Study protocol: understanding the pathophysiologic mechanisms underlying delirium in older people undergoing hip fracture surgery.

BACKGROUND: Postoperative delirium (POD) is a common complication of older people undergoing hip fracture surgery, which negatively affects clinical- and healthcare-related outcomes. Unfortunately, POD pathophysiology is still largely unknown, despite previous studies showing that neuroinflammation, neuroendocrine dysfunction, increased reactive oxidative stress (ROS), and endothelial dysfunctions may be involved. There is also evidence that many of the pathophysiological mechanisms which are involved in delirium are involved in sarcopenia too. This article describes the protocol of a pilot study to evaluate the feasibility of a larger one that will explore the pathophysiological mechanisms correlating POD with sarcopenia. We will analyse whether various biomarkers reflecting neuroinflammation, ROS, neuroendocrine disorders, and microvasculature lesions will be simultaneously expressed in in the blood, cerebrospinal fluid (CSF), and muscles of patients developing POD. METHODS: Two centres will be involved in this study, each recruiting a convenient sample of ten older patients with hip fracture. All of them will undergo a baseline Comprehensive Geriatric Assessment, which will be used to construct a Rockwood-based Frailty Index (FI). Blood samples will be collected for each patient on the day of surgery and 1 day before. Additionally, CSF and muscle fragments will be taken and given to a biologist for subsequent analyses. The presence of POD will be assessed in each patient every morning until hospital discharge using the 4AT. Delirium subtypes and severity will be assessed using the Delirium Motor Subtype Scale-4 and the Delirium-O-Meter, respectively. We will also evaluate the patient's functional status at discharge, using the Cumulated Ambulation Score. DISCUSSION: This study will be the first to correlate biomarkers of blood, CSF, and muscle in older patients with hip fracture.

Vessel-associated myogenic precursors control macrophage activation and clearance of apoptotic cells.

Swift and regulated clearance of apoptotic cells prevents the accumulation of cell remnants in injured tissues and contributes to the shift of macrophages towards alternatively activated reparatory cells that sustain wound healing. Environmental signals, most of which are unknown, in turn control the efficiency of the clearance of apoptotic cells and as such determine whether tissues eventually heal. In this study we show that vessel-associated stem cells (mesoangioblasts) specifically modulate the expression of genes involved in the clearance of apoptotic cells and in macrophage alternative activation, including those of scavenger receptors and of molecules that bridge dying cells and phagocytes. Mesoangioblasts, but not immortalized myoblasts or neural precursor cells, enhance CD163 membrane expression in vitro as assessed by flow cytometry, indicating that the effect is specific. Mesoangioblasts transplanted in acutely or chronically injured skeletal muscles determine the expansion of the population of CD163(+) infiltrating macrophages and increase the extent of CD163 expression. Conversely, macrophages challenged with mesoangioblasts engulf significantly better apoptotic cells in vitro. Collectively, the data reveal a feed-forward loop between macrophages and vessel-associated stem cells, which has implications for the skeletal muscle homeostatic response to sterile injury and for diseases in which homeostasis is jeopardized, including muscle dystrophies and inflammatory myopathies.

On the role of arbitration of discordant double readings of screening mammography: experience from two Italian programmes.

