogenic switch, in which proliferating cells acquire the ability to direct new vessel formation, is thought to be an early step in the natural history of solid tumors. Using a transgenic model of breast cancer, which shows many similarities to its human counterpart, including ability to metastasize, we targeted angiostatin production to an early stage of tumor formation. Liposome-delivered angiostatin considerably delayed primary tumor growth and, more importantly, inhibited the appearance of lung metastases. These findings can be relevant to the design of therapeutic intervention in humans.

Identification and genomic organization of a gene coding for a new member of the cell adhesion molecule family mapping to Xq25.

The gene coding for a new member of the Immunoglobulin (Ig)-like domain-containing molecule superfamily has been identified and mapped to the human Xq25 chromosomal band. It contains 12 Ig-like domains in two clusters of 5 and 7 motifs, respectively, separated by a linker segment, followed by a transmembrane and a cytoplasmic region. The gene is conserved in mammals and is expressed in muscle, heart, brain, testis, and pancreas with transcripts of different length, suggesting that it is subjected to alternative processing. The transcript is assembled from 19 exons which are distributed along approx. 20kb; each Ig-like domain is contained in distinct exons which constitute the unit of repeated genomic duplications. Elucidation of the IGDC1 genomic structure will allow the investigation of the basis of its alternative transcription and of its possible involvement in diseases mapped to the Xq25 interval.

Partial V(D)J recombination activity leads to Omenn syndrome.

Genomic rearrangement of the antigen receptor loci is initiated by the two lymphoid-specific proteins Rag-1 and Rag-2. Null mutations in either of the two proteins abrogate initiation of V(D)J recombination and cause severe combined immunodeficiency with complete absence of mature B and T lymphocytes. We report here that patients with Omenn syndrome, a severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T cells, hypereosinophilia, and high IgE levels, bear missense mutations in either the Rag-1 or Rag-2 genes that result in partial activity of the two proteins. Two of the amino acid substitutions map within the Rag-1 homeodomain and decrease DNA binding activity, while three others lower the efficiency of Rag-1/Rag-2 interaction. These findings provide evidence to indicate that the immunodeficiency manifested in patients with Omenn syndrome arises from mutations that decrease the efficiency of V(D)J recombination.