Autophagy induction in atrophic muscle cells requires ULK1 activation by TRIM32 through unanchored K63-linked polyubiquitin chains.

Optimal autophagic activity is crucial to maintain muscle integrity, with either reduced or excessive levels leading to specific myopathies. LGMD2H is a muscle dystrophy caused by mutations in the ubiquitin ligase TRIM32, whose function in muscles remains not fully understood. Here, we show that TRIM32 is required for the induction of muscle autophagy in atrophic conditions using both in vitro and in vivo mouse models. Trim32 inhibition results in a defective autophagy response to muscle atrophy, associated with increased ROS and MuRF1 levels. The proautophagic function of TRIM32 relies on its ability to bind the autophagy proteins AMBRA1 and ULK1 and stimulate ULK1 activity via unanchored K63-linked polyubiquitin. LGMD2H-causative mutations impair TRIM32's ability to bind ULK1 and induce autophagy. Collectively, our study revealed a role for TRIM32 in the regulation of muscle autophagy in response to atrophic stimuli, uncovering a previously unidentified mechanism by which ubiquitin ligases activate autophagy regulators.

[B-mode sonography visualizing microemboli flow in the main cerebral arteries]. / Visualisation du passage de micro-emboles cérébraux par ultrasonographie en mode B-Flow.

In a patient with a mechanical prosthetic aortic valve admitted for transient amnesia, transcranial duplex Doppler and B-mode sonography visualized the transit of microemboli along the main cerebral arteries. Gaseous microemboli resulting from a cavitation phenomenon at valve closure were seen as high-intensity transient signals (HITS). To our knowledge, this is the first report of microemboli flow visualized in B-mode.

Blood pressure changes after high- and low-salt diets: are intermittent arm measures and beat-by-beat finger measures equivalent?

The assessment of sodium sensitivity requires to measure the difference in mean arterial pressure (MAP) at the end of sodium-loading (SLoad) and sodium-depletion (SDepl) maneuvers with an arm-cuff manometer. Aim of this study is to evaluate whether MAP measuring devices based on the volume-clamp method at the finger can also be used for assessing sodium sensitivity. Sixty-eight normotensive volunteers underwent SLoad and SDepl diets in random order. MAP was simultaneously measured at the end of each diet with arm (Spacelabs 90207) and finger (Portapres model-2) cuff devices. The sodium sensitivity was assessed as the difference in MAP at the end of SLoad and SDepl diets (ΔMAP), and as salt-sensitivity index (SSI; SSI = ΔMAP divided by the difference in urinary-sodium-excretion rate at the end of the diets). Discrepancies between finger and arm-cuff devices in ΔMAP or SSI were evaluated by Bland and Altman analysis. Even if discrepancies between devices had null-fixed bias, results showed a significant proportional bias and large limits of agreement (between -25 and 25 mm Hg for ΔMAP, between -196 and 180 mm Hg mol(-1) per day for SSI). The SSI distribution over the group was larger, flatter and less symmetric if derived from finger-cuff rather than arm-cuff devices, and this influenced substantially the identification of salt-sensitive individuals. Therefore, the response of MAP to SLoad/SDepl diets and consequently the assessment of the salt-sensitivity condition depends importantly on the measurement site, and brachial measures should be preferred for consistency with literature and normative data.

ICF-based approach to evaluating functionality in cardiac rehabilitation patients after heart surgery.