PURPOSE: The authors sought to assess the role of arbitration by a third reader of discordant double readings to reduce the rate of recalls to diagnostic assessment. MATERIALS AND METHODS: A consecutive series of 7,660 double readings of screening examinations were considered. Discordant recalls were arbitrated by an expert reader (negative/positive). Diagnostic assessment was performed irrespective of arbitration results, and its outcome was used as reference standard for the study purpose. Assuming that negative arbitration would deny recall, its impact was assessed in terms of reduced recall rate and reduced cancer detection rate. Cost analysis of introducing arbitration was performed according to these results. RESULTS: Recalls at double reading were 528 (6.8%), of which 230 (43.5%) were concordant and 298 (56.5%) were discordant. The latter underwent arbitration, which was negative in 216 (72.4%) and positive in 82 (27.6%) cases, respectively. Overall, 49 cancers were detected (6.39 ‰ screened, 9.2% recalled): 43 cancers were detected among concordant (5.6 ‰ screened, 18.6% concordant) and six among discordant recalls (0.7 ‰ screened, 2.0% discordant). Six cancers were observed among arbitrated cases: five (6%) in positive and one (4.6 ‰) in negative arbitrations. Negative arbitration would have spared 216 assessment procedures (2.8% absolute, 40.9% relative reduction of recall rate) while missing one cancer case (0.13 ‰ absolute, 2.0% relative reduction of cancer detection rate). Arbitration cost was 74 euro, whereas 216 spared assessment procedures would have cost 14,558.4-23,346 euro. CONCLUSIONS: Arbitration is a cost-effective procedure that could be employed as a first measure to counterbalance excess recall rate observed in a double-reading scenario.

Benefits of double reading of screening mammograms: retrospective study on a consecutive series.

PURPOSE: The purpose of this study was to assess the performance of delayed second reading of screening mammograms when added to real-time reading plus immediate assessment. MATERIAL AND METHODS: The study setting was the mammography screening programme of an Italian Local Health Unit. Recall rate and cancer detection rate at first reading or informed second reading only were assessed in a cohort of 23,629 women aged 50-69 years screened during 2007-2008. Incremental recall rate, incremental cancer detection rate and incremental cost of second reading were determined. RESULTS: Recall rate was 13.0% at first and 2.7% at second reading (incremental recall rate +21.1%). Overall, recalls were more frequent in the younger decade and in the presence of denser breasts. Cancer detection rate was 7.06‰ (n=167) at first and 0.93‰ (n=22) at second reading (incremental cancer detection rate +13.1%). Compared with first reading, second reading detected more cancers depicted as isolated microcalcifications and distortions (40.9% vs. 16.2%, p=0.02) and at a lower stage (stage 0-I 81.8% vs. 69.5%, p=0.34). The cost of adding delayed second reading was + 3.65 per screened individual or 3,926.61 per incremental cancer detected. CONCLUSIONS: The study confirms the efficacy of second reading, even as an adjunct to real-time single reading plus immediate assessment. Incremental recall rate is acceptable in view of the incremental cancer detection rate, and both figures are within the range of literature reports on double-reading performance.

The Hybrid Subischial Socket for Persons With Transfemoral Amputation: Gait Parameters and Clinical Assessment of a Case Series.

BACKGROUND: The subischial socket interface design is a promising new shape of socket for persons with transfemoral amputation. Typically, the proximal trim line is located distal to the ischial tuberosity, improving comfort in prosthetic users without interfering with gait parameters compared to Ischial Containment Socket (ICS). No studies have investigated the performances of a subischial sockets with suction suspension system. A new subischial socket (Hybrid Subischial Socket - HySS) combined with a hypobaric passive suspension system has been recently developed. OBJECTIVE: To assess the effects of HySS in terms of comfort, hip range-of-motion and gait parameters. METHODOLOGY: Three persons with transfemoral amputation were tested first using their usual ICS and then after one month of continuous use of HySS. FINDINGS: The following parameters improved in all participants using HySS: 1) hip range-of-motion, 2) walking speed and distance, 3) Timed-Up-and-Go-Test time, 4) stride length, 5) double support duration, 6) peak value of hip extension during stance, 7) satisfaction with the prosthesis. CONCLUSION: These findings suggest that the use of HySS could allow improvements for prosthetic use.

A single-center experience of preemptive anticoagulation for patients with risk factors for allograft thrombosis in renal transplantation.

