Angiotensin II increases parathyroid hormone-related protein (PTHrP) and the type 1 PTH/PTHrP receptor in the kidney

Angiotensin II (AngII) participates in the pathogenesis of kidney damage. Parathyroid hormone (PTH)-related protein (PTHrP), a vasodilator and mitogenic agent, is upregulated during renal injury. The aim of this study was to investigate the potential relation between AngII and PTHrP system in the kidney. Different methods were used to find that both rat mesangial and mouse tubuloepithelial cells express PTHrP and the type 1 PTH/PTHrP receptor (PTH1R). In these cells, AngII increased PTHrP mRNA and protein production. In contrast, PTH1R mRNA was increased in mesangial cells and downregulated in tubular cells, but its protein levels were unmodified in both cells. AT(1) antagonist, but not AT(2), abolished AngII effects on PTHrP/PTH1R. The in vivo effect of AngII was further investigated by systemic infusion (a low dose of 50 ng/kg per min) into normal rats. In controls, PTHrP immunostaining was mainly detected in renal tubules. In AngII-infused rats, PTHrP staining increased in renal tubules and appeared in the glomerulus and the renal vessels. After AngII infusion, PTHR1 staining was markedly increased in all these renal structures at day 3 but remained elevated only in tubules at day 7. The AT(1) antagonist, but not the AT(2), significantly diminished AngII-induced PTHrP and PTHR1 overexpression in the renal tissue, associated with a decrease in tubular damage and fibrosis. The results indicate that AngII regulates renal PTHrP/PTH1R system via AT(1) receptors. These findings demonstrate that PTHrP upregulation occurs in association with the mechanisms of AngII-induced kidney injury.     

Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.     

Insulin-like growth factor I administration in young rats with acute renal failure

The outcome of ischemic acute renal failure (IARF) is better in young than adult rats. Insulin-like growth factor I (IGF-I) treatment may increase mortality of adult rats with IARF, probably because of an exaggerated inflammatory response. We report the response to IGF-I therapy in young rats with IARF. Male rats, aged 28+/-1 days, with IARF were given subcutaneous IGF-I, 50 microg/100 g at 0, 8, and 16 h after reperfusion (IGF) or were untreated (ARF). Sham-operated rats were used as controls. At 2 and 7 days after ischemia, serum urea nitrogen and histological damage score, cell proliferation, apoptosis, neutrophil infiltration, and IGF-I receptor mRNA in kidneys were analyzed. The degree of renal failure, mortality rate, histological damage, cell proliferation, and neutrophil infiltration were not different between IGF-I and ARF rats. Hence, short-term IGF-I treatment did not modify the course of IARF in young rats.     

Avoiding Axillary Treatment in Sentinel Lymph Node Micrometastases of Breast Cancer: A Prospective Analysis of Axillary or Distant Recurrence

Background

The need for axillary lymph node dissection (ALND) in breast cancer patients with sentinel lymph node (SLN) micrometastases remains controversial. The aims of the study were to evaluate the locoregional failure and outcome of breast cancer patients with sentinel node micrometastases who did not undergo completion ALND.

Methods

Between November 2000 and December 2006, SLN biopsy was successfully performed in 1178 patients with invasive breast carcinoma. Only patients with macrometastasis (>2 mm) underwent ALND, while patients with negative SLN or micrometastases did not undergo further treatment of the axilla, by either surgery or radiotherapy. Regarding adjuvant therapy decision, patients with SLN-micrometastases (pN1_mi) were considered as node-positive patients.

Results

Of 1,178 patients, 59 (5%) had micrometastases. Of those with micrometastases, 14 (24%) underwent ALND because the intraoperative study of the SLN yielded a positive result. With a median follow-up of 60 (range, 8–94) months, none of the patients with SLN micrometastases in whom ALND was omitted developed an axillary recurrence, while one patient in whom ALND was performed developed infraclavicular lymph node recurrence. One patient, who declined postoperative breast irradiation, developed breast recurrence and distant metastasis.

Conclusions

Breast cancer patients with SLN micrometastases in whom ALND was omitted had a very low locoregional failure rate. This study supports the theory that ALND might be avoided in these patients, providing that adjuvant systemic treatment equal to treatment provided to treat node-positive disease is administered. However, longer follow-up and results of additional prospective studies are needed.     

