The anabolic actions of growth hormone and thyroxine on protein metabolism in Snell dwarf and normal mice

The individual effects of GH and thyroxine (T4) on protein metabolism were determined in dwarf and normal mice in vivo. The hormone deficiencies of dwarf mice (low serum concentrations of GH and T4) resulted in decreased protein synthesis rates in skeletal muscle and liver, but no difference in synthesis rates in heart. The efficiency of synthesis (g protein/g RNA per day; KRNA) was lower in all three tissues in dwarf compared with normal mice, but effects on RNA concentration were not consistent; there was no change in muscle, a decrease in liver and an increase in heart. Treatment of dwarf mice for 9 days with either human GH or T4 caused increases in body weight and length. Protein synthesis rates were increased in muscle, liver and heart by either hormone, though much more so with T4 than GH. In muscle and liver both GH and T4 treatment resulted in an increased RNA concentration, but T4 treatment also increased KRNA. In heart, both GH and T4 increased KRNA with no change in RNA concentration. GH caused no significant changes in protein degradation rates so that growth rates were increased. T4 increased degradation rates so that there was no increased net growth in muscle or liver; in heart, T4 did induce increased growth despite the large increase in degradation rate. Tibial length was increased by both hormones; GH treatment of dwarf mice also increased cartilage sulphate incorporation on day 9, but T4 treatment did not, suggesting that bone growth is transient with T4 treatment. Normal mice showed no changes in growth or tissue protein metabolism in response to GH, but following T4 treatment there was increased protein turnover due to higher tissue RNA concentrations, although only heart growth was increased. Thus normal mice showed almost no net response to GH or T4, but dwarf mice showed a large response to both hormones. The response was different, however, in that GH caused concomitant increases in growth rates whereas T4 altered body tissue proportions.     

Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy

Radiocontrast-induced nephropathy (RCIN) is a common cause of hospital-acquired acute renal failure and is associated with a high mortality rate. RCIN is potentially preventable, because administration of the radiocontrast agent is predictable, and a high-risk population has been identified. This multicenter, prospective, randomized, double-blind, placebo-controlled trial was performed to evaluate the efficacy of intravenous atrial natriuretic peptide (anaritide, ANP 4-28) to prevent RCIN. Patients with stable chronic renal failure (serum creatinine greater than 1.8 mg/dL or serum creatinine between 1.5 and 1.8 mg/dL with estimated creatinine clearance of < or = 65 mL/min) were assigned to receive either placebo or one of three doses of anaritide (0.01 microg/kg/min, 0.05 microg/kg/min, or 0.1 microg/kg/min) for 30 minutes before and continuing for 30 minutes after radiocontrast administration. All patients were given intravenous 0.45% saline for 12 hours before the radiocontrast procedure and continuing for 12 hours after the last dose of radiocontrast. Both ionic and nonionic radiocontrast agents were administered. RCIN was defined as either an absolute increase of serum creatinine of > or = 0.5 mg/dL or a percent increase of > or = 25% over baseline. Of the 247 patients who completed the study, 50% had diabetes mellitus. There were no statistical differences in baseline serum creatinine, change in serum creatinine, or the incidence of RCIN. The incidence of RCIN was placebo, 19%; anaritide (0.01), 23%; anaritide (0.05), 23%; anaritide (0.1), 25%. Patients with diabetes mellitus had a significantly greater incidence of RCIN: placebo, 26% versus 9%; anaritide (0.01), 33% versus 13%; anaritide (0.05), 26% versus 21%; anaritide (0.1), 39% versus 8% (diabetic v nondiabetic, P < 0.002). There was no effect in the diabetic or nondiabetic groups by anaritide on the incidence of RCIN. Comparison of the highest-risk group of patients, defined as patients with diabetes mellitus and a baseline serum creatinine > or = 1.8 mg/dL, with the lowest-risk group, defined as patients without diabetes mellitus and a baseline serum creatinine of 1.8 mg/dL or less, did not show a beneficial effect of anaritide administration. In conclusion, administration of intravenous anaritide before and during a radiocontrast study did not reduce the incidence of RCIN in patients with preexisting chronic renal failure, with or without diabetes mellitus.     

Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring

Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.     

Individual Differences in Women’s Rape Avoidance Behaviors

Rape can exact severe psychological, physical, and reproductive costs on women, and likely was a recurrent adaptive problem over human evolutionary history. Therefore, women may have evolved psychological mechanisms that motivate rape avoidance behaviors. Guided heuristically by an evolutionary perspective, we tested the hypothesis that women’s rape avoidance behaviors would vary with several individual difference variables. Specifically, we predicted that rape avoidance behaviors would covary positively with (1) women’s attractiveness, (2) women’s involvement in a committed romantic relationship, and (3) the number of family members living nearby. We also predicted that women’s rape avoidance behaviors would covary negatively with age. We administered the Rape Avoidance Inventory (McKibbin et al., Pers Indiv Differ 39:336–340, 2009) and a demographic survey to a sample of women (n = 144). The results of correlational and regression analyses were consistent with the predictions, with the exception that women’s rape avoidance behaviors did not covary with women’s age. Discussion highlighted limitations of the current research and directions for future research on women’s rape avoidance psychology and behaviors.     