AIMS: to review our single-center experience of preemptive anticoagulation for the prevention of allograft thrombosis in patients with hypercoagulable states. MATERIAL AND METHODS: this is a retrospective cohort study. Included subjects were first-time kidney allograft recipients transplanted between 2003 and 2007 at a single center, with hypercoagulable states: prior venous thromboembolism, multiple vascular access thromboses, or identifiable thrombophilia. The predictor variable was preemptive anticoagulation and outcome variable was allograft thrombosis. Other risk factors for allograft thrombosis, characteristics of transplantation, and hemorrhagic complications were also examined. RESULTS: among this high-risk cohort (n = 48), 16 received preemptive anticoagulation and 32 did not. The anticoagulated group included significantly more subjects with identifiable thrombophilia (50.0% vs. 0%; p < 0.001). One subject (6.3%) in the anticoagulated group and 6 (18.8%) without anticoagulation developed allograft thrombosis (p = 0.40). A perinephric hematoma was observed in 5 (31.3%) and 2 (6.3%) with and without anticoagulation, respectively (p = 0.03). CONCLUSIONS: preemptive anticoagulation was associated with a non-significant trend towards decreased allograft thrombosis. It may be associated with increased risk of hemorrhage and should be considered cautiously in high-risk patients.

Anatomical variants and anomalies of the coronary tree studied with MDCT coronary angiography.

Anomalies of the coronary arteries are congenital and in most of the cases asymptomatic, although they may present with severe symptoms such as angina pectoris or cardiac arrest. Multidetector CT coronary angiography (MDCT-CA) permits, through curved multiplanar reconstructions and three-dimensional reformatting, noninvasive visualisation of the coronary tree and its variants and anomalies, providing a more accurate alternative to conventional coronary angiography (CCA). The purpose of this pictorial essay is to describe the main variants and anomalies of the coronary arteries using MDCT imaging with multiplanar and three-dimensional reconstructions.

A Literature Review of the Quality of Life, Health Status and Prosthesis Satisfaction in Older Patients With A Trans-tibial Amputation.

BACKGROUND: Several reviews have been published regarding quality of life (QoL) and Health Status (HS) in persons with lower limb amputation (LLA). However, little has been discussed in the literature with respect to older populations (i.e. age>60 years) with trans-tibial amputation. Furthermore, the perceived satisfaction with prosthesis is another important aspect for consideration in the amputees' life. OBJECTIVE: The purpose of this review was to evaluate the impact of trans-tibial amputation on the QoL, HS and prosthesis satisfaction, in order to determine the appropriate intervention to improve these aspects in older population of trans-tibial amputees (TTA). METHODS: Research articles, published between January 2000 to March 2019, were found using Scopus, PubMed and Google Scholar databases. The methodological quality of the selected articles was assessed using the Critical Review Form-Quantitative Studies checklist. RESULTS: Ten articles that met the inclusion criteria were selected. In these papers, we can summarize that people with trans-tibial amputation have a better QoL compared to those with above knee amputation. Moreover, physical functioning and mobility are the most influencing factors for QoL and HS in older people with lower limb amputation. Finally, the prosthesis weight reduction may improve satisfaction with the prosthetic limb. CONCLUSION: Efforts have to be made in order to improve mobility in older population with transtibial amputation for better QoL and HS. This can be accomplished by means of adequate rehabilitation, pain management and an accurate choice of appropriate prosthetic components. We observed that the quality of evidence in the literature available is inadequate and future research would benefit from more prospective observational cohort studies with appropriate inclusion criteria and larger sample sizes to better understand the QoL and HS in this population.

Cardiac mesoangioblasts are committed, self-renewable progenitors, associated with small vessels of juvenile mouse ventricle.

Different cardiac stem/progenitor cells have been recently identified in the post-natal heart. We describe here the identification, clonal expansion and characterization of self-renewing progenitors that differ from those previously described for high spontaneous cardiac differentiation. Unique coexpression of endothelial and pericyte markers identify these cells as cardiac mesoangioblasts and allow prospective isolation and clonal expansion from the juvenile mouse ventricle. Cardiac mesoangioblasts express many cardiac transcription factors and spontaneously differentiate into beating cardiomyocytes that assemble mature sarcomeres and express typical cardiac ion channels. Cells similarly isolated from the atrium do not spontaneously differentiate. When injected into the ventricle after coronary artery ligation, cardiac mesoangioblasts efficiently generate new myocardium in the peripheral area of the necrotic zone, as they do when grafted in the embryonic chick heart. These data identify cardiac mesoangioblasts as committed progenitors, downstream of earlier stem/progenitor cells and suitable for the cell therapy of a subset of juvenile cardiac diseases.

