Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine.

With their proliferation, differentiation into specific cell types, and secretion properties, mesenchymal stromal/stem cells (MSC) are very interesting tools to be used in regenerative medicine. Bone marrow (BM) was the first MSC source characterized. In the frame of autologous MSC therapy, it is important to detect donor's parameters affecting MSC potency. Age of the donors appears as one parameter that could greatly affect MSC properties. Moreover, in vitro cell expansion is needed to obtain the number of cells necessary for clinical developments. It will lead to in vitro cell aging that could modify cell properties. This review recapitulates several studies evaluating the effect of in vitro and in vivo MSC aging on cell properties.

Application of breast tomosynthesis in screening: incremental effect on mammography acquisition and reading time.

OBJECTIVE: The aim of this study was to supplement the paucity of information available on logistical aspects of the application of three-dimensional (3D) mammography in breast screening. METHODS: We prospectively examined the effect on radiographers' and radiologists' workload of implementing 3D mammography in screening by comparing image acquisition time and screen-reading time for two-dimensional (2D) mammography with that of combined 2D+3D mammography. Radiologists' accuracy was also calculated. RESULTS: Average acquisition time (measured from start of first-view breast positioning to compression release at completion of last view) for seven radiographers, based on 20 screening examinations, was longer for 2D+3D (4 min 3 s; range 3 min 53 s-4 min 18 s) than 2D mammography (3 min 13 s; range 3 min 0 s-3 min 26 s; p<0.01). Average radiologists' reading time per screening examination (three radiologists reading case-mix of 100 screens: 10 cancers, 90 controls) was longer for 2D+3D (77 s; range 60-90 s) than for 2D mammography (33 s; range 25-46 s; p<0.01). 2D+3D screen-reading was associated with detection of more cancers and with substantially fewer recalls than 2D mammography alone. CONCLUSION: Relative to standard 2D mammography, combined 2D+3D mammography prolongs image acquisition time and screen-reading time (at initial implementation), and appears to be associated with improved screening accuracy. ADVANCES IN KNOWLEDGE: These findings provide relevant information to guide larger trials of integrated 3D mammography (2D+3D) and its potential implementation into screening practice.

A diagnostic flowchart, including TCD, Xe-CT and angiography, to improve the diagnosis of vasospasm critically affecting cerebral blood flow in patients with subarachnoid haemorrhage, sedated and ventilated.

The aim of this study was to prospectively evaluate a clinical protocol including transcranial doppler (TCD), Xenon-CT (Xe-CT) and angiography, for the detection of vasospasm leading to critical reductions of regional cerebral blood flow (rCBF) in both ventilated and sedated SAH patients, i.e. patients in whom clinical evaluation was not possible. Seventy-six patients were prospectively included in a surveillance protocol for daily TCD vasospasm monitoring. When TCD showed a V(mean) above 120 cm/sec in the middle cerebral artery (MCA), patients underwent Xe-CT study. If rCBF in the MCA was reduced to below 20 ml/100 g/min or if there was a reduction in the rCBF with significant asymmetry between the two MCAs, angiography was performed. Conversely, further Xe-CT and angiography were not obtained unless the TCD V(mean) values reached values above 160 cm/sec. In 35 patients, V(mean) attained values above 120 cm/sec, but only in five of them, rCBF was suggestive of vasospasm, and angiography confirmed the diagnosis in four. The protocol suggests that in sedated and ventilated patients, detection of a critical rCBF reduction due to vasospasm is possible to allow for more specific treatment and to reduce undue medical complications.

PON1 activity and genotype in patients with arterial ischemic stroke and in healthy individuals.

OBJECTIVE: Paraoxonase-1 (PON1) is an esterase with antioxidant properties. Low PON1 enzyme activity or specific allelic polymorphisms seem to be associated with the risk of developing coronary artery disease or acute ischemic stroke (AIS). Our objective was to determine the distribution of both PON1 enzyme activity and its genotype in a group of patients with AIS. MATERIALS AND METHODS: PON1 activity and the relative Q192R and L55M polymorphisms in the PON1 gene were assessed on 126 survivors of a first AIS and in 92 healthy subjects. RESULTS: The genotype distribution for PON1 Q192R and L55M polymorphisms was similar in AIS patients and healthy subjects, but patients carrying the QRLL or RRLL genotype combination had lower PON1 enzyme activity compared with healthy subjects with the same genotype. CONCLUSION: We postulate that lower than expected PON1 enzyme activity within specific genotypes might explain the reported association between R and L alleles and the risk of developing AIS.