BACKGROUND: Heart surgery is a frequent reason for admission to in-patient cardiac rehabilitation programmes. ICF approach has never been used to evaluate cardiac patients after major heart surgery. AIM: The aim was to evaluate and measure functionality in cardiac patients who have undergone heart surgery, using for the first time the ICF-based approach and to assess whether such approach can be feasible and useful in cardiac rehabilitation. DESIGN: Observational study. SETTING: In-patients cardiac Rehabilitation Unit in Milan. POPULATION: Fifty consecutively admitted patients who had undergone heart surgery (34 males, 16 females; mean age 65.7±12.5 years). METHODS: We prepared a ICF-core set short enough to be feasible and practical. Patients were individually interviewed by different healthcare professionals (randomly selected from a group of two physicians, two physiotherapists and two psychologists) at the beginning (T1) and end of cardiac rehabilitation (T2) RESULTS: The sum of the scores of each ICF body function, body structure, activity and participation code significantly decreased between T1 and T2 (P<0.001). The environmental code scores significantly decreased in the case of facilitators between T1 and T2 (P=0.0051), but not in the case of barriers. There were significant correlations between the ICF body function scores and Barthel's index (ρ=0.381; P=0.006), NYHA class (ρ=0.404; P=0.004) and plasma Cr-P levels (r=0.31; P=0.03), between the ICF body structure codes and the Conley scale (ρ=0.306; P=0.02), and between the activity/participation codes and SpO2 (ρ=0.319; P=0.04). There were no correlations between the ICF environmental codes and clinical parameters. CONCLUSION: The ICF-based data provided functional information that was consistent with the patients' clinical course. CLINICAL REHABILITATION IMPACT: The core set used allowed to quantify important body functions and activities, including some areas that are generally insufficiently considered by healthcare professionals during cardiac rehabilitation, and document their improvement.

Wearable seismocardiography: towards a beat-by-beat assessment of cardiac mechanics in ambulant subjects.

Seismocardiogram (SCG) is the measure of the micro-vibrations produced by the heart contraction and blood ejection into the vascular tree. Over time, a large body of evidence has been collected on the ability of SCG to reflect cardiac mechanical events such as opening and closure of mitral and aortic valves, atrial filling and point of maximal aortic blood ejection. We recently developed a smart garment, named MagIC-SCG, that allows the monitoring of SCG, electrocardiogram (ECG) and respiration out of the laboratory setting in ambulant subjects. The present pilot study illustrates the results of two different experiments performed to obtain a first evaluation on whether a dynamical assessment of indexes of cardiac mechanics can be obtained from SCG recordings obtained by MagIC-SCG. In the first experiment, we evaluated the consistency of the estimates of two indexes of cardiac contractility, the pre-ejection period, PEP, and the left ventricular ejection time, LVET. This was done in the lab, by reproducing an experimental protocol well known in literature, so that our measures derived from SCG could have been compared with PEP and LVET reference values obtained by traditional techniques. Six healthy subjects worn MagIC-SCG while assuming two different postures (supine and standing); PEP was estimated as the time interval between the Q wave in ECG and the SCG wave corresponding to the opening of aortic valve; LVET was the time interval between the SCG waves corresponding to the opening and closure of the aortic valve. The shift from supine to standing posture produced a significant increase in PEP and PEP/LVET ratio, a reduction in LVET and a concomitant rise in the LF/HF ratio in the RR interval (RRI) power spectrum. These results are in line with data available in literature thus providing a first support to the validity of our estimates. In the second experiment, we evaluated in one subject the feasibility of the beat-by-beat assessment of LVET during spontaneous behavior. The subject was continuously monitored by the smart garment from 8 am to 8 pm during a workday. From the whole recording, three data segments were selected: while the subject was traveling to work (M1), during work in the office (O) and while traveling back home (M2). LVET was estimated on a beat-by-beat basis from SCG and the RRI influence was removed by regression analysis. The LVET series displayed marked beat-by-beat fluctuations at the respiratory frequency. The amplitude of these fluctuations changed in the three periods and was lower when the LF/HF RRI power ratio was higher, at O, thus suggesting a possible influence of the autonomic nervous system on LVET short-term variability. To the best of our knowledge this case report provides for the first time a representation of the beat-by-beat dynamics of a systolic time interval during daily activity. The statistical characterization of these findings remains to be explored on a larger population.

K-nearest-neighbor conditional entropy approach for the assessment of the short-term complexity of cardiovascular control.