Choice strategy of different dose-saving protocols in 64-slice MDCT coronary angiography.

PURPOSE: Multidetector-row computed tomography coronary angiography (MDCT-CA) produces high-level radiation dose because of submillimetre slice thickness and short scan time. As a result, manufacturers have produced different dose-saving protocols that may, however, reduce image quality and thus diagnostic accuracy. The aim of our study was to assess the diagnostic quality of MDCT-CA using different dose-saving protocols. MATERIALS AND METHODS: Between April and August 2008, we examined 65 patients with 64-slice MDCT-CA: 6/65 using the step-and-shoot dose-saving protocol, 45/65 the cardiac dose right protocol and 14/65 using a standard protocol. Image quality was evaluated on a per-patient and per-segment basis, and the effective dose of each protocol was recorded. RESULTS: In the per-patient analysis, image quality was excellent in 100% of the step-and-shoot protocols, in 91.1% of the cardiac dose right protocols and in 85.8% of the standard protocols. Effective dose to the patient considering the whole study (i.e. scout, calcium score, triggering and MDCT-CA) was 20.49 mSv in the standard protocol, 14.8 mSv in the cardiac dose right protocol and 6.63 mSv in the step-and-shoot protocol. CONCLUSIONS: The radiologist should apply the appropriate protocol in relation to the clinical indications, type of patient and information required in order to spare as much dose as possible while maintaining high image quality.

Which is the Best Way to Perform the Physiological Cost Index in Active Individuals With Unilateral Trans-Tibial Amputation?

BACKGROUND: Physiological Cost Index (PCI) is a simple method used to estimate energy expenditure during walking. It is based on a ratio between heart rate and self-selected walking speed. Previous studies reported that PCI is reliable in individuals with lower limb amputation but only if there is an important walking impairment. No previous studies have investigated the correlation of PCI with the Energy Cost Walking (ECW) in active individuals with traumatic unilateral trans-tibial amputation, considering that this particular category of amputees has an ECW quite similar to healthy individual without lower limb amputation. Moreover, it is important to determine if PCI is also correlated to ECW in the treadmill test so as to have an alternative to over-ground test. OBJECTIVES: The aim of this study was to evaluate the correlation between PCI and ECW in active individuals with traumatic trans-tibial amputation in different walking conditions. The secondary aim was to evaluate if this correlation permits to determine ECW from PCI values. METHODOLOGY: Ninety traumatic amputees were enrolled. Metabolic data, heart rate and walking speed for the calculation of ECW and for PCI were computed over-ground and on a treadmill with 0% and 12% slopes during a 6-minute walking test. FINDINGS: There is a significant correlation between ECW and PCI walking over-ground (p=0.003; R2=0.10) and on treadmill with 12% slopes (p=0.001; R2=0.11) but there is only a poor to moderate correlation around the trendline. No significant correlation was found walking on treadmill with 0% slope. The Bland-Altman plot analysis suggests that is not possible to evaluate ECW directly from PCI. CONCLUSIONS: PCI is a reliable alternative measure of energy expenditure during walking in active individuals with trans-tibial amputation when performing over-ground or at high intensity effort on treadmill. PCI is therefore useful only for monitoring a within subject assessment.

Improved recovery time and sensitivity to H2 and NH3 at room temperature with SnOx vertical nanopillars on ITO.