Regional cerebral blood flow levels as measured by xenon-CT in vascular territorial low-density areas after subarachnoid hemorrhage are not always ischemic.

INTRODUCTION: The aim of this study was to assess regional cerebral blood flow (rCBV) in areas of CT hypoattenuation appearing in the postoperative period in patients treated for aneurysmal subarachnoid hemorrhage (SAH) using xenon-enhanced CT scanning (Xe-CT). METHODS: We analyzed 15 patients (5 male and 10 female; mean age 49.7+/-12.1 years) with SAH on CT performed on admission to hospital and who showed a low-density area within a well-defined vascular territory on CT scans after clipping or coiling of a saccular aneurysm. All zones of hypoattenuation were larger than 1 cm(2) and showed signs of a mass effect suggesting a subacute phase of evolution. Two aneurysms were detected in two patients. Aneurysms were located in the middle cerebral artery (n=7), in the anterior communicating artery (n=6), in the internal carotid artery (n=3), and in the posterior communicating artery (n=1). Treatments were surgical (n=8), endovascular (n=2) or both (n=1). A total of 36 Xe-CT studies were performed and rCBF values were measured in two different regions of interest (ROI): the low-density area, and an area of normal-appearing brain tissue located symmetrically in the contralateral hemisphere. RESULTS: rCBF levels were significantly lower in the low-density area than in the contralateral normal-appearing area (P<0.01). In the low-density areas, irreversible ischemia (CBF <10 ml/100 g per minute) was present in 11/36 lesions (30.6%), ischemic penumbra (CBF 10-20 ml/100 g per minute) and oligemia (CBF 20-34 ml/100 g per minute) in 8/36 lesions (22.2%), relative hyperemia (CBF 34-55 ml/100 g per minute) in 7/36 lesions (19.4%), and absolute hyperemia (CBF >55 ml/100 g per minute) in 2/36 lesions (5.6%). CONCLUSION: Our study confirmed that rCBF is reduced in new low-density lesions related to specific vascular territories. However, only about one-third of the lesions showed rCBF levels consistent with irreversible ischemia and in a relatively high proportion of lesions, rCBF levels indicated penumbral, oligemic and hyperemic areas.

Diagnostic impact of the spectrum of ischemic cerebral blood flow thresholds in sedated subarachnoid hemorrhage patients.

OBJECTIVE: Ischemia is the main cause of secondary damage in subarachnoid hemorrhage (SAH). Cerebral blood flow (CBF) measurement is useful to detect critical values. We analyzed the diagnostic impact of CBF ischemic thresholds to predict a new low attenuation area on computed tomography (CT) due to failure of large vessel perfusion. METHODS: We analyzed 48 xenon CT (Xe-CT) studies from 10 patients with SAH. CBF measurements were obtained by means of Xe-CT and cortical regions of interest (ROls). The ROIs which appeared in a hypoattenuation area were recorded. Cortical CBF was tested for specificity and sensitivity as a predictor of hypoattenuation by means of a receiver operating characteristic curve. RESULTS: Mean age was 58 (SD +/- 12.4) years. The median Fisher score and Hunt and Hess scale were 2 and 3, respectively. The area under the receiver operating characteristic curve was 0.912 (CI 0.896 to 0.926). The cut-off value for best accuracy was 6 mL/ 100 g/min, with a likelihood ratio of 37. CONCLUSION: The present study suggests a threshold of 6 mL/100 g/ min as a predictor of a new low attenuation area. However, each clinician should choose the most useful threshold according to pre-test probability and the cost/effectiveness ratio of the applied therapies.

Reperfusion of low attenuation areas complicating subarachnoid hemorrhage.

