IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23.

End-stage renal disease (ESRD) is a major public health problem, affecting 1 in 1,000 individuals and with an annual death rate of 20% despite dialysis treatment. IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of ESRD worldwide; it affects up to 1.3% of the population and its pathogenesis is unknown. Kidneys of people with IgAN show deposits of IgA-containing immune complexes with proliferation of the glomerular mesangium (Fig. 1). Typical clinical features include onset before age 40 with haematuria and proteinuria (blood and protein in the urine), and episodes of gross haematuria following mucosal infections are common; 30% of patients develop progressive renal failure. Although not generally considered a hereditary disease, striking ethnic variation in prevalence and familial clustering, along with subclinical renal abnormalities among relatives of IgAN cases, have suggested a heretofore undefined genetic component. By genome-wide analysis of linkage in 30 multiplex IgAN kindreds, we demonstrate linkage of IgAN to 6q22-23 under a dominant model of transmission with incomplete penetrance, with a lod score of 5.6 and 60% of kindreds linked. These findings for the first time indicate the existence of a locus with large effect on development of IgAN and identify the chromosomal location of this disease gene.

Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium.

The autosomal dominant, giant-platelet disorders, May-Hegglin anomaly (MHA; MIM 155100), Fechtner syndrome (FTNS; MIM 153640) and Sebastian syndrome (SBS), share the triad of thrombocytopenia, large platelets and characteristic leukocyte inclusions ('Döhle-like' bodies). MHA and SBS can be differentiated by subtle ultrastructural leukocyte inclusion features, whereas FTNS is distinguished by the additional Alport-like clinical features of sensorineural deafness, cataracts and nephritis. The similarities between these platelet disorders and our recent refinement of the MHA (ref. 6) and FTNS (ref. 7) disease loci to an overlapping region of 480 kb on chromosome 22 suggested that all three disorders are allelic. Among the identified candidate genes is the gene encoding nonmuscle myosin heavy chain 9 (MYH9; refs 8-10), which is expressed in platelets and upregulated during granulocyte differentiation. We identified six MYH9 mutations (one nonsense and five missense) in seven unrelated probands from MHA, SBS and FTNS families. On the basis of molecular modelling, the two mutations affecting the myosin head were predicted to impose electrostatic and conformational changes, whereas the truncating mutation deleted the unique carboxy-terminal tailpiece. The remaining missense mutations, all affecting highly conserved coiled-coil domain positions, imparted destabilizing electrostatic and polar changes. Thus, our results suggest that mutations in MYH9 result in three megakaryocyte/platelet/leukocyte syndromes and are important in the pathogenesis of sensorineural deafness, cataracts and nephritis.

Endovascular repair of aortic rupture due to Brucella aortitis.

Brucellosis is a zoonosis, caused by bacteria belonging to the genus Brucella. Aortic involvement is a rare complication, often following embolization from infective endocarditis. However, contiguous propagation from vertebral involvement may occur. We report the case of an 81 year old patient abruptly presenting with aortic rupture due to Brucella melitensis infection. The diagnosis of aortic rupture was made by CT. The patient underwent urgent endovascular treatment using endoprosthesis deployment in the abdominal aorta and iliac arteries. Long term antibiotic treatment was given. Resolution of the acute event was obtained without further surgical treatment. 18 months after endovascular treatment, the patient remains in good health.

A novel frame-shift deletion causing analbuminaemia in an Italian paediatric patient.

BACKGROUND: Analbuminaemia (OMIM #103600) is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. The trait is caused by a variety of mutations within the albumin gene. DESIGN: We report here the clinical and molecular characterization of a new case of congenital analbuminaemia in a 4-year-old Italian girl diagnosed on the basis of the low level of circulating albumin (= 10.0 g L(-1)). The albumin gene was screened by single-strand conformation polymorphism and heteroduplex analysis and the mutated region submitted to DNA sequencing. RESULTS: The proband was found to be homozygous, and both parents heterozygous, for a novel deletion in exon 8 (c.920delT). The subsequent frame-shift should have given rise to a putative polypeptide chain of 304 amino acid residues, which we could not identify in the proband's serum. CONCLUSIONS: A novel analbuminaemia causing mutation was identified and characterized at the clinical level in a child. The molecular diagnosis of the trait is based on the rapid localization of the mutation within the albumin gene by single-strand conformation polymorphism and heteroduplex analysis, followed by DNA sequencing of the mutated region.