Nanostructured SnO2 is a promising material for the scalable production of portable gas sensors. To fully exploit their potential, these gas sensors need a faster recovery rate and higher sensitivity at room temperature than the current state of the art. Here we demonstrate a chemiresistive gas sensor based on vertical SnOx nanopillars, capable of sensing < 5 ppm of H2 at room temperature and 10 ppt at 230 °C. We test the sample both in vacuum and in air and observe an exceptional improvement in the performance compared to commercially available gas sensors. In particular, the recovery time for sensing NH3 at room temperature is more than one order of magnitude faster than a commercial SnO2 sensor. The sensor shows an unique combination of high sensitivity and fast recovery time, matching the requirements on materials expected to foster widespread use of portable and affordable gas sensors.

Prognostic factors in prosthetic rehabilitation of bilateral dysvascular above-knee amputee: is the stump condition an influencing factor?

AIM: The aim of this study was to evaluate the prognostic factors for rehabilitation outcome in bilateral dysvascular lower limb amputees, specifically to ascertain how the stump condition can influence the mobility outcome. METHODS: A retrospective study of 30 selected bilateral above-knee amputees for vascular disease was carried out. Barthel Index (BI) was given and stump condition was assessed at admission and at discharge. Influence of age, comorbidities and stump condition on effectiveness of BI was evaluated. Locomotor Capability Index (LCI) was performed at discharge. Influence of stump problems (pain, flexion, pain with flexion) on LCI was evaluated. RESULTS: At discharge, 25 patients were able to ambulate. Age and pathological conditions of stumps correlated negatively with BI effectiveness. LCI values were higher for patients with ideal stumps and lower for patients with combined stump pain and flexion deformities. Post hoc analysis showed that the principal factor negatively influencing the LCI score was the presence of stump flexion deformities. CONCLUSIONS: In our homogeneous group of bilateral amputees, age reduced the possibility of improving the level of autonomy. Good stump quality is one of the major determinants of mobility outcome. Efforts should be made to minimize stump complications. In particular, incorrect positioning of the stump, which is responsible for hip flexor retraction, should be avoided after surgery.

Rats bred for high versus low anxiety responses neonatally demonstrate increases in lordosis, pacing behavior, and midbrain 3 alpha, 5 alpha-THP levels as adults.

Duration and intensity of lordosis is mediated by actions of the progesterone (P) metabolite, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP) at GABA-sub(A) receptors in the midbrain ventral tegmental area. Because rats selectively bred for infantile vocalizations may differ in endogenous 3 alpha,5 alpha-THP secretion, their sexual behavior, midbrain, and plasma 3 alpha,5 alpha-THP levels as adult rats in behavioral estrus was examined. Rats bred for high rates of infantile vocalizations had shorter latencies and intervals between intromissions and ejaculation, higher lordosis quotients and ratings, more pacing of their sexual contacts, and had higher P and 3 alpha,5 alpha-THP levels in plasma and midbrain than did rats bred for low rats of infantile vocalizations. Thus, levels of 3 alpha,5 alpha-THP in the midbrain are associated with differences in sexual behavior of these rats.

The complex interplay of the DQB1 and DQA1 loci in the generation of the susceptible and protective phenotype for insulin-dependent diabetes mellitus.

IDDM patients of North East Italian region were molecularly typed for their HLA-DQB1 and DQA1 loci by using allele specific oligonucleotide probes and PCR amplified genomic DNA. IDDM status strongly correlated with DQB1 alleles carrying a non-aspartic acid residue in position 57 of DQ beta chain and DQA1 alleles with an arginine residue in position 52 of DQ alpha chain. Genotype analysis revealed that individuals with two DQB1 alleles having a non-aspartic residue in position 57 and two DQA1 alleles with an arginine residue in position 52 had the highest relative risk of disease: they constituted 41% of IDDM patients as compared to 0% of controls. Heterozygosity either at residue 57 of DQB1 or residue 52 of DQA1 was sufficient to abrogate statistical significance for disease association, although 43.6% of IDDM patients were included in these two groups as compared to 21.6% of normal controls. On the other hand the presence of two DQB1 alleles with aspartic acid in position 57 was sufficient to confer resistance to disease irrespective of the DQA1 genotype. Based on the number of possible susceptible heterodimers an individual can form, it was found that 85% of IDDM cases could form two or more heterodimers (two in cis and two in trans), but no IDDM case was found to form one susceptible heterodimer in cis. These results demonstrate that the complete HLA-DQ genotype, more than single DQB1 or DQA1 alleles or DQB1-DQA1 haplotypes, is associated with the highest risk of disease. Screening of the population for preventive purposes and/or early signs of IDDM should then take advantage of this result and "susceptible homozygous" individuals should be followed very closely and considered the first group of choice for possible new therapeutical trials.