Hypoattenuation areas shown on brain CT scans after subarachnoid hemorrhage (SAH) are believed to be associated with persistent ischemia. The aim of this study was to evaluate regional cerebral blood flow (rCBF) in hypoattenuation areas and its evolution over time by means of Xenon CT (Xe-CT). We enrolled 16 patients with SAH who developed a hypoattenuation area in the middle cerebral artery territory. Patients were studied at time zero (the first Xe-CT), within 24 to 96 hours, and 96 hours after the initial Xe-CT. We analyzed 19 hypoattenuation areas caused by vascular distortion, vasospasm, or post-surgical embolization in 48 Xe-CT studies. Areas of hypoattenuation were divided in 2 groups according to initial rCBF. In the first group (n = 15), rCBF was initially above 6 mL/100 gr/min but only 2 were still ischemic (rCBF < 18 mL/ 100 gr/min) 96 hours after the first Xe-CT, while 7 (58%) were hyperemic. Conversely, in the second group with severe ischemia (rCBF < 6 mL/100 gr/min; n = 4) mean rCBF increased (p = 0.08) but still remained below the ischemic threshold. In severely ischemic lesions, rCBF reperfusion occurs but is probably marginally relevant. Conversely, in lesions not initially severely ischemic, residual CBF gradually improved and frequently became hyperemic. The functional recovery of these zones remains to be evaluated.

An Italian survey of severe head trauma management during extracranial surgery.

BACKGROUND AND OBJECTIVE: Anaesthetic drugs and procedures interfere with secondary brain injury following severe head trauma, yet studies regarding the anaesthetic management of these patients are lacking. We investigated the behaviour of Italian anaesthetists regarding this topic. METHODS: A questionnaire investigating the approach to a patient with severe head trauma requiring an urgent splenectomy for ruptured spleen was sent to 250 Italian anaesthetists. Questions regarded the pre-, intra- and postoperative phases, and concerned the rationale use and availability of specific monitoring systems, and indications for invasive procedures and use of drugs, fluids and blood products. RESULTS: There were 162 (64.8%) responders. Seventy-five percent believed that early tracheal intubation within the emergency room was necessary, while 25% postponed it to the operating room. Basic monitoring was defined as essential by all responders, 147 (90.7%) considered invasive arterial pressure monitoring to be essential. Fifty-seven (84%) anaesthetists working in hospitals without neurosurgical facilities would have transferred the patient after splenectomy. Prophylactic hyperventilation was frequently used (36%). Sixty-eight percent of responders would have preferred in intracranial pressure monitoring inserted before laparotomy, but only 35% actually had this possibility. In case of acute intraoperative arterial hypotension after splenectomy, 54% of the responders advocated the use of blood or blood products to optimize peripheral oxygen transport. CONCLUSIONS: More widespread knowledge of certain areas of severe head trauma management such as early tracheal intubation, avoidance of prophylactic hyperventilation, adequate invasive monitoring, appropriate use of blood products, and timing of transfer to hospitals with neurosurgical facilities is needed.

Estimated cerebral respiratory quotient and arteriovenous differences of CO2 in the ultra early detection of global ischemia in severe head injury.

The specificity of jugular bulb saturation (SjO2) and arteriovenous oxygen difference (AVDO2) to detect global cerebral ischemia remains controversial. An absolute increase in the arteriovenous difference of carbon dioxide tension (AVDpCO2) and, more specifically, the estimated respiratory quotient (eRQ = AVDpCO2/AVDO2) may indicate anaerobic CO2 production. We compared these variables with SjO2 to predict global cerebral ischemia. We selected 36 patients from a cohort of 69 consecutive patients suffering from severe traumatic brain injury. All patients had jugular bulb sampling within 6 hours after injury. Brain death at 48 hours was used as a surrogate index of irreversible ischemia to build a receiver operating characteristics (ROC) curve analysis. The mean (+/- standard deviation) eRQ in the 13 patients who died early (3.7 +/- 3.2 mmHg/ml/dl) was higher than the survivors (1.78 +/- 0.45 mmHg/ml/dl, P = 0.03). There was no differences in SjO2 between groups. The area under the ROC curves for eRQ, but not that of AVDpCO2, was greater (P = 0.04) than that of SjO2. The eRQ, more than AVDpCO2, appears to be a potentially more informative index of global cerebral ischemia than SjO2.

Cerebral blood flow in mean cerebral artery low density areas is not always ischemic in patients with aneurysmal subarachnoid hemorrhage--relationship with neurological outcome.

