Head down tilt 15° in experimental intracerebral hemorrhage: a randomized noninferiority safety trial.

BACKGROUND AND PURPOSE: Head down tilt 15° (HDT15°), applied before recanalization, increases collateral flow and improves outcome in experimental ischemic stroke. For its simplicity and low cost, HDT15° holds considerable potential to be developed as an emergency treatment of acute stroke in the prehospital setting, where hemorrhagic stroke is the major mimic of ischemic stroke. In this study, we assessed safety of HDT15° in the acute phase of experimental intracerebral hemorrhage. METHODS: Intracerebral hemorrhage was produced by stereotaxic injection of collagenase in Wistar rats. A randomized noninferiority trial design was used to assign rats to HDT15° or flat position (n = 64). HDT15° was applied for 1 h during the time window of hematoma expansion. The primary outcome was hematoma volume at 24 h. Secondary outcomes were mass effect, mortality, and functional deficit in the main study and acute changes of intracranial pressure, hematoma growth, and cardiorespiratory parameters in separate sets of randomized animals (n = 32). RESULTS: HDT15° achieved the specified criteria of noninferiority for hematoma volume at 24 h. Mass effect, mortality, and functional deficit at 24 h showed no difference in the two groups. HDT15° induced a mild increase in intracranial pressure with respect to the pretreatment values (+2.91 ± 1.76 mmHg). HDT15° had a neutral effect on MRI-based analysis of hematoma growth and cardiorespiratory parameters. CONCLUSIONS: Application of HDT15° in the hyperacute phase of experimental intracerebral hemorrhage does not worsen early outcome. Further research is needed to implement HDT15° as an emergency collateral therapeutic for acute stroke.

ICA-based denoising for ASL perfusion imaging.

Arterial Spin Labelling (ASL) imaging derives a perfusion image by tracing the accumulation of magnetically labeled blood water in the brain. As the image generated has an intrinsically low signal to noise ratio (SNR), multiple measurements are routinely acquired and averaged, at a penalty of increased scan duration and opportunity for motion artefact. However, this strategy alone might be ineffective in clinical settings where the time available for acquisition is limited and patient motion are increased. This study investigates the use of an Independent Component Analysis (ICA) approach for denoising ASL data, and its potential for automation. 72 ASL datasets (pseudo-continuous ASL; 5 different post-labeling delays: 400, 800, 1200, 1600, 2000 m s; total volumes = 60) were collected from thirty consecutive acute stroke patients. The effects of ICA-based denoising (manual and automated) where compared to two different denoising approaches, aCompCor, a Principal Component-based method, and Enhancement of Automated Blood Flow Estimates (ENABLE), an algorithm based on the removal of corrupted volumes. Multiple metrics were used to assess the changes in the quality of the data following denoising, including changes in cerebral blood flow (CBF) and arterial transit time (ATT), SNR, and repeatability. Additionally, the relationship between SNR and number of repetitions acquired was estimated before and after denoising the data. The use of an ICA-based denoising approach resulted in significantly higher mean CBF and ATT values (p < 0.001), lower CBF and ATT variance (p < 0.001), increased SNR (p < 0.001), and improved repeatability (p < 0.05) when compared to the raw data. The performance of manual and automated ICA-based denoising was comparable. These results went beyond the effects of aCompCor or ENABLE. Following ICA-based denoising, the SNR was higher using only 50% of the ASL-dataset collected than when using the whole raw data. The results show that ICA can be used to separate signal from noise in ASL data, improving the quality of the data collected. In fact, this study suggests that the acquisition time could be reduced by 50% without penalty to data quality, something that merits further study. Independent component classification and regression can be carried out either manually, following simple criteria, or automatically.

Impact of automated ICA-based denoising of fMRI data in acute stroke patients.

Different strategies have been developed using Independent Component Analysis (ICA) to automatically de-noise fMRI data, either focusing on removing only certain components (e.g. motion-ICA-AROMA, Pruim et al., 2015a) or using more complex classifiers to remove multiple types of noise components (e.g. FIX, Salimi-Khorshidi et al., 2014 Griffanti et al., 2014). However, denoising data obtained in an acute setting might prove challenging: the presence of multiple noise sources may not allow focused strategies to clean the data enough and the heterogeneity in the data may be so great to critically undermine complex approaches. The purpose of this study was to explore what automated ICA based approach would better cope with these limitations when cleaning fMRI data obtained from acute stroke patients. The performance of a focused classifier (ICA-AROMA) and a complex classifier (FIX) approaches were compared using data obtained from twenty consecutive acute lacunar stroke patients using metrics determining RSN identification, RSN reproducibility, changes in the BOLD variance, differences in the estimation of functional connectivity and loss of temporal degrees of freedom. The use of generic-trained FIX resulted in misclassification of components and significant loss of signal (< 80%), and was not explored further. Both ICA-AROMA and patient-trained FIX based denoising approaches resulted in significantly improved RSN reproducibility (p < 0.001), localized reduction in BOLD variance consistent with noise removal, and significant changes in functional connectivity (p < 0.001). Patient-trained FIX resulted in higher RSN identifiability (p < 0.001) and wider changes both in the BOLD variance and in functional connectivity compared to ICA-AROMA. The success of ICA-AROMA suggests that by focusing on selected components the full automation can deliver meaningful data for analysis even in population with multiple sources of noise. However, the time invested to train FIX with appropriate patient data proved valuable, particularly in improving the signal-to-noise ratio.

