High-level intrathymic thyrotrophin receptor expression in thyroiditis-prone mice protects against the spontaneous generation of pathogenic thyrotrophin receptor autoantibodies.

The thyrotrophin receptor (TSHR) A-subunit is the autoantigen targeted by pathogenic autoantibodies that cause Graves' hyperthyroidism, a common autoimmune disease in humans. Previously, we reported that pathogenic TSHR antibodies develop spontaneously in thyroiditis-susceptible non-obese diabetic (NOD).H2h4 mice bearing a human TSHR A-subunit transgene, which is expressed at low levels in both the thyroid and thymus (Lo-expressor transgene). The present study tested recent evidence that high intrathymic TSHR expression protects against the development of pathogenic TSHR antibodies in humans. By successive back-crossing, we transferred to the NOD.H2h4 background a human TSHR A-subunit transgene expressed at high levels in the thyroid and thymus (Hi-expressor transgene). In the sixth back-cross generation (> 98% NOD.H2h4 genome), only transgenic offspring produced spontaneously immunoglobulin (Ig)G class non-pathogenic human TSHR A-subunit antibodies. In contrast, both transgenic and non-transgenic offspring developed antibodies to thyroglobulin and thyroid peroxidase. However, non-pathogenic human TSHR antibody levels in Hi-expressor offspring were lower than in Lo-expressor transgenic mice. Moreover, pathogenic TSHR antibodies, detected by inhibition of TSH binding to the TSHR, only developed in back-cross offspring bearing the Lo-expressor, but not the Hi-expressor, transgene. High versus low expression human TSHR A-subunit in the NOD.H2h4 thymus was not explained by the transgene locations, namely chromosome 2 (127-147 Mb; Hi-expressor) and chromosome 1 (22.9-39.3 Mb; low expressor). Nevertheless, using thyroiditis-prone NOD.H2h4 mice and two transgenic lines, our data support the association from human studies that low intrathymic TSHR expression is associated with susceptibility to developing pathogenic TSHR antibodies, while high intrathymic TSHR expression is protective.

Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A(k) NOD mice.

NOD.H2(k) and NOD.H2(h4) mice carry the major histocompatibility complex (MHC) class II molecule I-A(k) associated with susceptibility to experimentally induced thyroiditis. Dietary iodine-enhanced spontaneous thyroid autoimmunity, well known in NOD.H2(h4) mice, has not been investigated in NOD.H2(k) mice. We compared NOD.H2(h4) and NOD.H2(k) strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2(h4) compared with NOD.H2(k) mice on NaI, and TPOAb developed in NOD.H2(h4) mice but not in NOD.H2(k) mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2(k) mice, and particularly NOD.H2(h4) mice, have substantial non-MHC parental DNA. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7, and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 Tg haplotype, associated with experimentally induced thyroiditis, is absent in NOD.H2(h4) and NOD.H2(k) mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2(h4) and NOD.H2(k) mice in TgAb levels and, as in humans, autoantibody spreading to TPO.

Oncological outcomes of nephron sparing nephrectomy. 17-year analysis.

OBJECTIVES: Nephron sparing renal surgery is considered the technique of choice for renal tumors smaller than 4 cm. We present our oncological results in a 17-year period. METHODS: Between January 1995 and December 2012, 130 renal tumor surgeries (58 open, 72 laparoscopic) were performed. We analize the pathological results, presence of positive surgical margins, local relapse, distant metastases and death. RESULTS: The most frequent tumor was clear cell carcinoma (73%) in a pT1 stage (87%). Mean tumor size was 3 cm. Positive surgical margin rate was 7%, currently without any tumor recurrence among these cases (follow up 37 months). Cancer specific mortality is 0% and local recurrence rate 3%. Mean follow up is 71 months. CONCLUSIONS: Nephron sparing surgery results are similar to radical nephrectomy in tumors smaller than 4 cm. Positive surgical margins do not seem to have an important repercussion in cancer specific survival.

Late ascended testes: is non-orthotopic gubernacular insertion a confirmation of an alternative embryological etiology?

