Upon entry into the central nervous system (CNS), serum insulin-like growth factor-1 (IGF-I) modulates neuronal growth, survival, and excitability. Yet mechanisms that trigger IGF-I entry across the blood-brain barrier remain unclear. We show that neuronal activity elicited by electrical, sensory, or behavioral stimulation increases IGF-I input in activated regions. Entrance of serum IGF-I is triggered by diffusible messengers (i.e., ATP, arachidonic acid derivatives) released during neurovascular coupling. These messengers stimulate matrix metalloproteinase-9, leading to cleavage of the IGF binding protein-3 (IGFBP-3). Cleavage of IGFBP-3 allows the passage of serum IGF-I into the CNS through an interaction with the endothelial transporter lipoprotein related receptor 1. Activity-dependent entrance of serum IGF-I into the CNS may help to explain disparate observations such as proneurogenic effects of epilepsy, rehabilitatory effects of neural stimulation, and modulatory effects of blood flow on brain activity.

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This study aimed to investigate the suitability of using ultrasonograph muscle thickness (MT) measurements to estimate the muscle volume (MV) of the quadriceps femoris as an alternative approach to magnetic resonance imaging (MRI). The subjects were 46 men aged from 20 to 70 years who were randomly allocated to either a validation or a cross-validation group. In the validation group, multiple and simple regression equations, which used a set of MT values determined at mid-thigh and thigh length (1) and the product of pi, (MT/2)2, and l [pi x (MT/2)2 x l], respectively, as independent variables, were derived to estimate the MV measured by MRI. Because the two equations were cross-validated, the data from the two groups were pooled to generate the final prediction equations: MV (cm3)=(MT x 311.732)+(l x 53.346) -2058.529 as the multiple regression equation and MV (cm3) = [pi x (MT/ 2)2 x l] x 1.1176+663.040 as the simple regression equation. In the multiple regression equation, MT explained 75% of the variation in the MV measured by MRI. The r2 and the standard error of the estimate (SEE) of the equations were 0.824 and 175.6 cm3 (10.6%), respectively, for the multiple regression equation and 0.829 and 173.7 cm3 (10.5%), respectively, for the simple regression equation. Thus, the present results indicate that ultrasonograph MT measurements at mid-thigh are useful for estimating the MV of knee extensors. However, the observed SEE values suggest that the prediction equation obtained in this study may be limited to population studies rather than individual assessments in longitudinal studies.

BackgroundTreatment with tenofovir is sometimes associated with renal dysfunction. Limited information is available on this side effect in patients with small body weight, although the use of tenofovir will spread rapidly in Asia and Africa, where patients are likely to be of smaller body weight.MethodsIn a single-center cohort, Japanese patients with HIV infection who started tenofovir-containing antiretroviral therapy were retrospectively analyzed. The incidence of tenofovir-associated renal dysfunction, defined as more than 25% decrement of estimated glomerular filtration rate (eGFR) from the baseline, was determined. The effects of small body weight and body mass index (BMI) on tenofovir-associated renal dysfunction, respectively, were estimated in univariate and multivariate Cox hazards models as the primary exposure. Other possible risk factors were evaluated by univariate analysis and those found significant were entered into the multivariate analysis.ResultsThe median weight of 495 patients was 63 kg. Tenofovir-related renal dysfunction occurred in 97 (19.6%) patients (incidence: 10.5 per 100 person-years). Univariate analysis showed that the incidence of tenofovir-related renal dysfunction was significantly associated with smaller body weight and BMI, respectively (per 5 kg decrement, HR = 1.23; 95% CI, 1.10–1.37; p<0.001)(per 1 kg/m2 decrement, HR = 1.14; 95% CI, 1.05–1.23; p = 0.001). Old age, high baseline eGFR, low serum creatinine, low CD4 count, high HIV viral load, concurrent nephrotoxic drugs, hepatitis C infection, and current smoking were also associated with tenofovir-related renal dysfunction. Multivariate analysis identified small body weight as a significant risk (adjusted HR = 1.13; 95% CI, 1.01–1.27; p = 0.039), while small BMI had marginal significance (adjusted HR = 1.07; 95% CI 1.00–1.16; p = 0.058).ConclusionThe incidence of tenofovir-associated renal dysfunction in Japanese patients was high. Small body weight was identified as an independent risk factor for tenofovir-associated renal dysfunction. Close monitoring of renal function is advocated for patients with small body weight treated with tenofovir.

This is the first study of our knowledge to identify the association between SNPs in ABCC2 and tenofovir-induced KTD in an Asian population. Close monitoring of renal function is warranted in tenofovir-treated patients with these SNPs.

In this cohort of patients with low body weight, TDF exposure increased the risk of renal dysfunction. Furthermore, the loss in eGFR relative to the control increased continuously up to 5 years.

The incidence of renal stones was substantially higher among patients in the ATV/r group, compared with patients in the other PIs group. Continuation of ATV/r after diagnosis of renal stones was associated with a high rate of recurrence. Switching ATV/r to other ARVs is warranted in patients who develop renal stones.