Complexity analysis of short-term cardiovascular control is traditionally performed using entropy-based approaches including corrective terms or strategies to cope with the loss of reliability of conditional distributions with pattern length. This study proposes a new approach aiming at the estimation of conditional entropy (CE) from short data segments (about 250 samples) based on the k-nearest-neighbor technique. The main advantages are: (i) the control of the loss of reliability of the conditional distributions with the pattern length without introducing a priori information; (ii) the assessment of complexity indexes without fixing the pattern length to an arbitrary low value. The approach, referred to as k-nearest-neighbor conditional entropy (KNNCE), was contrasted with corrected approximate entropy (CApEn), sample entropy (SampEn) and corrected CE (CCE), being the most frequently exploited approaches for entropy-based complexity analysis of short cardiovascular series. Complexity indexes were evaluated during the selective pharmacological blockade of the vagal and/or sympathetic branches of the autonomic nervous system. We found that KNNCE was more powerful than CCE in detecting the decrease of complexity of heart period variability imposed by double autonomic blockade. In addition, KNNCE provides indexes indistinguishable from those derived from CApEn and SampEn. Since this result was obtained without using strategies to correct the CE estimate and without fixing the embedding dimension to an arbitrary low value, KNNCE is potentially more valuable than CCE, CApEn and SampEn when the number of past samples most useful to reduce the uncertainty of future behaviors is high and/or variable among conditions and/or groups.

Short-term complexity indexes of heart period and systolic arterial pressure variabilities provide complementary information.

It is unclear whether the complexity of the variability of the systolic arterial pressure (SAP) provides complementary information to that of the heart period (HP). The complexity of HP and SAP variabilities was assessed from short beat-to-beat recordings (i.e., 256 cardiac beats). The evaluation was made during a pharmacological protocol that induced vagal blockade with atropine or a sympathetic blockade (beta-adrenergic blockade with propranolol or central sympathetic blockade with clonidine) alone or in combination, during a graded head-up tilt, and in patients with Parkinson's disease (PD) without orthostatic hypotension undergoing orthostatic challenge. Complexity was quantified according to the mean square prediction error (MSPE) derived from univariate autoregressive (AR) and multivariate AR (MAR) models. We found that: 1) MSPE(MAR) did not provide additional information to that of MSPE(AR); 2) SAP variability was less complex than that of HP; 3) because HP complexity was reduced by either vagal blockade or vagal withdrawal induced by head-up tilt and was unaffected by beta-adrenergic blockade, HP was under vagal control; 4) because SAP complexity was increased by central sympathetic blockade and was unmodified by either vagal blockade or vagal withdrawal induced by head-up tilt, SAP was under sympathetic control; 5) SAP complexity was increased in patients with PD; and 6) during orthostatic challenge, the complexity of both HP and SAP variabilities in patients with PD remained high, thus indicating both vagal and sympathetic impairments. Complexity indexes derived from short HP and SAP beat-to-beat series provide complementary information and are helpful in detecting early autonomic dysfunction in patients with PD well before circulatory symptoms become noticeable.

24h seismocardiogram monitoring in ambulant subjects.

Sternal seismocardiogram (SCG) is the assessment of microvibrations produced by the beating heart as detected by an accelerometer positioned on the sternum. This signal reflects mechanical events of the heart contraction, including the opening and closure of mitral and aortic valves and maximal blood flow acceleration. Traditionally, SCG has been detected in a laboratory setting with the subject lying at rest in supine position. Aims of this study were 1) to investigate the feasibility of a SCG monitoring over the 24 hours in ambulant subjects, and 2) to calculate number and time distribution of the SCG estimates obtainable over the 24 hours. In 5 healthy subjects ECG, respiration, body accelerations and sternal SCG were recorded for 24 hours in a workday by a smart garment recently developed in our laboratory, the MagIC-SCG system. Each recording was split into a series of contiguous 5-s data segments and SCG was estimated in each segment where the magnitude of the acceleration vector was < 4 milli-g (this condition indicates that the subject was not moving).All the 24-h recordings were found of good quality and could be entirely analyzed. A large number of SCG estimates could be obtained over the 24 hours. In particular, more than 100 estimates per hour were available during the day; at night this rate was three times higher.Thus our study indicates that not only the 24h SCG monitoring in daily life is feasible but also that possible changes over time in SCG and its derived parameters may be tracked with an extreme temporal detail.

The sequence technique revised: additional concepts on the assessment of spontaneous baroreflex function.

The sequence technique is commonly employed to estimate the baroreflex sensitivity from the analysis of systolic blood pressure (SBP) and RR Interval (RRI) recordings. Traditionally, the RRI+/SBP- and RRI-/SBP+ sequences are excluded from this analysis.