Partial Portal Vein Ligation Plus Thioacetamide: A Method to Obtain a New Model of Cirrhosis and Chronic Portal Hypertension in the Rat

To obtain a new model of chronic portal hypertension in the rat, two classical methods to produce portal hypertension, partial portal vein ligation and the oral administration of thioacetamide (TAA), have been combined. Male Wistar rats were divided into four groups: 1 (control; n?=?10), 2 [triple partial portal vein ligation (TPVL); n?=?9], 3 (TAA; n?=?11), and 4 (TPVL plus TAA; n?=?9). After 3 months, portal pressure, types of portosystemic collateral circulation, laboratory hepatic function tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase) and liver histology were studied. The animals belonging to group 2 (TPVL) developed extrahepatic portosystemic collateral circulation, associated with mesenteric venous vasculopathy without hepatic destructurization or portal hypertension. Animals from group 3 (TAA) developed cirrhosis and portal hypertension but not extrahepatic portosystemic collateral circulation, or mesenteric venous vasculopathy. Finally, the animals from group 4 (TPVL?+?TAA) developed cirrhosis, portal hypertension, portosystemic collateral circulation, and mesenteric venous vasculopathy. The association of TPVL and TAA can be used to obtain a model of chronic portal hypertension in the rat that includes all the alterations that patients with hepatic cirrhosis usually have. This could, therefore, prove to be a useful tool to study the pathophysiological mechanisms involved in these alterations.     

Severe hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with fluoxetine: case report

Hyponatremia is a significant complication of treatment with serotonin selective reuptake inhibitors (SSRI). We describe a case of a 53-year-old woman that was started on fluoxetine 20 mg/day for depression. Nine days later, the patient started with weakness, nausea, progressing to confusion, inappetence and vomit. Three hours later she became unresponsive and had a generalized seizure. She was brought to our emergency service. On admission, the patient was normovolemic, without focal motor deficits, but had mild generalized muscle rigidity and Babinski's sign bilaterally. Serum sodium was 105 mmol/L, serum osmolality, 220 mmol/L, and urinary osmolality, 400 mmol/L. The other laboratory exams, chest X-ray, cerebrospinal fluid and cranium tomography were normal. She was found to have fluoxetine-induced SIADH and it was discontinued. We started the hyponatremia correction and, in 5 days, the mental status of the patient gradually returned to a normal baseline, paralleling the resolution of her hyponatremia, without recurrence. Hyponatremia and SIADH should be considered if a patient experiences deterioration in his or her clinical condition while taking SSRI. The use of SSRI antidepressants should be remembered in the differential diagnosis of drug-induced hyponatremia.     

KCNQ1 gene variants and risk of new-onset diabetes in tacrolimus-treated renal-transplanted patients

Recent genome-wide association studies identified single-nucleotide polymorphisms (SNPs) in the gene encoding the pore-forming subunit of the voltage-gated K+ channel (KCNQ1) as a risk factor for type 2 diabetes. Tacrolimus (Tac) increased the risk of new-onset diabetes after transplantation (NODAT). The aim of this study was to analyze the association between KCNQ1 variants and the risk for NODAT in kidney-transplanted patients who received Tac as primary immunosuppressor. We genotyped three common KCNQ1 SNPs in 145 Spanish patients who received a cadaveric kidney graft and developed NODAT in the first-year post-transplant (the NODAT group), and 260 patients who remained non-diabetics (non-NODAT). In addition, we searched for DNA variants in the whole KCNQ1 coding exons in these patients. SNP rs2237895 (genotype CC) was associated with an increased risk for NODAT in our population (p = 0.008; OR = 1.83, 95% CI = 1.14-2.93), independently of other risk factors as body mass index, recipient age, or tacrolimus dosage. Other KCNQ1 variants were not associated with NODAT in our patients. Our work supported a role for KCNQ1 gene variants as determinants of the risk of developing NODAT among Tac-treated patients.     

Early steroid withdrawal in pediatric renal transplant: five years of follow-up

This prospective, comparative trial investigated the impact on mean change in height standard deviation score (SDS), acute rejection rate, and renal function of early steroid withdrawal in 96 recipients with 5 years of follow-up. Recipients under basiliximab induction and steroid withdrawal (SW: TAC/MMF; n = 55) were compared with a matched steroid control group (SC: TAC/MMF/STEROID, n = 41). SW received steroids until Day 6, SC decreased to 10 mg/m(2) within 2 months post-transplant. Five years after SW, the longitudinal growth (SDS) gain was 1.4 ± 0.4 vs. 1.1 ± 0.3 for SC group (p < 0.02). Height benefits in prepubertal and pubertal status in both groups were demonstrated in the delta growth trends (mixed model; p < 0.01). Biopsy-proven acute rejection in SW was 11% and 17.5%, SC (p: ns). Mean eGFR (ml/min/1.73 m(2)) at 5 years post-transplant was SW 80.6 ± 27.8 vs. 82.6 ± 25.1 for SC (p: ns). The death-censored graft survival rate at 1 and 5 years was 99 and 90% for SW; 98 and 96% for SC (p = ns). PTLD incidence in SW 3.3 vs. 2.5% in SC (p: ns). Five years post-transplant, early steroid withdrawal showed positive impacts on growth, stable renal function without increased acute rejection risk, and PTLD incidence.