Aneurysmal subarachnoid hemorrhage (SAH) can be complicated by reduction of regional cerebral blood flow (rCBF) from large conductance vessels leading to focal edema appearing as an area of hypoattenuation on CT. In this study we included 29 patients with SAH due to aneurysmal rupture, having 36 CT low density areas within the middle cerebral artery territory in whom a total of 56 Xenon-CT (Xe-CT) studies were performed. Collectively, we evaluated 70 hypoattenuated areas. rCBF levels were measured in two different regions of interest drawn manually on the CT scan, one in the low density area and the other in a corresponding contralateral area of normal-appearing brain tissue. In the low density area (22.6 +/- 22.7 ml/100 gr/min) rCBF levels were significantly lower than in the contralateral area (32.8 +/- 17.1 7 ml/100 gr/min) (p = 0.0007). In the injured areas deep ischemia (CBF < 6 ml/ 100 g/min) was present in only 25.7% of Xe-CT studies, suggesting that hypodense areas are not always ischemic, whereas in 43.7% of the lesions/Xe-CT studies we found hyperemic values. Patients with a better outcome had hyperemic lesions, suggesting brain tissue recovery in injured areas.

Cerebral blood flow mapping in two different subtypes of intraparenchymal hemorrhagic traumatic lesions.

The pathogenesis and the viability of edematous tissue may be different in traumatic hematomas and traumatic contusions. We tested the hypothesis that mapping of regional Cerebral Blood Flow (rCBF) was different in these two subtypes of traumatic intraparenchymal lesions. We evaluated rCBF by means of Xenon-enhanced computerized tomography (Xe-CT) in 59 traumatic intracerebral lesions from 43 patients with severe head injury. One-hundred-nine intracerebral lesions/Xe-CT CBF measurements were obtained. The rCBF was measured in the hemorrhagic core, in the intralesional oedematous low density area and in a 1 cm rim of apparently normal perilesional parenchyma of both lesion subtypes. Not statistically significant lower rCBF levels were found in the edematous area of traumatic contusions. In traumatic hematomas rCBF levels were lower in the core than in the low density area, suggesting that rCBF in edematous area is marginally involved in the initial traumatic injury and that edema is probably influenced by the persistence of the hemorrhagic core. Conversely, in the traumatic contusions a difference in rCBF values was found between core, low density area and perilesional area, indicating that rCBF of the low density area is related to a concentrical distribution of the initial injury.

Normal jugular bulb oxygen saturation.

BACKGROUND: Normal values of the jugular bulb oxygen saturation were obtained in 1942 and in 1963. Correct catheter positioning was not confirmed radiologically. OBJECTIVES: To replicate the measurements during angiographic catheterisation of the jugular bulb. METHODS: Oxygen saturation in the jugular bulb (SjO(2)), inferior petrosal sinus (SipsO(2)), and internal jugular vein was bilaterally measured in 12 patients with Cushing's syndrome undergoing selective bilateral catheterisation of the inferior petrosal sinus. In addition, data from the two old series were reanalysed for comparison. RESULTS: SjO(2) values (44.7%) were significantly lower than in the two old series, particularly concerning the normal lower limit (54.6% and 55.0% respectively). Comparative analysis suggests that contamination with the extracerebral blood of the facial veins and inferior petrosal sinuses was responsible for falsely high SjO(2) values in the two old series. CONCLUSIONS: The normal lower SjO(2) limit is lower than previously recognised. This may have practical implications for treating severe head trauma patients.

Mixed dishomogeneous hemorrhagic brain contusions. Mapping of cerebral blood flow.

The aim of the study was to verify whether regional cerebral blood flow (rCBF) was distributed centrifugally in traumatic hemorrhagic contusions with multiple cores within an oedematous area. Seventeen traumatic brain contusions, from 14 patients with severe head injury (GCS < 9), were analyzed during 39 Xenon-enhanced computerized tomography (Xe-CT) studies. The CBF was measured in 3 concentric regions of interest (ROls): the hemorrhagic core, the intracontusional oedematous low density area and a 1 cm rim of pericontusional normal-appearing brain tissue surrounding the contusion. Differences between rCBFs in the three ROIs were found (p < 0.0001). rCBF in both the hemorrhagic core (21.4 +/- 19.4 ml/ 100gr/min) and the intracontusional low density area (28.4 +/- 19 ml/100gr/min) were lower than rCBF in pericontusional normal-appearing area (41.9 +/- 16 ml/100gr/min) (p < 0.0001). No significant differences were found between rCBF measured in the hemorrhagic core and intracontusional low density area (p = 0.184). Our study suggests that in the mixed density contusions with multiple hemorrhagic cores, the CBF is concentrically distributed, improving from the core to the periphery.