Linear and fractal heart rate dynamics during sleep at high altitude. Investigation with textile technology.

OBJECTIVES: To investigate the effects of hypoxia during sleep on linear and self-similar components of heart rate variability (HRV) in eight healthy subjects at high altitude on Mount Everest. METHODS: ECG was monitored by using an innovative textile-based device, the MagIC system. For each subject three night recordings were performed at sea level (SL), at 3500 m and 5400 m above SL. RR Interval (RRI) was derived on a beat-by-beat basis from the ECG and the VLF, LF and HF spectral components and the LF/HF ratio were estimated. Short- (α1) and long-term (α2) scale exponents as well as the recently proposed spectrum of self-similarity coefficients, α(n) were estimated by detrended fluctuation analysis (DFA). RESULTS: With respect to SL, all HRV parameters but one (α2) were significantly modified at 3500 m. However, at 5400 m they tended to return to the SL values and this was in contrast with the increase in the hypobaric hypoxia and in the number of central sleep apneas occurring at higher altitude. The only HRV index that displayed changes at 5400 m was the DFA α(n) spectrum, with α(n) values significantly lower than at SL for 20 < n <50 and higher for 200 < n <400, being n the box size. CONCLUSIONS: While the biological interpretation of these results is still in progress, our data indicates that the cardiac response to high altitude hypoxia during sleep can hardly be fully explored by traditional HRV estimators only, and requires the additional support of more sophisticated indexes exploring also nonlinear and fractal features of cardiac variability.

Baroreflex contribution to blood pressure and heart rate oscillations: time scales, time-variant characteristics and nonlinearities.

The aim of this paper is to highlight the aspects of the baroreflex control of the cardiovascular system that could be relevant to the analysis and modelling of cardiovascular oscillations and regulation. In particular, complex and/or controversial issues of the baroreflex control are addressed on the basis of results obtained in previous studies by others as well as by our group. Attention has been focused on time-variant and nonlinear characteristics of the baroreflex function and on the influence of this physiological mechanism on different frequency regions of blood pressure and heart rate spectra.

Upgraded diagnostic value of Gen-Probe PACE 2 assay for detection of Chlamydia trachomatis infection.

In this study, we evaluate the performance of a nucleic acid amplification assay, COBAS AMPLICOR (Roche Molecular systems) (PCR), compared to non-amplified DNA probe assay PACE2 (Gen-Probe Inc.) for the detection of C. trachomatis in a total of 2,916 samples (2,114 females and 802 males) consecutively collected in two different clinical pathology laboratories, over a period of three years. In the females, the endocervical swabs showed a similar range of detection when using the two different methods: out of 1,581 females processed with PACE 2, 1.4% (2005), 0.9% (2006), 0.5% (2007), resulted positive for C. trachomatis; out of 533 females processed with PCR, 1.3% (2005), 1.5% (2006) and 1.2% (2007), resulted positive. However, in the male subjects we found an increased positivity of Chlamydia detection on urethral swabs by using PACE 2: 4.8% (2005), 1.9% (2006) and 2.9% (2007), compared to urine specimen processed by PCR: 1% (2005), 1.4% (2006) and 0% (2007). Even if PCR should be considered a most promising tool for routine diagnosis of Chlamydia infection, Gen Probe allowed us to better identify Chlamydia trachomatis (in 4.8% of urethral swabs compared to urine) leading to a hypothesis that extracellular EB forms of Chlamydia could be absent in urine in persistent infectious.

Dynamic adaptation of cardiac baroreflex sensitivity to prolonged exposure to microgravity: data from a 16-day spaceflight.