Loss of Fibroblast Growth Factor Receptor 2 (FGFR2) Leads to Defective Bladder Urothelial Regeneration after Cyclophosphamide Injury

Cyclophosphamide may cause hemorrhagic cystitis and eventually bladder urothelial cancer. Genetic determinants for poor outcomes are unknown. We assessed actions of fibroblast growth factor receptor (FGFR) 2 in urothelium after cyclophosphamide exposure. Conditional urothelial deletion of Fgfr2 (Fgfr2KO) did not affect injury severity or proliferation of keratin 14⁺ (KRT14⁺) basal progenitors or other urothelial cells 1 day after cyclophosphamide exposure. Three days after cyclophosphamide exposure, Fgfr2KO urothelium had defective regeneration, fewer cells, larger basal cell bodies and nuclei, paradoxical increases in proliferation markers, and excessive replication stress versus controls. Fgfr2KO mice had evidence of pathologic basal cell endoreplication associated with absent phosphorylated ERK staining and decreased p53 expression versus controls. Mice with conditional deletion of Fgfr2 in urothelium enriched for KRT14⁺ cells reproduced Fgfr2KO abnormalities after cyclophosphamide exposure. Fgfr2KO urothelium had defects up to 6 months after injury versus controls, including larger basal cells and nuclei, more persistent basal and ectopic lumenal KRT14⁺ cells, and signs of metaplasia (attenuated E-cadherin staining). Mice missing one allele of Fgfr2 also had (less severe) regeneration defects and basal cell endoreplication 3 days after cyclophosphamide exposure versus controls. Thus, reduced FGFR2/ERK signaling apparently leads to abnormal urothelial repair after cyclophosphamide exposure from pathologic basal cell endoreplication. Patients with genetic variants in FGFR2 or its ligands may have increased risks of hemorrhagic cystitis or urothelial cancer from persistent and ectopic KRT14⁺ cells.

Cyclophosphamide, an alkylating agent used to treat solid tumors, leukemias, lymphomas, and nononcologic diseases such as systemic lupus erythematosus or nephrotic syndrome, is highly toxic to the blader.¹ The bladder toxicity effects arise from the metabolite acrolein, which concentrates in the urine and directly contacts the lumenal superficial cells. Even with current therapies, such as mesna (that binds urinary acrolein) or hydration (that dilutes urinary acrolein),^2,3 many patients still develop acute toxic effets that manifest as hemorrhagic cystitis. Although some patients with hemorrhagic cystitis have minor symptoms, such as lower urinary tract symptoms or microscopic hemorrhage, others experience life-threatening bleeding.^1,4,5 In addition, studies of patients treated with cyclophosphamide for cancers or nononcologic disease have reported dose-dependent increased risks of subsequent urothelial cancer.6, 7, 8, 9 One study of >6000 patients with non-Hodgkin lymphoma treated with cyclophosphamide found that the patients had an overall 4.5-fold increased risk of developing urothelial cancer; strikingly, those given a cumulative dose of >50 g had a 15-fold increased risk.¹⁰ With few exceptions, genetic determinants that predict more severe acute or chronic bladder disease are unclear.The bladder urothelial injury pattern and regeneration response after cyclophosphamide exposure have been widely examined in rodent models. Studies have found that acute urothelial injury is characterized by a combination of necrosis and apoptosis.11, 12, 13 We recently described the spatiotemporal injury pattern in wild-type female mice given a single intraperitoneal dose of cyclophosphamide.¹⁴ Superficial cells were found to undergo necrosis starting 2 hours after cyclophosphamide exposure and largely lost by 6 hours. Intermediate and many basal cells then undergo apoptosis from 4 hours to a peak at 24 hours after cyclophosphamide exposure. The regenerative response, characterized by expansion and proliferation of largely keratin (KRT) 14⁺ basal cells (a presumptive progenitor cell in the urothelium), starts at 24 hours, peaks at 3 days, and diminishes thereafter. By 10 days after cyclophosphamide exposure, the return of many mature superficial cells was observed. By 28 days after cyclophosphamide exposure, nearly complete urothelial repair was observed, although pockets of proliferating KRT14⁺ cells persisted.We and others have found a role for fibroblast growth factor receptor (FGFR) 2 signaling in the urothelium, including in cyclophosphamide-induced urothelial injury and repair. FGFRs consist of a family of four signaling receptor tyrosine kinases that have different binding affinities to fibroblast growth factors (FGFs) of which there are 22 in mammals.¹⁵ All signaling FGFRs are constitutively bound to fibroblast growth factor receptor substrate (FRS) 2α, which on receptor activation leads to activation of ERK and/or AKT signaling, both of which often have roles in proliferation and cell survival, respectively.¹⁶ FGFR1 to FGFR3 have two major isoforms: a IIIb isoform, which is typically expressed in epithelial cells, and a IIIc isoform, which is usually found in mesenchymal cells. FGFR2IIIb is expressed highly in bladder urothelium and has high binding affinities to FGF7 and FGF10 (the group is often referred to as the FGF7/FGF10/FGFR2IIIb family).¹⁷ Previous studies have found that administration of exogenous FGF7 or FGF10 to whole animals and/or urothelial cells in in vitro drove urothelial proliferation (although the specific cell types responding were not identified).18, 19, 20 In addition, others have found that exogenous FGF7 administration to rats before cyclophosphamide exposure led to a reduced bladder injury, although the reason(s) for the better outcomes were not identified.²¹ We recently found that treatment with FGF7 before cyclophosphamide exposure in mice led to cytoprotection of intermediate and basal cells likely via AKT activation and led to early regeneration of superficial cells possibly secondary to proliferation of KRT5⁺/KRT14^- urothelial cells via ERK activation.¹⁴Although exogenous activation of FGFR2IIIb led to cytoprotection and enhanced regeneration of urothelium after cyclophosphamide exposure, the role of endogenous FGFR2 signaling in the urothelium is not well characterized. Global deletion of Fgf7 in mice appears to cause a thinning of the urothelium, particularly in the intermediate cell layer (although no urothelial cell markers were examined in the study).²² FGFR2 may act as a tumor suppressor in bladder urothelium ²³; moreover, human transitional cell carcinomas of the bladder that have reduced FGFR2 expression are associated with poor prognosis.^24,25 In the context of cyclophosphamide, a published abstract suggested that inducible attenuation of Fgf10/Fgfr2IIIb signaling in mice alters the acute injury timeline after drug administration.²⁶ The abstract reported bladder injury within only 24 hours after cyclophosphamide infusion, did not examine regeneration or repair, and did not report mechanisms underlying pathologic responses to cyclophosphamide. In this study, we examine the role of endogenous FGFR2 signaling in urothelial injury and long-term regeneration and repair after cyclophosphamide exposure largely using a conditional knockout approach.     