Induced acute arterial hypertension and regional cerebral flow in intracontusional low density area.

Traumatic brain contusions have been associated with regional ischemia. We aimed to measure the effect of induced supra-normal values of cerebral perfusion pressure (CPP) on regional cerebral blood flow (rCBF) in the intracontusional low density area surrounding the contusional hemorrhagic core. In 7 severely head injured patients (GCS < or = 8) harbouring a contusion larger than 2 cm, the rCBF levels were measured, by means of Xenon-enhanced CT, in: 1) the intracontusional low density area: 2) contralaterally, in a normal brain symmetric area. CBF studies were performed at a baseline CPP of 65.3 mmHg +/- 7 and after 20 minutes of norepinephrine-induced CPP supernormal values (88.3 mmHg +/- 10.5) (p = 0.0013). A "paradoxical" reduction of rCBF levels was observed in both the intracontusional low density area (p = 0.07) and the contralateral "normal" area (p = 0.08). In particular, this decrease of rCBF in the intracontusional low density area (-25.7 + 10 ml/100gr/min) (p = 0.0009) was present in only 4 cases, having a mean rCBF at baseline of 25 +/- 16 ml/100gr/min. In the remaining 3 cases in which rCBF at baseline was abnormally low (12 +/- 7 ml/ 100gr/min), rCBF values improved slightly (3.6 +/- 2 ml/100gr/min) (p = 0.61). An acute increase of CPP seems to marginally affect rCBF in the intracontusional low density area having critically reduced initial values, but may greatly reduce rCBF in subjects starting from non-critical baseline values.

Detection of early ischemia in severe head injury by means of arteriovenous lactate differences and jugular bulb oxygen saturation. Relationship with CPP, severity indexes and outcome. Preliminary analysis.

UNLABELLED: Early ischemia may be highly relevant in patients with severe head injuries. The aims of the study were: 1) to define if abnormal arteriovenous lactate difference (AVDL) and jugular bulb oxygen saturation (SjO2) are found in the early 24 hrs post injury; 2) to compare if abnormalities of SjO2 and of AVDL were associated with a specific typology of severity indexes and outcome; 3) to detect any association between abnormal AVDL and SjO2 with levels of cerebral perfusion pressure (CPP). The study involved 29 patients, with CPP, AVDL and SjO2 measured within 24 hours post-injury. RESULTS: 1) Abnormal AVDL was found in 21% while abnormal SjO2 was detected in 38% of the patients; 2) abnormal AVDL was associated with cases of most severe injury; 3) CPP level below 60 mmHg was associated with abnormal AVDL and SjO2. Low CPP appeared to be the most likely measurable cause of early ischemia. Abnormalities of AVDL appeared to be more sensitive, than SjO2, with regard to detection of the most severe cases.

Evolving lesions in traumatic subarachnoid hemorrhage: prospective study of 110 patients with emphasis on the role of ICP monitoring.

We have consecutively studied 110 patients with traumatic subarachnoid hemorrhage (tSAH) on the first Computed Tomography (CT) scan (obtained in each case within 3 hours from injury). The only exclusion criteria were brain death on admission, and severe hypotension due to extracranial injuries. All CTs were reviewed by one of us and the "worst" CT examination was determined. We defined the worst CT examination as that showing the most extensive degree of parenchymal-associated damage. Intracranial pressure was monitored in 25 severely head injured patients. Seventy-four patients (66%) showed an evolution from the initial CT scan (worst CT not corresponding to the admission CT). The outcome was favorable in 53 cases (73%) of patients with evolving lesions and in 32 cases (89%) with non evolving lesion. In the 25 severely head injured patients, Intra-cranial Pressure (ICP) monitoring (in combination with scheduled repeat CT scan) was helpful to identify the timing of the worst parenchymal damage and of surgery in those patients with an initial normal intracranial pressure in spite of an evolving lesion.