This study explored the process of arterial baroreflex adaptation to microgravity, starting from the first day of flight, during the 16-day STS-107 Columbia Space Shuttle mission. Continuous blood pressure (BP), ECG, and respiratory frequency were collected in four astronauts on ground (baseline) and during flight at days 0-1, 6-7, and 12-13, both at rest and during moderate exercise (75 W) on a cycle ergometer. Sensitivity of the baroreflex heart rate control (BRS) was assessed by sequence and spectral alpha methods. Baroreflex effectiveness index (BEI); low-frequency (LF) power and high-frequency (HF) power of systolic BP (SBP), diastolic BP (DBP), and R-R interval (RRI); the RRI LF/HF ratio; and the RRI root mean square of successive differences (RMSSD) index were also estimated. We found that, at rest, BRS increased in early flight phase, compared with baseline (means +/- SE: 18.3 +/- 3.4 vs. 10.4 +/- 1.2 ms/mmHg; P < 0.05), and it tended to return to baseline in subsequent days. During exercise, BRS was lower than at rest, without differences between preflight and in-flight values. At rest, in the early flight phase, RMSSD and RRI HF power increased (P < 0.05) compared with baseline, whereas LF powers of SBP and DBP decreased. No statistical difference was found in these parameters during exercise before vs. during flight. These findings demonstrate that heart rate baroreflex sensitivity and markers of cardiac vagal modulation are enhanced during early exposure to microgravity, likely because of the blood centralization, and return to baseline values in subsequent flight phases, possibly because of the fluid loss. No deconditioning seems to occur in the baroreflex control of the heart.

Heart rate monitoring and control in altered gravity conditions.

On the basis of indirect evidences it has been hypothesized that during space missions the almost complete absence of gravity might impair the baroreflex control of circulation. In the first part of this paper we report results obtained from a series of experiments carried out to directly verify this hypothesis during the 16-day STS 107 Shuttle flight. Spontaneous baroreflex sensitivity was assessed in four astronauts before flight (baseline) and at days 0-1, 6-7 and 12-13 during flight, both at rest and while performing moderate exercise. Our results indicate that at rest the baroreflex sensitivity significantly increased in the early flight phase, as compared to pre-flight values and tended to return to baseline in the mid-late phase of flight. During exercise, baroreflex sensitivity was lower than at rest, without any difference among pre-flight and in-flight values. These findings seem to exclude the hypothesis of an impairment of the baroreflex control of heart rate during exposure to microgravity, at least over a time window of 16 days. In the second part of the paper we propose a novel textile-based methodology for heart rate and other vital signs monitoring during gravity stress. The positive results obtained from its use during parachute jumps support the use of smart garments for the unobtrusive assessment of physiological parameters in extreme environments.

Autonomic cardiovascular regulation in quiescent ulcerative colitis and Crohn's disease.

BACKGROUND: In inflammatory bowel diseases, changes in autonomic enteric regulation may also affect neural cardiovascular control. However, while cardiac autonomic modulation has been shown to be impaired in active ulcerative colitis, the occurrence of cardiovascular autonomic alterations, also in the quiescent phase of inflammatory bowel diseases, is still a matter of debate. The aim of our study was thus to explore the features of cardiovascular autonomic regulation in ulcerative colitis and Crohn's disease during their remission phase. MATERIALS AND METHODS: Autonomic cardiovascular control was evaluated by time- and frequency-domain indexes of spontaneous heart rate and blood pressure variability and by assessing the baroreflex heart rate control (sequence technique) in 26 patients with ulcerative colitis, in 26 patients with Crohn's disease and in 23 healthy controls. RESULTS: The groups were matched for age, gender and body mass index. They had similar blood pressure mean levels and variability. By contrast, mean heart rate, its overall variability (standard deviation), and baroreflex sensitivity were lower in ulcerative colitis patients than in controls. Moreover, all indexes related to cardiac vagal control were significantly lower in ulcerative colitis patients with respect not only to controls but also to Crohn's disease patients. CONCLUSIONS: Cardiac vagal control is impaired in quiescent ulcerative colitis only, and not in Crohn's disease, while in both bowel diseases vascular control appears preserved. Since cardiovagal modulation seems related to anti-inflammatory mechanisms, the reduced parasympathetic cardiac regulation in apparently quiescent ulcerative colitis suggests that such systemic derangement is accompanied by local subclinical inflammations, even in the absence of clinically active inflammatory processes.

Baroreflex control of heart rate during sleep in severe obstructive sleep apnoea: effects of acute CPAP.