Muscle-specific Drp1 overexpression impairs skeletal muscle growth via translational attenuation.

Mitochondrial fission and fusion are essential processes in the maintenance of the skeletal muscle function. The contribution of these processes to muscle development has not been properly investigated in vivo because of the early lethality of the models generated so far. To define the role of mitochondrial fission in muscle development and repair, we have generated a transgenic mouse line that overexpresses the fission-inducing protein Drp1 specifically in skeletal muscle. These mice displayed a drastic impairment in postnatal muscle growth, with reorganisation of the mitochondrial network and reduction of mtDNA quantity, without the deficiency of mitochondrial bioenergetics. Importantly we found that Drp1 overexpression activates the stress-induced PKR/eIF2α/Fgf21 pathway thus leading to an attenuated protein synthesis and downregulation of the growth hormone pathway. These results reveal for the first time how mitochondrial network dynamics influence muscle growth and shed light on aspects of muscle physiology relevant in human muscle pathologies.

A number of schizencephaly patients including 2 brothers are heterozygous for germline mutations in the homeobox gene EMX2.

We report here that some patients affected by schizencephaly are heterozygous for mutations in EMX2, a homeobox gene implicated in the patterning of the developing forebrain. Schizencephaly is a very rare human congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. Large portions of these may be absent and replaced by cerebrospinal fluid. We previously reported the presence of EMX2 mutations in 7 out of 8 sporadic cases of schizencephaly. We now extend this analysis to 10 additional patients, including 2 brothers. Six patients were found to be heterozygous for de novo mutations in EMX2. In particular, the 2 brothers show the same mutation affecting the splicing of the first intron, while this mutation is absent in their parents and in the 2 unaffected siblings.

Maternal interactions prior to separation potentiate isolation-induced calling in rat pups.

The vocal response rates of 12-13-day-old infant rats to isolation in a bare test box are markedly increased by brief (1-min) periods of contact with an anesthetized dam prior to isolation, without affecting other isolation-induced behaviors. No such potentiation followed brief contact with littermates, novel test conditions, or experimenter handling. Brief contact with the dam was equally effective in the test chamber or home cage and was not further enhanced by repeated contact-separation sequences. Passive contact became ineffective when prolonged to 30 min, and potentiation could not be restored by providing the additional reinforcing events of continuous suckling, periodic oxytocin-induced milk letdown, or bouts of simulated maternal licking. However, when pups engaged in active interaction with an awake dam, potentiation was significantly enhanced following 1-, 10-, and 30-min periods. A working hypothesis is outlined for the adaptive role of potentiation in the development of the rat pup.

Behavioral mechanisms for active maternal potentiation of isolation calling in rat pups.

The ultrasonic vocalization (USV) response of the isolated infant rat is a promising model for studying the neurobiology of an early anxiety state, and potentiation of the USV response after brief maternal encounters is a newly discovered behavioral regulator of this state. Using experimental variations in the contexts and patterns of maternal behavior during pup encounters and manual simulations of maternal behavior, we have identified several specific mother-pup interactions that cause potentiation. When one of these, pup carrying, was manually simulated, potentiation followed only if a characteristic postural transport response had been fully expressed by the pup. These behavioral mechanisms and other data suggest hypotheses for the development and adaptive role of maternal potentiation.