Ketogenic diets cause opposing changes in synaptic morphology in CA1 hippocampus and dentate gyrus of late-adult rats

Ketogenic diets (KDs) have beneficial effects on several diseases, such as epilepsy, mitochondriopathies, cancer, and neurodegeneration. However, little is known about their effects on aging individuals. In the present study, late-adult (19-month-old) rats were fed for 8 weeks with two medium chain triglycerides (MCT)-KDs, and the following morphologic parameters reflecting synaptic plasticity were evaluated in stratum moleculare of hippocampal CA1 region (SM CA1) and outer molecular layer of hippocampal dentate gyrus (OML DG): average area (S), numeric density (Nv(s)), and surface density (Sv) of synapses, and average volume (V), numeric density (Nv(m)), and volume density (Vv) of synaptic mitochondria. In SM CA1, MCT-KDs induced the early appearance of the morphologic patterns typical of old animals (higher S and V, and lower Nv(s) and Nv(m)). On the contrary, in OML DG, Sv and Vv of MCT-KDs-fed rats were higher (as a result of higher Nv(s) and Nv(m)) versus controls; these modifications are known to improve synaptic function and metabolic supply. The opposite effects of MCT-KDs might reflect the different susceptibility to aging processes: OML DG is less vulnerable than SM CA1, and the reactivation of ketone bodies uptake and catabolism might occur more efficiently in this region, allowing the exploitation of their peculiar metabolic properties. Present findings provide the first evidence that MCT-KDs may cause opposite morphologic modifications, being potentially harmful for SM CA1 and potentially advantageous for OML DG. This implies risks but also promising potentialities for their therapeutic use during aging.     

The need for patient-focused therapy for children and teenagers with allergic rhinitis: a case-based review of current European practice

Allergic rhinitis is a common problem in childhood and adolescence, with a negative impact on the quality of life of patients and their families. The treatment modalities for allergic rhinitis include allergen avoidance, anti-inflammatory symptomatic treatment and allergen specific immunotherapy. In this review, four cases of children with allergic rhinitis are presented to illustrate how the recently published EAACI Guidelines on Pediatric Allergic Rhinitis can be implemented in clinical practice.     

An Italian matrix sentence test for the evaluation of speech intelligibility in noise

Objective: Development of an Italian matrix sentence test for the assessment of speech intelligibility in noise. Design: The development of the test included the selection, recording, optimization with level adjustment, and evaluation of speech material. The training effect was assessed adaptively during the evaluation measurements with six lists of 20 sentences, using open- and closed-set response formats. Reference data were established for normal-hearing listeners with adaptive measurements. Equivalence of the test lists was investigated using the open-set response format at three signal-to-noise ratios (SNRs). Study sample: A total of 55 normal-hearing Italian mother-tongue listeners. Results: The evaluation measurements at fixed SNRs resulted in a mean speech reception threshold (SRT) of ? 7.3 ± 0.2 dB SNR and slope of 13.3 ± 1.2 %/dB. The major training effect of 1.5 dB was observed for the first two consecutive measurements. Mean SRTs of ? 6.7 ± 0.7 dB SNR and ? 7.4 ± 0.7 dB SNR were found from the third to the sixth adaptive measurement for open- and closed-set test response formats, respectively. Conclusions: A good agreement has been found between the SRTs and slope and those of other matrix tests. Since sentences are difficult to memorize, the Italian matrix test is suitable for repeated measurements.     

Length and clinical effectiveness of pulmonary rehabilitation in outpatients with chronic airway obstruction

STUDY OBJECTIVE: To assess the clinical effectiveness of pulmonary rehabilitation (PR) after 10 or 20 consecutive sessions in outpatients with chronic airway obstruction (CAO). DESIGN: Observational prospective cohort trial. SETTING: Outpatient clinic of a rehabilitation center. PATIENTS AND INTERVENTIONS: Twenty-five outpatients (mean age, 65 +/- 9 years [+/- SD]; FEV1, 64 +/- 12% predicted) admitted to a comprehensive PR program, including exercise training. MEASUREMENTS AND RESULTS: The load reached on a cycloergometer (maximal achieved load [W-max]), the maximal and isoload dyspnea and leg fatigue on a Borg scale, 6-min walk distance (6MWD), and the health-related quality of life as assessed using the St. George's Respiratory Questionnaire (SGRQ) [total and components score] have been recorded as outcome measures at baseline, after 10 sessions (T10), and after 20 sessions (T20). The predefined criteria of the clinically significant improvement were as follows: + 15% W-max, + 54 m at 6MWD, - 1 point at isoload dyspnea and leg fatigue, and - 4% at SGRQ scores. There was a mean significant difference between changes at T20 and T10 for 6MWD (- 42.96 m; 95% confidence interval [CI], - 57.79 to - 28.12 m; p = 0.001), total SGRQ (4.80; 95% CI, 2.29 to 7.31; p = 0.001), activity SGRQ (3.60; 95% CI, 0.48 to 6.71; p = 0.025), and symptoms SGRQ (5.96; 95% CI, 2.72 to 9.2; p = 0.001). The percentage of patients who improved was different at T20 as compared with T10 for W-max (68% and 48%, respectively; p = 0.025), 6MWD (76% and 20%, p = 0.001), and total SGRQ (64% and 36%, p = 0.008). CONCLUSIONS: A 10-session course of PR provides only limited clinically significant changes of outcome measures when compared with a 20-session course in outpatients with CAO of mild-to-moderate severity.     

