MR Brain Screening in ADPKD Patients : To Screen or not to Screen?

BACKGROUND: Adult polycystic kidney disease (ADPKD) still represents a major cause of renal failure and intracranial aneurisms (IA) have a higher prevalence in ADPKD than in the general population. Current guidelines suggest performing brain MRI only in the subjects with a positive familiar history of IAs or subarachnoid hemorrhage (SAH). This is a retrospective case-control analysis to evaluate the usefulness of a MR screening program in ADPKD patients. METHODS: We retrospectively analyzed all ADPKD patients followed in our outpatient clinic between 2016 and 2019 who underwent a brain MRI screening. We evaluated the presence of IAs and others brain abnormalities and compared our results with a non-ADPKD population (n = 300). We performed univariate and multivariate regression analysis to evaluate if general and demographic features, laboratory findings, clinical parameters and genetic test results correlated with IAs or other brain abnormalities presence. RESULTS: Among the patients evaluated 17 out of 156 (13.6%) ADPKD patients had IAs, compared to 16 out of 300 (5.3%) non-ADPKD controls (p < 0.005). Considering ADPKD patients presenting IAs, 12 (70.6%) had no family history for IAs or SAH. Genetic analysis was available for 97 patients: in the sub-population with IAs, 13 (76.5%) presented a PKD1 mutation and none a PKD2 mutation. We found that arachnoid cysts (AC) (p < 0.001) and arterial anatomical variants (p < 0.04) were significantly more frequent in ADPKD patients. CONCLUSION: In our population ADPKD patients showed a higher prevalence of IAs, AC and arterial variants compared to non-ADPKD. Most of the IAs were found in patients presenting a PKD1 mutation. We found a significant number of alterations even in those patients without a family history of IAs or SAH. The practice of submitting only patients with familial IAs or kidney transplantation candidates to MRI scan should be re-evaluated.

Intracranial Arterial Tortuosity in Marfan Syndrome and Loeys-Dietz Syndrome: Tortuosity Index Evaluation Is Useful in the Differential Diagnosis.

BACKGROUND AND PURPOSE: The association of arterial tortuosity and connective tissue diseases is widely reported in the literature, but only a few studies were based on a quantitative evaluation of this arterial phenotype, and none of the latter examined the intracranial vasculature. The aim of this study was to evaluate the degree of intracranial arterial tortuosity in patients with Marfan syndrome and those with Loeys-Dietz syndrome, and to assess its usefulness in the differential diagnosis. MATERIALS AND METHODS: We performed a retrospective analysis of 68 patients with genetically confirmed Marfan syndrome (n = 36) or Loeys-Dietz syndrome (n = 32), who underwent at least 1 MRA of the brain at our institution. Fifty-two controls were randomly selected among patients who presented with headache and without any known comorbidity. Tortuosity indexes of 4 intracranial arterial segments were measured on a 3D volume-rendered angiogram by using the following formula: [Formula: see text]. RESULTS: Both Marfan syndrome and Loeys-Dietz syndrome showed a significantly higher tortuosity index compared with controls in all examined vessels. The tortuosity index of the vertebrobasilar system showed an excellent interrater reliability (intraclass correlation coefficient, 0.99) and was the strongest independent predictor of Loeys-Dietz syndrome in patients with connective tissue disease (P = .002), with a 97% specificity for this pathology when its value was > 60. CONCLUSIONS: The tortuosity index of intracranial arteries is an easily calculated and highly reproducible measure, which shows a high specificity for Marfan syndrome and Loeys-Dietz syndrome and may be useful in differentiating these 2 entities.

A new MEFV gene mutation in an Iranian patient with familial Mediterranean fever.

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.

Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis.

Usher syndrome is an autosomal recessive disorder characterized by retinitis pigmentosa, sensorineural hearing loss and, in some cases, vestibular dysfunction. The disorder is clinically and genetically heterogeneous and, to date, mutations in 11 genes have been described. This finding makes difficult to get a precise molecular diagnosis and offer patients accurate genetic counselling. To overcome this problem and to increase our knowledge of the molecular basis of Usher syndrome, we designed a targeted resequencing custom panel. In a first validation step a series of 16 Italian patients with known molecular diagnosis were analysed and 31 out of 32 alleles were detected (97% of accuracy). After this step, 31 patients without a molecular diagnosis were enrolled in the study. Three out of them with an uncertain Usher diagnosis were excluded. One causative allele was detected in 24 out 28 patients (86%) while the presence of both causative alleles characterized 19 patients out 28 (68%). Sixteen novel and 27 known alleles were found in the following genes: USH2A (50%), MYO7A (7%), CDH23 (11%), PCDH15 (7%) and USH1G (2%). Overall, on the 44 patients the protocol was able to characterize 74 alleles out of 88 (84%). These results suggest that our panel is an effective approach for the genetic diagnosis of Usher syndrome leading to: 1) an accurate molecular diagnosis, 2) better genetic counselling, 3) more precise molecular epidemiology data fundamental for future interventional plans.