Baroreflex control of heart rate during sleep (baroreflex sensitivity; BRS) has been shown to be depressed in obstructive sleep apnoea (OSA), and improved after treatment with continuous positive airway pressure (CPAP). Whether CPAP also acutely affects BRS during sleep in uncomplicated severe OSA is still debatable. Blood pressure was monitored during nocturnal polysomnography in 18 patients at baseline and during first-time CPAP application. Spontaneous BRS was analysed by the sequence method, and estimated as the mean sequence slope. CPAP did not acutely affect mean blood pressure or heart rate but decreased cardiovascular variability during sleep. Mean BRS increased slightly during CPAP application (from 6.5+/-2.4 to 7.5+/-2.9 ms x mmHg(-1)), mostly in response to decreasing blood pressure. The change in BRS did not correlate with changes in arterial oxygen saturation or apnoea/hypopnoea index. The small change in baroreflex control of heart rate during sleep at first application of continuous positive airway pressure in severe obstructive sleep apnoea was unrelated to the acute resolution of nocturnal hypoxaemia, and might reflect autonomic adjustments to positive intrathoracic pressure, and/or improved sleep architecture. The small increase in baroreflex control of heart rate during sleep may be of clinical relevance as it was accompanied by reduced cardiovascular variability, which is acknowledged as an independent cardiovascular risk factor.

Multi- and monofractal indices of short-term heart rate variability.

Indices of heart rate variability (HRV) based on fractal signal models have recently been shown to possess value as predictors of mortality in specific patient populations. To develop more powerful clinical indices of HRV based on a fractal signal model, the study investigated two HRV indices based on a monofractal signal model called fractional Brownian motion and an index based on a multifractal signal model called multifractional Brownian motion. The performance of the indices was compared with an HRV index in common clinical use. To compare the indices, 18 normal subjects were subjected to postural changes, and the indices were compared on their ability to respond to the resulting autonomic events in HRV recordings. The magnitude of the response to postural change (normalised by the measurement variability) was assessed by analysis of variance and multiple comparison testing. Four HRV indices were investigated for this study: the standard deviation of all normal R-R intervals; an HRV index commonly used in the clinic; detrended fluctuation analysis, an HRV index found to be the most powerful predictor of mortality in a study of patients with depressed left ventricular function; an HRV index developed using the maximum likelihood estimation (MLE) technique for a monofractal signal model; and an HRV index developed for the analysis of multifractional Brownian motion signals. The HRV index based on the MLE technique was found to respond most strongly to the induced postural changes (95% CI). The magnitude of its response (normalised by the measurement variability) was at least 25% greater than any of the other indices tested.

Surgical conservative treatment for Bauhin's syndrome.

BACKGROUND AND STUDY AIMS: Hypertrophy of ileocaecal sphincter seems to be the basic etiological factor of Bauhin's valve syndrome (BVS). In the rare literature all cases are treated by means of an hemicolectomy. A patient with Bauhin's valve syndrome is described, whose pathologic characteristics were hypertrophy of ileocaecal sphincter and a circular submucosal lipoma on the caecal side of the valve. Lipomata, although uncommon, may arise throughout the whole gastrointestinal tract, mostly asymptomatic, and submucosal layer is most frequently involved than subserosal one. More than two-thirds of gut lipoma are found in the large bowel, where they represent the most common benign lesion after adenoma. PATIENTS AND METHODS: A 36 year old woman suffering from periodic upper abdominal pain, nausea and diarrhea, was submitted to an explorative surgical procedure, after imaging study of the bowel showed only an indistict mass in the caecum. Though a caecotomy a dissection of an hypertrophic and swollen portion of the ileocaecal valve was performed, saving the ileo-caecal sphincter. The residual mucosal margins were sutured, the last tract of the ileum was fixed to the caecum, completing with a caecorrhaphy and appendectomy. RESULTS: Normal post-operative period, discharging the patient after few days. Since the operation all symptoms disappeared, and after four years there is a total well-being of the patient with complete disappearance of the former symptoms. CONCLUSIONS: If the BVS is only due to a lipomatous hypertrophy of the mucosa and submucosa of ileo-caecal valve, hemicholectomy seems to be not justified: it is an exceedingly invasive procedure for a non-malignant disease. It is important a throughout radiological diagnosis and a caecotomy direct control during an operative exploration for a correct surgical choice.