Autonomic neuropathy in streptozotocin diabetic rats: effect of acetyl-L-carnitine

The present study was designed to characterize cardiac autonomic neuropathy in streptozotocin-induced (45 mg/kg i.v.) diabetic rat by analysis of heart rate variability (HRV), and to assess, in this model, the effects of treatment with acetyl-L-carnitine (ALC). Heart rate was reduced in diabetic rats (332+/-22 vs. 411+/-35 beat per min; P<0.0001). This bradycardia was partly reversed with ALC (369+/-52 beat per min; P<0.05 vs. untreated). Both time- and frequency-domain parameters of HRV were significantly reduced in diabetic rats. The reduction of spectral power was around 50% at high frequencies and about 70% at low frequencies, suggesting a decrease of parasympathetic activity. Low/high frequency ratio was significantly decreased in diabetic rats suggesting decreased sympathetic tone, while nonlinear analysis indicated a reduction of the chaotic complexity of heart rate dynamics in diabetic rats. Standard deviation of heart rate in ALC-treated rats was significantly higher than in untreated diabetic rats (P<0.0001). ALC counteracts the reduction of the power spectrum observed in diabetic animals (P<0.0005) normalizing the spectra profile. ALC restored chaotic complexity of heart rate dynamics. These results on the whole indicate that both sympathetic and parasympathetic cardiac tone were reduced significantly in diabetic rats and that ALC treatment prevents the development of autonomic neuropathy in streptozotocin-induced diabetes in rats.     

Morphometric investigations of the mitochondrial damage in ceroid lipopigment accumulation due to vitamin E deficiency

Numeric (Nv) and volume (Vv) densities, as well as the average size (skeleton: Sk) of synaptic mitochondria from adult, normally fed and adult, vitamin E deficient animals (11 months of age) were semiautomatically measured by computer-assisted morphometry in the cerebellar granular layer. Nv, Vv and the average mitochondrial volume (V) were measured on perikaryal Purkinje cell organelles preferentially stained for succinic dehydrogenase (SDH) activity. Adult vitamin E deficient animals showed a significant decrease of Nv, a significant increase of Sk and an unchanged value of Vv. While in adult normally fed animals the mitochondria of increased size (Sk>5 microm) were 5.3%, in the adult vitamin E deficient rats this fraction accounted for 25.5%. In Purkinje cell perikarya, vitamin E deficiency resulted in a significant decrease of Vv, Nv and V, as well as a steeper reduction of the percentage of SDH-positive mitochondria of larger size. Taken together, these findings document that vitamin E deficiency is responsible of mitochondrial morphometric alterations in adult rats. Structurally deteriorated mitochondria are reported to play a role in producing increased amounts of free radicals, which can facilitate the accumulation of ceroid pigment.     

MTHFR C677T polymorphism,folate status and colon cancer risk in acromegalic patients

Background

Acromegalic patients have a higher risk of developing colorectal tumours (CRT). The common C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene is a well-documented CRT risk factor in the general population, but its role in acromegaly has never been examined.

Purpose

We investigated the influence of MTHFR C677T polymorphism, folate status and other lifestyle, nutritional and disease-specific variables on CRT risk in acromegaly.

Methods

Clinical data were collected from 115 acromegalic patients (25 with active disease) who underwent a complete colonoscopy. C677T MTHFR genotype, homocysteine, vitamin B₁₂, insulin growth factor and insulin levels, as well as metabolic variables were evaluated.

Results

Colorectal tumours were identified in 51 patients (3 adenocarcinomas). MTHFR C677T distribution was in the Hardy–Weinberg equilibrium and similar in patients with or without CRT. There was a correlation between patients with TT genotype and CRT occurrence (Spearman’s test: P = 0.03), with an Odds Ratio (OR) of 1.32 (95 % CI 0.522–3.362, P NS). A folate–MTHFR genotype interaction on CRT risk was found (P = 0.037): in the lower folate subgroup, TT patients showed a 2.4 higher OR for CRT (95 % CI 0.484–11.891; P NS) than C-allele carriers. Smoking (P = 0.007), increased HbA_1c levels (P = 0.021), dyslipidaemia (P = 0.049), acromegaly control (P = 0.057), and folate–MTHFR genotype interaction (P = 0.088) were associated with CRT at multivariate analysis.

Conclusions

In this cohort of acromegalic patients, CRT risk is increased in 677TT MTHFR patients with low plasma folate levels. Smoking, high HbA_1c levels, dyslipidaemia and disease activity were also associated with increased CRT risk.     

Direct acute tubular damage contributes to Shigatoxin‐mediated kidney failure

The pathogenesis and therapy of Shigatoxin 2 (Stx2)‐mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2‐producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2‐receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild‐type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule‐specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2‐associated kidney failure (n = 11, aged 22–44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement‐inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31–17.60) mg/dl, lactate dehydrogenase 1944 (753–2792) U/l, platelets 33 (19–124)/nl and haemoglobin 6.2 (5.2–7.8) g/dl; median (range)], all patients were discharged after 33 (range 19–43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84–2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66–1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2‐mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.