A haplotype spanning KIAA0319 and TTRAP is associated with normal variation in reading and spelling ability.

BACKGROUND: KIAA0319 (6p22.2) has recently been implicated as a susceptibility gene for dyslexia. We aimed to find further support for this gene by examining its association with reading and spelling ability in adolescent twins and their siblings unselected for dyslexia. METHODS: Ten single nucleotide polymorphisms (SNPs) in or near the KIAA0319 gene were typed in 440 families with up to five offspring who had been tested on reading and spelling tasks. Family-based association analyses were performed, including a univariate analysis of the principal component reading and spelling score derived from the Components of Reading Examination (CORE) test battery and a bivariate analysis of whole-word reading tests measured in a slightly larger sample. RESULTS: Significant association with rs2143340 (TTRAP) and rs6935076 (KIAA0319) and with a three-SNP haplotype spanning KIAA0319 and TTRAP was observed. The association with rs2143340 was found in both analyses, although the effect was in the opposite direction to that previously reported. The effect of rs6935076 on the principal component was in the same direction as past findings. Two of the three significant individual haplotypes showed effects in the opposite direction to the two prior reports. CONCLUSIONS: These results suggest that a multilocus effect in or near KIAA0319 may influence variation in reading ability.     

Patient choice promotes adherence in preventive treatment for latent tuberculosis.

The aim of the present study was to compare the effect of patient choice on completion rates and adverse drug reactions for patients treated for latent tuberculosis infection (LTBI) using 3-month rifampicin and isoniazid treatment (3RH) or 6-month isoniazid treatment (6H). Data for all patients treated using 3RH or 6H for LTBI between 1998 and 2004 were analysed. In total, 675 patients attended for chemoprophylaxis. Of these, 314 received 3RH and 277 received 6H. From April 1, 2000, patients were offered a choice of regimen; 53.5% completed the regimen successfully, a further 10.3% potentially completed it successfully and 36.2% failed to complete treatment. Logistic regression analysis suggested that successful completion was more likely in patients who were younger (an association that was lost after removing all patients aged <16 yrs), were offered a choice of regimen and attended all clinic visits before commencing treatment. Treatment was discontinued due to adverse reactions in 16 (5.1%) patients who were prescribed 3RH and 16 (5.8%) who were prescribed 6H. Treatment failure was most likely during the first 4 weeks of treatment for both regimens. At 13 weeks of treatment, more patients taking 6H had stopped compared with those completing the 3RH regimen. Drug costs were greater using 6H compared with 3RH. In conclusion, offering a choice of regimen improves completion. Most patients chose the 3-month rifampicin and isoniazid treatment over the 6-month isoniazid treatment. Adverse drug reaction rates between the two regimens were similar.