Bypass surgery for the treatment of upper limb chronic ischaemia.

OBJECTIVES: This study aims to evaluate the results and complications of surgical arterial revascularisation of the upper limb for treatment of chronic ischaemia using infrabrachial bypass. Results of limb salvage and follow-up with graft patency are analysed. DESIGN: This study is a retrospective analysis of 23 patients affected by chronic upper limb ischaemia and treated by surgical bypass. MATERIALS AND METHODS: We retrospectively analysed 23 patients with upper limb ischaemia treated between January 1998 and January 2008, by means of bypass graft revascularisation. After surgical revascularisation, eight patients (35%) with digital gangrene underwent minor amputations during the same surgical session, or within the following few days. Postoperatively, patients were followed up at regular intervals of 1, 3 and 6 months, and every 6 months thereafter, both clinically and with a duplex ultrasound scan. RESULTS: The mean 34 months' follow-up was 96% complete. Life table analysis revealed a primary patency of 82.6% and secondary patency of 91.3%. Limb salvage was 100%. During the follow-up period, four patients sustained graft occlusion and, of these, two underwent re-do revascularisation with success. CONCLUSIONS: We believe upper limb bypass surgery represents a valid treatment in this clinical setting, both for limb salvage and for relief of symptoms.

Water disinfection by orifice-induced hydrodynamic cavitation.

Hydrodynamic Cavitation (HC) is considered as a promising water-disinfection technique. Due to the enormous complexity of the physical and chemical processes at play, research on HC reactors is usually carried out following an empirical approach. Surprisingly, past experimental studies have never been designed on dimensional-analysis principles, which makes it difficult to identify the key processes controlling the problem, isolate their effects and scale up the results from laboratory to full-scale scenarios. The present paper overcomes this issue and applies the principles of dimensional analysis to identify the major non-dimensional parameters controlling disinfection efficacy in classical HC reactors, namely orifice plates. On the basis of this analysis, it presents results from a new set of experiments, which were designed to isolate mainly the effects of the so-called cavitation number (σv). Experimental data confirm that the disinfection efficacy of orifice plates increases with decreasing σv. Finally, in order to discuss the significance of the results presented herein and frame the scope of future research, the present paper provides an overview of the drawbacks associated with dimensional analysis within the context of HC.

[The role of laparoscopic surgery in the treatment of occlusive and abdominal aortic aneurys. Review of the literature]. / Il ruolo della chirurgia laparoscopica nella patologia aneurismatica e occlusiva dell'aorta addominale. Revisione della letteratura.

UNLABELLED: The objective of this systematic review of the literature is to evaluate whether a laparoscopic operation can be performed on patients with occlusive or abdominal aortic aneurysm as a minimally invasive and durable alternative. For this purpose, the literature was reviewed and laparoscopic surgery results were compared with those of conventional and endovascular surgery. All series were included, even when containing also one case. Operative and clamping times, mortality and morbidity and hospital stay were evaluated. Thirty-five studies were identified about conventional (4), minilaparotomy (4), endovascular (4), total (12) and video-assisted (11) laparoscopic surgery. Operative and clamping times were shorter for video-assisted procedures than total-laparoscopic procedures. The mortality rate ranged from 3% to 4.5% for conventional surgery, from 0% to 3% for endovascular surgery, from 0% to 6% for total-laparoscopic surgery and from 0% to 4.2% for video-assisted laparoscopic surgery. A variable morbidity was described for all techniques, with a higher incidence in total-laparoscopic surgery. Mean hospital stay was similar for laparoscopic surgery procedures. The learning curve of a surgical team performing laparoscopic surgery improves the RESULTS: Laparoscopic abdominal aortic surgery is feasible and may offer good postoperative recovery with excellent mid-term patency. Shorter hospital stay and simple mid-term follow-up allow more comfort for the patient and probably monetary savings for the community. A steep learning curve is needed. For these reasons laparoscopic video-assisted technique can be considered a third means of treating severe occlusive and aortic aneurysm, but only new instruments for performing aortoprosthetic anastomoses can diffuse the total laparoscopic technique as a routine approach.