INTRODUCTION: Re-ascended testes account for a proportion of all undescended testes (UDTs); one main hypothesis relating to their etiology relates to a patent processus vaginalis peritonei. The aim was to investigate gubernacular insertion points in boys with late ascended testis as a possible guide to an alternative embryological etiology. PATIENTS AND METHODS: Patients with proven ascended testes were recruited from four different pediatric urology centers between May 2016 and September 2017. All patients were evaluated regarding their gubernacular insertion during orchidopexy. The presence of accompanying patent processus vaginalis and the association between the epididymis and testis were also documented. RESULTS: Seventy-seven children (mean age = 73.1 ± 41.2 months [range 18-176]) were enrolled into the study. A non-orthotopic gubernacular insertion point was found in 96.1% (n = 74); 34.2% (n = 26) of these were located in the groin and 63.2% (n = 48), high within the scrotum. Figure A. An open processus vaginalis peritonei was found in 35.1%. Twelve patients (15.6%) had small, dysplastic appearing testis with testis-epididymis dissociation. Boys with a higher insertion of the non-orthotopic gubernaculum (n = 48, groin) were operated earlier (mean age at surgery, 62.3 months) compared with those with a gubernacular insertion at a high scrotal site (mean age at surgery, 90.5 months; p = 0.004). Figure B. DISCUSSION: This study revealed that non-orthotopic gubernacular insertion is found in the vast majority of the ascending testis cases. Patent processus vaginalis was accompanying only 35.1% of all children and might be the cause of the ascending testis in this small subgroup of patients in line with the earlier reports [1]. In boys with ascending testes, in this population, the gubernaculum was very likely to insert non-orthotopically. In concordance with previous reports [2] and regarding the finding of a an earlier age at surgery in boys with higher inserting gubernacula, this could provide a logical explanation as to how these testes are initially palpable in the scrotum and then, during body growth are retracted to the groin. CONCLUSION: In 96.1% of the patients, a non-orthotopic gubernacular insertion was found. This points to embryologic etiology, complying well with earlier reports and further underlining the critical importance of timely diagnosis and treatment for this group of patients.

Resultados oncológicos de la cirugía conservadora de parénquima renal. Análisis de 17 años / Oncological outcomes of nephron sparing nephrectomy. 17-year analysis

OBJETIVO: La cirugía renal conservadora de parénquima se considera la técnica de elección en tumores renales menores de 4 cm. Presentamos nuestros resultados oncológicos de un periodo de 17 años. MÉTODOS: Entre enero de 1995 y diciembre de 2012 se han realizado 130 cirugías renales por tumor (58 abiertas, 72 laparoscópicas). Analizamos los resultados anatomopatológicos, la presencia de márgenes positivos, recidiva local, metástasis a distancia y exitus. RESULTADOS: El tumor más frecuente es el de células claras (73%) en un estadio pT1 (87%). El tamaño medio tumoral es de 3,4 cm. La tasa de márgenes positivos es de 7%, sin recidiva tumoral en estos casos en la actualidad (seguimiento de 37 meses). La mortalidad cáncer específica es del 0% y la tasa de recidiva local es del 3%. El seguimiento medio es de 71 meses. CONCLUSIONES: La cirugía conservadora de parénquima tiene resultados superponibles a la nefrectomía radical en tumores por debajo de 4 cm. Los márgenes positivos no parecen tener una repercusión importante en la supervivencia cáncer específica

OBJECTIVES: Nephron sparing renal surgery is considered the technique of choice for renal tumors smaller than 4 cm. We present our oncological results in a 17-year period. METHODS: Between January 1995 and December 2012, 130 renal tumor surgeries (58 open, 72 laparoscopic) were performed. We analize the pathological results, presence of positive surgical margins, local relapse, distant metastases and death. RESULTS: The most frequent tumor was clear cell carcinoma (73%) in a pT1 stage (87%). Mean tumor size was 3 cm. Positive surgical margin rate was 7%, currently without any tumor recurrence among these cases (follow up 37 months). Cancer specific mortality is 0% and local recurrence rate 3%. Mean follow up is 71 months. CONCLUSIONS: Nephron sparing surgery results are similar to radical nephrectomy in tumors smaller than 4 cm. Positive surgical margins do not seem to have an important repercussion in cancer specific survival