9q31.1q31.3 deletion in two patients with similar clinical features: a newly recognized microdeletion syndrome?

Interstitial deletions of the long arm of chromosome 9 are rare and most patients have been detected by conventional cytogenetic techniques. Disparities in size and localization are large and no consistent region of overlap has been delineated. We report two similar de novo deletions of 6.3 Mb involving the 9q31.1q31.3 region, identified in two monozygotic twins and one unrelated patient through array-CGH analysis. By cloning the deletion breakpoints, we could show that these deletions are not mediated by segmental duplications. The patients displayed a distinct clinical phenotype characterized by mild intellectual disability, short stature with high body mass index, thick hair, arched eyebrows, flat profile with broad chin and mild prognathism, broad, and slightly overhanging tip of the nose, short neck with cervical gibbus. The twin patients developed a metabolic syndrome (type 2 diabetes, hypercholesterolemia, vascular hypertension) during the third decade of life. Although long-term follow-up and collection of additional patients will be needed to obtain a better definition of the phenotype, our findings characterize a previously undescribed syndromic disorder associated with haploinsufficiency of the chromosome 9q31.1q31.3 region.

[Clinical and genetic analysis of idiopathic intellectual disability based on array comparative genomic hybridization].

In this study authors searched for chromosomal aberrations in 71 children with developmental delay or idiopathic mental retardation using Human Genome CGH Microarray Kits 4×44K and 8×60K (Agilent Technologies, USA). Microdeletions and microduplications, as well as CNV, which may be related to intellectual disability and associated with regions of known hereditary diseases or chromosomal syndromes were identified in 14 (20%) children (these patients are described in this article). During the analysis, candidate genes localized within the regions of aberrations and associated with development and functioning of nervous system were denoted.

Fulminant digital necrosis in a patient with prostate adenocarcinoma

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Nefrectomia e interferon alfa como tratamiento del carcinoma renal metastasico / Nephrectomy and interferon alpha for treatment of metastatic renal carcinoma

Introduccion: El carcinoma renal metastasico (CRM) esta asociado con un mal pronostico. Recientes avances en la inmunoterapia han despertado el interes en su aplicacion para el carcinoma reanl, demostrando un aumento de la sobrevida cuando es administrada luego de la nefrectomia en pacientes portadores de CRM. Objetivos: Evaluar la eficacia y la toxicidad del interferon alpha (IFNa) en pacientes con CRM nefrectomizados previamente. Material y métodos: Se evaluo en forma retrospectiva la evolucion de doce pacientes consecutivos, con nefrectomia previa, a los cuales se les administro IFNa en forma trisemanal subcutanea. Los pacientes fueron atendidos en el "Hospital Carlos G. Durand" e iniciaron tratamiento entre julio de 2002 y julio de 2004. El seguimiento se realizo mediante evaluacion clinica y humoral mensual y estudios diagnosticos complementarios para valorar las respuestas. Resultados: Seis pacientes fueron sometidos a nefrectomia citorreductiva seguida de IFNa. Seis pacientes nefrectomizados inicialmente, recibieron IFNa ante la recaida. Los doce pacientes presentaron un performande status de 0-2 inicial. Nueve de ellos resultaron evaluables para respuesta. En el 77,7 por ciento (n7) no se observo progresion de la enfermedad. Las respuestas fueron: completa, 11,1 por ciento (n1), parcial, 22,2 por ciento (n2), enfermedad estable, 44,4 por ciento (n4) y progresion de la enfermedad 22,2 por ciento (n2). La toxicidad asociada con el INFa consistio en: cefaleas G2, nauseas G2, hipotermia G1 y artralgias G1 en todos los pacientes. Solo un paciente requirio internacion por presentar vomitos G3. En todos los casos la toxicidad fue reversible. Conclusion: La nefrectomia (inical o citorreductiva) seguida de la administracion de IFNa amplia la indicacion de la cirugia en pacientes portadores de CRM, y se vislumbra como una estrategia terapeutica factible, eficaz con una toxicidad bien tolerada y aceptable control de los sintomas

Nefrectomia e interferon alfa como tratamiento del carcinoma renal metastasico / Nephrectomy and interferon alpha for treatment of metastatic renal carcinoma