Surgical treatment of tumors involving the inferior vena cava. Personal experience.

AIM: Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor that frequently produces non-specific symptoms. Surgical treatment is complex. In this review of our experience, we highlight replacement modalities of the vena cava or other vessels after complete tumor resection. METHODS: During the last 20 years, we treated 12 patients (6 women and 6 men; age range, 38-72 years) with IVC leiomyosarcoma, all apparently free of distant metastases. Tumor location, graft patency, long-term survival and tumor recurrence were recorded. The tumor arose from the IVC in 8 patients; in 2 cases the intracaval mass reached the right atrium; in 4 patients the tumor arose from the femoroiliac axis. Surgical approach was by sternolaparotomy in 5 cases and by median xyphopubic access in 7. Extracorporeal circulation (ECC) was needed in 2 cases. All tumors were removed by en bloc resection. The IVC was directly sutured in 2 patients and patched in 4; no reconstruction was necessary in 2 patients; the IVC was replaced in the remaining cases. Four patients had an additional arteriovenous fistula. One patient underwent bifurcated Dacron graft replacement of the aortic carrefour involved by tumor. RESULTS: Two patients died postoperatively. One patient developed late stenosis of the polytetrafluoroethylene (PTFE) graft, which was treated by stenting. The mean follow-up period was 35 months. The 4-year survival rate was 51% and survival free of recurrence was 63%. CONCLUSION: Leiomyosarcoma of the IVC is an uncommon tumor that produces non-specific symptoms. In the absence of distant malignancy, an aggressive approach can obtain late survival free of recurrence.

Endovascular repair in atypical traumatic rupture of thoracic aorta.

INTRODUCTION: The traumatic rupture of thoracic aorta is a surgical emergency with high risk of morbidity and mortality. CASE REPORT: We describe the case of an atypical rupture of retro-cardiac thoracic aorta with dissection of brachiocephalic trunk and spleen trauma occurred after a road accident. TC scan and perioperative angiography showed an atypical rupture of thoracic aorta. CONCLUSION: A combined treatment, endovascular for retro-cardiac thoracic aorta and surgical for brachiocephalic artery, has been useful to diminish the hemodynamic and organ ischemic problems associated with open surgery.

[The chronic renal failure epidemic: an underestimated public health problem]. / L'epidemia d'insufficienza renale cronica. Un sottovalutato problema sanitario di prima grandezza.

Renal failure is considered a rare disease. However, recent epidemiological surveys like the NHANES III survey in the USA have shown that mild and moderate renal insufficiency is much more common: 31% and 4% of Americans, respectively, are affected by a mild or moderate degree of renal insufficiency. Such an epidemic is of particular concern because of the high cardiovascular risk brought about by kidney failure. Renal insufficiency is now considered a public health priority. Together with diabetes and smoking, the metabolic syndrome is the principal factor responsible for this epidemic. The prevalence of chronic renal insufficiency is in fact strictly proportional to the number of components of the metabolic syndrome being present in individual patients. As renal function deteriorates, other risk factors come into play like those peculiar to renal insufficiency (anemia, hyperparathyroidism) and some so-called emerging risk factors (inflammation, hyperhomocysteinemia and high plasma levels of endogenous inhibitors of NO synthase such as asymmetric dimethylarginine).

Podocin-related mechanisms in posttransplant [corrected] recurrence of focal segmental glomerulosclerosis [corrected].

