Properties of Contextual Memory Formed in the Absence of αCaMKII Autophosphorylation

Background

Sleep homeostasis is characterized by a positive correlation between sleep length and intensity with the duration of the prior waking period. A causal role for brain-derived neurotrophic factor (BDNF) in sleep homeostasis has been suggested, but the underlying mechanisms remain unclear. Cortistatin, a neuropeptide expressed primarily in a subset of cortical GABAergic interneurons, is another molecule implicated in sleep homeostasis.

Results

We confirmed that sleep deprivation leads to an increase in cortical cortistatin mRNA expression. Disruption of activity-dependent BDNF expression in a genetically modified mouse line impairs both baseline levels of cortistatin mRNA as well as its levels following sleep deprivation. Disruption of activity-dependent BDNF also leads to a decrease in sleep time during the active (dark) phase.

Conclusion

Our studies suggest that regulation of cortistatin-expressing interneurons by activity-dependent BDNF expression may contribute to regulation of sleep behavior.     

Linezolid-induced interstitial nephritis in a kidney-transplant patient

Linezolid is a recent oral antibiotic used in drug-resistant Gram-positive cocci infections. Herein, we report on the first case of linezolid-related acute renal failure in a kidney-transplant patient. A 60-year-old male having autosomic polycystic kidney disease with liver involvement, on cyclosporin A, mycophenolate mofetil and very low dose prednisolone, presented with an Enterococcus faecium abscess of a huge liver cyst, which was treated by percutaneous drainage and linezolid therapy. Eight days after starting linezolid, he presented with acute renal failure, i.e. serum creatinine increased from 136- 221 micromol/l, associated with mild hypereosinophilia, anemia and thrombocytopenia. There was no skin rash, arthralgia, eosinophiluria or proteinuria. The transplant kidney biopsy, performed 15 days after the beginning of linezolid therapy, showed interstitial nephritis and focal tubular atrophy. After linezolid withdrawal and increasing prednisolone daily dose to 20 mg/d, within a few days, serum creatinine had decreased; after 2 and 4 weeks post linezolid withdrawal, his serum creatinine was 166 and 159 micromol/l, respectively. Because of the potential side effects of linezolid, i.e. myelosuppression and possibly nephrotoxicity, we recommend close monitoring of these parameters when linezolid therapy is attempted in kidney transplant patients.     

Nailfold capillaroscopy in Beh?et’s disease,analysis of 128 patients

The aims of this study were to find the characteristics and prevalence of nailfold capillary changes in a large series of patients with Behçet’s disease (BD) and to analyze their possible relation to other clinical characteristics of the disease. We performed nailfold capillaroscopy in 128 randomly selected patients fulfilling the international classification criteria for BD. Capillaroscopy was done in eight fingers with a ×3.2 microscopy. All patients were questioned for history of Raynaud's phenomenon, ischemic ulcers, smoking, and hypertension. A computerized form including demographic, clinical, and para-clinical features was used to collect data. Univariate and multivariate logistic regressions were used to analyze the relation between capillaroscopic findings and disease characteristics. Odds ratio and a confidence interval at 95% (CI) were calculated for each item. The mean age of the patients was 37?±?10 years, and the male to female ratio was 1.56:1. Capillaroscopy was abnormal in 51 patients (40%, CI 8.5). Enlarged capillaries were seen in 33 patients (26%, CI 7.6), hemorrhages in 21 (16%, CI 6.4), and capillary loss only in one patient. In univariate logistic regression analysis, the presence of enlarged capillaries was associated with lower age at disease onset (OR?=?0.9, CI 0.9–1; p?=?0.04), hypertension (OR?=?4.2, CI 1.5–11.4; p?=?0.006), superficial phlebitis (OR?=?5.5, CI 1.2–24.4; p?=?0.03), and negative pathergy test (OR?=?0.4, CI 0.2–0.9; p?=?0.04). The presence of hemorrhages tended to be associated with articular symptoms (p?=?0.05). Multivariate analysis also confirmed the association of enlarged capillaries with lower age at disease onset (p?=?0.01), hypertension (p?=?0.001), and superficial phlebitis (p?=?0.03). Nailfold abnormalities, mainly enlarged capillaries, are frequent in patients with BD. Our results suggest that these abnormalities may be related to other vascular features of the disease such as superficial phlebitis, but it does not seem to confer special risk for any other specific clinical symptom of the disease.     