Introduccion: El carcinoma renal metastasico (CRM) esta asociado con un mal pronostico. Recientes avances en la inmunoterapia han despertado el interes en su aplicacion para el carcinoma reanl, demostrando un aumento de la sobrevida cuando es administrada luego de la nefrectomia en pacientes portadores de CRM. Objetivos: Evaluar la eficacia y la toxicidad del interferon alpha (IFNa) en pacientes con CRM nefrectomizados previamente. Material y métodos: Se evaluo en forma retrospectiva la evolucion de doce pacientes consecutivos, con nefrectomia previa, a los cuales se les administro IFNa en forma trisemanal subcutanea. Los pacientes fueron atendidos en el "Hospital Carlos G. Durand" e iniciaron tratamiento entre julio de 2002 y julio de 2004. El seguimiento se realizo mediante evaluacion clinica y humoral mensual y estudios diagnosticos complementarios para valorar las respuestas. Resultados: Seis pacientes fueron sometidos a nefrectomia citorreductiva seguida de IFNa. Seis pacientes nefrectomizados inicialmente, recibieron IFNa ante la recaida. Los doce pacientes presentaron un performande status de 0-2 inicial. Nueve de ellos resultaron evaluables para respuesta. En el 77,7 por ciento (n7) no se observo progresion de la enfermedad. Las respuestas fueron: completa, 11,1 por ciento (n1), parcial, 22,2 por ciento (n2), enfermedad estable, 44,4 por ciento (n4) y progresion de la enfermedad 22,2 por ciento (n2). La toxicidad asociada con el INFa consistio en: cefaleas G2, nauseas G2, hipotermia G1 y artralgias G1 en todos los pacientes. Solo un paciente requirio internacion por presentar vomitos G3. En todos los casos la toxicidad fue reversible. Conclusion: La nefrectomia (inical o citorreductiva) seguida de la administracion de IFNa amplia la indicacion de la cirugia en pacientes portadores de CRM, y se vislumbra como una estrategia terapeutica factible, eficaz con una toxicidad bien tolerada y aceptable control de los sintomas(AU)

Heat shock protein 27 inhibits apoptosis in human neutrophils.

BACKGROUND: Prolonged neutrophil(PMN) survival has been implicated in tissue injury following sepsis. A variety of bacterial products have been identified which inhibit PMN apoptosis including lipopolysaccharide(LPS). Extracellular heat shock proteins(Hsp) have recently been identified as potent regulatory signals for the innate immune system during the inflammatory response. We hypothesized that Hsp 27 can affect PMN phenotype with respect to apoptosis and cytokine profile. MATERIALS AND METHODS: PMN were isolated from the peripheral blood of healthy human volunteers by red blood cell sedimentation and gradient centrifugation. Cells were placed in media and cultured for 18 h with and without recombinant human Hsp 27 at various concentrations. In parallel experiments, PMN were stimulated with LPS, a known inhibitor of PMN apoptosis, for comparison. Apoptosis was quantified using annexin V and propidium iodide staining with flow cytometric analysis. Culture supernatants were assayed for secretion of TNF-alpha, IL-10, and IL-12. RESULTS: Hsp 27 significantly inhibits PMN apoptosis [control; 81.8 +/- 3.6%, vs Hsp 27, 60.4 +/- 4.1% p < 0.05]. The reduction is similar to that signaled by LPS, alone. Together their effect is not synergistic. The Hsp 27 response is dose-dependent. Hsp 27 does not induce secretion of TNF-alpha, IL-10, or IL-12, whereas LPS does signal IL-12 and TNF-alpha secretion. CONCLUSION: These data demonstrate that exogenous Hsp 27 may play a role in neutrophil-mediated tissue injury during trauma and sepsis via its ability to inhibit neutrophil apoptosis. However, Hsp 27 does not significantly alter neutrophil phenotype with respect to cytokine production profile.

Loss of chemokine SDF-1alpha-mediated CXCR4 signalling and receptor internalization in human hepatoma cell line HepG2.

Expression of the chemokine stromal cell-derived factor-1alpha (SDF-1alpha) is absent from many carcinomas, including hepatomas. We note an early signalling defect in the hepatocellular carcinoma (HCC) cell line HepG2 that expresses the CXCR4 receptor and binds biotin-labelled SDF, but fails to stimulate downstream signalling events after engagement with SDF. In HepG2, the SDF/CXCR4 interaction did not result in calcium influx, phosphorylation and internalization of CXCR4, nor in a rapid phosphorylation of p44/42 MAP kinase. There were no CXCR4 mutations in the second chemokine binding loop or C terminal phosphorylation and internalization domains. The downstream signalling machinery in HepG2 appears to be intact since transfection of wild-type CXCR4 restored functional responsiveness. We conclude that HepG2 is unresponsive to SDF stimulation because of a defect located after receptor binding but before the activation of the signalling cascade. A hypothetical blocking molecule could hinder receptor internalization or CXCR4 signalling.