Posttransplantation recurrence of focal segmental glomerulosclerosis (FSGS) is one of the most disarming events in human pathology with important social and psychological consequences. It usually occurs in 30% to 50% of patients affected by the primary form of the disease with an abrupt onset in the majority of cases occurring within 1 month of the transplantation. Prediction of recurrent cases and early therapy with plasmapheresis are the main goals of the therapy. Although the mechanism of posttransplantation recurrence is still obscure, it has been proposed to be of a multifactorial origin, in which plasma factors determine the shedding of proteins of the slit-diaphragm, such as nephrin and podocin, with structural alterations of the ultra-filtering unit of the glomerulus. Low resynthesis of podocin and/or haplo-insufficiency due to heterozygous mutations should represent significant predisposing factors to proteinuria. In this review, the role of podocin in posttransplantation recurrence will be evaluated focusing on the possibility that resynthesis of the protein could represent a key step also for stable normalization of the renal filter. The recent characterization of the podocin promoter cis- and trans- acting elements and the possibility to characterize low- and high-podocin producer haplotypes offer opportunities to evaluate the capacity for podocin resynthesis in the donor kidney. A review of the literature on posttransplantation recurrence of FSGS in patients originally carrying homozygous and/or heterozygous NPHS2 mutations supports the general idea of a multifactorial origin of the primary disease that can be extended to the pathogenesis of posttransplantation recurrence.

Localisation of the gene responsible for fechtner syndrome in a region <600 Kb on 22q11-q13.

Fechtner syndrome is an autosomal dominant disorder which has been thought to be a variant of Alport syndrome. It is characterised by nephritis, sensorineural hearing loss and eye abnormalities, as well as by macrothrombocytopenia and polymorphonuclear inclusion bodies. Recently, the Fechtner syndrome has been mapped in a 5.5 Mb region on the long arm of chromosome 22 by linkage analysis in an extended Israeli family. We describe here the genetic refinement of the Fechtner critical interval to a region less than 600 Kb by linkage analysis performed in a large Italian pedigree. The presence of several recombination events allowed the disease gene to be localised between markers D22S278 and D22S426, in a region containing only two non-recombinant markers, D22S1173 and D22S283. This interval, spanning <600 Kb on genomic DNA, has been entirely sequenced and contains six known and three putative genes.

Prognostic significance of estrogen receptor determination in primary breast cancer.

The authors report on 767 consecutive primary Stage I-II breast cancer cases followed-up from 3 to 8 years. The estrogen receptor (ER) content was determined in all cases and did not influence the treatment choice. A correlation was attempted between ER and menstrual or pathological nodal status (N) or the 5-year disease-free survival (DFS). ER was correlated with menopausal status ER+ cases being more frequent in postmenopausal patients, whereas no correlation was observed between ER and nodal status. In absence of nodal involvement (N-) the prognosis was not influenced by the ER status. A significantly better DFS was evident for ER+ respect to ER- patients in the N+ series but such a correlation is questionable as the adjuvant treatment (hormone or chemotherapy) given to such patients may have influenced the DFS according to the ER status. According to the present study, ER determination should not be used as a discriminant in the performance of adjuvant postoperative treatment based on a prognostic judgment.

Improved strategy for molecular genetic diagnostics in juvenile nephronophthisis.

Juvenile or type 1 nephronophthisis (NPH1), an autosomal recessive cystic kidney disease, represents the most common genetic cause of end-stage renal disease in the first two decades of life. Because the disease is caused by large homozygous deletions of the NPHP1 gene in approximately 66% of patients with nephronophthisis, molecular genetic testing offers a method for the definite diagnosis of NPH1 and avoids the invasive procedure of renal biopsy. We recently developed an algorithm for molecular genetic diagnosis of NPH1 that efficiently detects homozygous deletions. However, a major limitation remained for the detection of heterozygous deletions that cause NPH1 in combination with point mutations at the other NPHP1 allele. Because a partial sequence from the NPHP1 region recently became available through the Human Genome Projects, we exploited this information to develop novel polymorphic markers from this genetic region for the detection of heterozygous deletions of NPHP1, thus bridging the diagnostic gap. Five novel polymorphic microsatellites positioned within the large common NPHP1 deletion were generated. Two multiplex polymerase chain reaction sets using two and three polymorphic markers from the NPHP1 deletion region together with one positive control marker allowed four different diagnostic problems to be solved in one diagnostic setup: (1) detection of the classic homozygous deletion of NPH1, (2) detection of a rare smaller homozygous deletion of NPH1, (3) testing for a heterozygous deletion, and (4) potential exclusion of linkage to NPHP1. The newly generated multiplex marker sets will greatly enhance the efficacy of molecular diagnostics in NPH through improved detection of heterozygous deletions.

Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus.

Tapeto-retinal degeneration is frequent in patients with nephronophthisis. Association of the most severe forms of tapeto-retinal dystrophy with NPH identifies a syndrome described first by Senior et al and Loken et al. This syndrome is distinct on molecular grounds from pure renal nephronophthisis (NPH1), which has its gene locus mapped on chromosome 2q13. We describe three families with large homozygous deletion of the NPH1 locus in which mild to moderate ocular lesions due to tapeto-retinal degeneration coexisted and were correlated to renal defects. This new association of NPH1 with retinal dystrophy is characterized by focal lesions of retina and is pauci-symptomatic in clinical presentation. For this reason it may remain unrecognized in most NPH1 patients.

Clinical and molecular heterogeneity of juvenile nephronophthisis in Italy: insights from molecular screening.

Autosomal recessive nephronophthisis (NPH) is a renal disorder histologically characterized by tubulointerstitial lesions that are, in some cases, associated with extrarenal manifestations such as tapeto-retinal degeneration or liver fibrosis. The disease is usually pauci-symptomatic in an early phase but invariably evolves to end-stage renal failure in childhood or early adulthood. The recent discovery of the NPHP1 gene (nephrocystin) has prompted research into putative genotype-phenotype correlations. We screened a population of 68 Italian children (10 multiplex families, 47 sporadic cases) with a clinical and histopathologic picture of NPH and found a large homozygous deletion at 2q13 involving nephrocystin in 30 cases, and heterozygous deletion associated with new point mutations at exons 15 (Tyr518Ter) and 17 (Arg585Ter) of the gene in two other cases. The remaining 36 children had no apparent molecular defects of nephrocystin. In spite of this genetic heterogeneity, the two groups, with and without detectable molecular defects of nephrocystin, showed similar renal defects and comparable cumulative survival considering the start of dialysis as an end-point. The unique difference observed was a less frequent requirement of dialysis in NPH1 patients with pure renal form. Finally, tapeto-retinal degeneration was associated with renal lesions in seven cases presenting deletion of the nephrocystin gene and in five sporadic cases without molecular defects. These data show that a molecular defect of nephrocystin is involved in approximately 50% of patients with NPH, and another 50% require further molecular characterization. Research therefore should now be aimed at characterizing a new locus. In spite of the molecular heterogeneity, NPH in children presents similar renal and extrarenal manifestations, thus suggesting the involvement of common pathological routes.

N-(4-hydroxyphenyl) retinamide inhibits cystogenesis by polycystic epithelial cell lines in vitro.

Primary tubular epithelial cells develop spherical monolayered cysts when cultured in collagenI matrix, a model that has been used to study the mechanism of cystogenesis. In an attempt to block cystogenesis, we have evaluated the effect of N-(4-hydroxyphenyl) retinamide (HPR), a synthetic derivative of retinoic acid, on both formation and growth of cysts in a human model of polycystic kidney cells. Number, dimension and submicroscopical characteristics of cysts were evaluated after 2 and 4 weeks from treatment with HPR. A marked inhibitory effect of HPR on cystogenesis was found at concentration of 1 microM, while a complete block was observed at concentration between 5 and 10 microM. Furthermore, treatment with HPR of already formed cysts resulted in their disruption. HPR at 10 microM also induced apoptosis of several tubular epithelial cell models suggesting a correlation between the two phenomena. Taken together these observations demonstrate that HPR blocks cystogenesis by polycystic kidney cells "in vitro" and that it also reverts the fate of already formed cysts. Apoptosis may be the mechanism which mediates the inhibitory effect on cystogenesis in this model.