Cytomegalovirus prophylaxis with valganciclovir in cytomegalovirus-seropositive kidney-transplant patients

The aims of this prospective, open-label, single-center pilot study were to assess the efficacy and safety of human cytomegalovirus (HCMV) prophylaxis using valganciclovir in HCMV- seropositive kidney-transplant patients to prevent HCMV infection and disease. Fifty-one HCMV seropositive kidney-transplant patients recipients who received transplants between 1 December 2005 and 30 November 2006 were included in the study. Valganciclovir was given from transplantation up to 114 (37-329) days, and was adapted to renal function, i.e., 900 mg/d if calculated creatinine clearance was >60 ml/min, or 450 mg/day if it was <60 ml/min. HCMV DNAemia was assessed every 2 weeks during prophylaxis, and on the same basis for 3 months post-prophylaxis. Immunosuppression was based on calcineurin inhibitors (ciclosporine A=22; tacrolimus=11), with mycophenolate mofetil (n=51), and low-dose steroids. Eighteen patients received no calcineurin-inhibitors, but Belatacept instead. During valganciclovir prophylaxis, asymptomatic HCMV DNAemia was observed in one patient, and no case of HCMV disease occurred. Within 252 days (45-425) post-valganciclovir prophylaxis, HCMV DNAemia was detected in 23.5% (n=12) of patients, of whom two had two or more consecutive HCMV DNAemias. Valganciclovir prophylaxis in HCMV-seropositive kidney-transplant patients is effective for preventing cytomegalovirus disease.     

Exhaled nitric oxide measure using multiple flows in clinically relevant subgroups of COPD

Although there is widespread interest in fractional exhaled nitric oxide (FeNO) as a non-invasive, time and cost effective biomarker for assessing airway inflammation in chronic obstructive pulmonary disease (COPD), its usefulness is still controversial. We examined the FeNO levels in clinically meaningful subgroups of COPD in a group of 91 COPD patients with FEV(1) 17-77% of predicted. Multiple flow rates FeNO at 10, 30, 50, 100 and 200 mL/s were measured and a two-compartment model was used to estimate the diffusion Capacity (D), alveolar NO concentration (Calv) and airway wall NO concentration (Caw). All patients had spirometry, assessment of symptoms with questionnaires and low-dose CT scan as well as assessment of weight and body composition. We examined the following subgroups of COPD: Patients with 1) Severe emphysema, 2) Chronic bronchitis, 3) Frequent exacerbations, 4) Loss of lean body mass and 5) Low fat-free mass index. We used advanced non-linear mixed model adjusted for age and gender. The modelled differences in D, Calv or Caw among COPD subgroups were small and not statistically significant. The analysis showed significant effects of current smoking on Caw and of gender on D and Calv. The results were the same if the advanced non-linear mixed model was substituted by more standard analysis techniques. This study questions the relevance of using FeNO as a biomarker to evaluate local inflammation in COPD and points to a need for developing novel non-invasive biomarkers for research laboratory work and daily clinical practice.     

Reduction of Extended‐Release Tacrolimus Dose in Low‐Immunological‐Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor‐Specific Antibodies: A Randomized Study

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended‐release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid‐free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C₀) >3 μg/L; group B had no change in TacER dose (TacER C₀ 7–12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent‐to‐treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C₀ was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti‐HLA donor‐specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C₀ should be maintained >7 μg/L during the first year after transplantation in low‐immunological‐risk, steroid‐free KTRs receiving a moderate dose of mycophenolic acid.