Do different dialytic techniques have different atherosclerotic and antioxidant activities?

To compare the chronic effect of several dialytic techniques (bicarbonate dialysis, BHD; acetate free biofiltration, AFB; hemodiafiltration, HDF; paired filtration dialysis, PFD) on atherosclerosis and antioxidant activity, three different indices were created. The first (atherosclerotic index = AI) is formed using the sum of three plasma substances: MDA, Hcy, and Cys (malondialdehyde, homocysteine, cysteine). The second (antioxidant activity index = AOAI) is the sum of five erythrocyte (E) parameters: E-GSH, GPx, CAT, SOD, GR (E-glutathione, E-glutathione peroxidase, E-catalase, E-superoxide dismutase, E-glutathione reductase). The third (defense index = DI) is derived from the previous two: (AOAI - AI). The indices were so expressed as AI in mmol/L, AOAI in U/g hemoglobin (Hb), and DI in arbitrary units. These indices were calculated in 20 controls and 51 chronic HD patients (26 female, 25 male) before, during, and after the first session of the week. HD patients were divided according to their dialytic technique: BHD, n = 35; AFB, n = 5 patients; HDF, n = 7 patients; or PFD = 4 patients. All patients had been treated with a given technique for at least 12 months, before entering the study. As expected, HD patients had AI values higher than controls, both before and after the session, with a mean value of 541 (before) and 331 (after), whereas controls had a mean value of 205. The AOAI was lower than controls, both before and after the session, the mean value being 1,122 (before) and 1,582 (after), that of controls being 2,424. In all cases, PFD gave the best "acute" results; at the end of a PFD session, near normal values of AI, AOAI, and DI (defensive index = AOAI - AI) were obtained.

[Malignant fibrous histiocytoma of the larynx. Presentation of a clinical case and review of the literature]. / L'istiocitoma fibroso maligno della laringe. Presentazione di un caso clinico e revisione della Letteratura.

Malignant Fibrous Histiocytoma (MFH) is a tumor of mesenchymal origin which rarely occurs in head and neck. At the laryngeal level this neoplasm manifests itself as a sessile or peduncolate mass with ulcerations. Histological diagnosis of small biopsy samples is difficult and is, therefore, performed on the full surgical piece. The treatment of choice is complete exeresis of the mass within a safety margins. The Authors present a case report, the 37th laryngeal MFH reported in the literature and, in particular, the 5th case presented in a supraglottic site. Surgical treatment performed in this patient was exeresis of the neoplasm through pharyngothyrotomy conduced with safety margins and reconstruction by thyrohyoidpexy.

Prematurely detected traumatic carotid-cavernous sinus fistula, by means of unintentional contralateral inferior petrosal sinus catheterization: bilateral jugular bulb oxygen saturation findings.

A traumatic carotid-cavernous sinus fistula (CCSF) was prematurely suspected following the detection of arterial-like hemoglobin oxygen saturation values, sampled from a catheter placed for cerebrovenous monitoring. A high-resolution scan of jugular foramina revealed that the catheter tip had been unintentionally placed in the inferior petrosal sinus, contralateral to the CCSF, instead of in the superior jugular bulb. Jugular bulb hemoglobin oxygen saturation (SjO2), ipsilateral to CCSF, later approached arterial hemoglobin oxygen saturation (SaO2) values.The possibility and consequences of unintentional catheterization of the inferior petrosal sinus, and of extracerebral contamination of blood in the jugular bulb due to blood in the inferior petrosal sinus, are discussed. We also discuss the reliability of SjO2 monitoring in the present CCSF case.

Cerebral arteriovenous PCO2 difference and early global cerebral ischemia in a patient with acute severe head injury.

We report a case of acute head injury with severe diffuse brain swelling in which early global cerebral ischemia was followed by brain death. Global cerebral ischemia was detected by cerebral arteriovenous lactate content difference, cerebral arteriovenous carbon dioxide tension (PCO2) difference, and cerebral arteriovenous hydrogen ion content difference. Physiopathological aspects of cerebrovenous hypercarbia are discussed.