Pravastatin acute neuroprotective effects depend on blood brain barrier integrity in experimental cerebral ischemia.

Statins have since long been reported to exert acute neuroprotection in experimental stroke models. However, crucial questions still need to be addressed as far as the timing of their cerebral effects after intravascular administration and the role played by the blood brain barrier (BBB) crossing properties. We tested the effects of an hydrophilic statin (pravastatin, 100 nM), which poorly crosses BBB under physiological conditions. Pravastatin was administered either 90 min before or immediately after transient middle cerebral artery occlusion in the in vitro isolated guinea pig brain preparation. A multi-modal outcome assessment was performed, through electrophysiological and cerebral vascular tone recordings, MAP-2 immunohistochemistry, BBB evaluation via ZO-1/FITC-albumin analysis, AKT and ERK activation and whole-cell antioxidant capacity. Pravastatin pre-ischemic administration did not produce any significant effect. Pravastatin post-ischemic administration significantly prevented MAP-2 immunoreactivity loss in ischemic areas, increased ERK phosphorylation in the ischemic hemisphere and enhanced whole-cell antioxidant capacity. Electrophysiological parameters, vascular tone and AKT signaling were unchanged. In all tested ischemic brains, ZO-1 fragmentation and FITC albumin extravasation was observed, starting 30 min from ischemia onset, indicating loss of BBB integrity. Our findings indicate that the rapid anti-ischemic effects of intravascular pravastatin are highly dependent on BBB increased permeability after stroke.

Efficacy of different gonadotropin combinations to support ovulation induction in WHO type I anovulation infertility: clinical evidences of human recombinant FSH/human recombinant LH in a 2:1 ratio and highly purified human menopausal gonadotropin stimulation protocols.

BACKGROUND: The World Helath Organization (WHO) Group I anovulation, or hypogonadotropic hypogonadism (HH), is characterized by reduced hypothalamic/pituitary activity which results in abnormally low serum FSH and LH levels and negligible estrogen activity. AIM: To compare the efficacy of human recombinant FSH (r-hFSH) plus human recombinant LH (r-hLH) in a 2:1 ratio with highly purified human menopausal gonadotropin (hMG-HP) urinary extract, containing LH-like activity, in women with HH. SUBJECTS AND METHODS: This two-arm randomized open-label study included 35 HH women (aged 25-36 yr) attending our Center. Eighteen patients received 150 IU hMG-HP (150 IU FSH + 150 IU LH-like activity) and seventeen received 150IU r-hFSH/75IU rhLH daily for a maximum of 16 days. Ovulation was induced by a single administration of hCG on the day after the last hMG-HP or r-hFSH/r-hLH. RESULTS: The primary efficacy endpoint was ovulation induction as measured by follicle ≥17 mm, pre-ovulatory estradiol (E 2 ) ≥400 pmol/l and mid-luteal phase progesterone (P 4 ) ≥25 nmol/l. Secondary efficacy endpoints included E 2 levels/follicle at mid-cycle, number of follicles at mid-cycle and pregnancy rate (PR). Following a total of 70 cycles, 70% of r-hFSH/r-hLH treated patients met the primary endpoint vs 88% in hMG-HP group (p=0.11). However, PR in r-hFSH/r-hLH group was 55.6% compared to 23.3% in hMG-HP group (p=0.01). CONCLUSIONS: The primary endpoint achievement did not correlate with PR. This study has shown the superiority of LH compared to hCG in supporting FSH-induced follicular development in HH women.

Centromere conversion and retention in somatic cell hybrids.

The generation of somatic cell hybridization-derived cell lines between highly divergent species affords the opportunity to examine the concept of 'genome dominance' in the context of genetic and epigenetic changes. While whole-scale genome dominance has been well documented in natural hybrids among closely related species, an examination of centromere position and sequence retention in 2 marsupial-eutherian hybrids has revealed a mechanism for 'centromere dominance' as a driving force in the generation of stable somatic cell hybrids following an initial period of genomic instability. While one somatic cell hybrid cell line appeared to retain marsupial centromere sequences which remained competent to recruit the centromere-specific histone variant CENP-A in a Chinese hamster background, fusion events between marsupial and mouse-derived chromosomes in another hybrid line led to a centromere sequence conversion from one species to the other. We postulate that the necessity to maintain an epigenetically defined centromere following genome hybridization may be responsible for retention of specific chromosomes and may result in rapid sequence turnover to facilitate the recruitment of CENP-A containing histones.

Semi-automatic brain region extraction (SABRE) reveals superior cortical and deep gray matter atrophy in MS.

In multiple sclerosis (MS), atrophy occurs in various cortical and subcortical regions. However, it is unclear whether this is mostly due to gray (GM) or white matter (WM) loss. Recently, a new semi-automatic brain region extraction (SABRE) technique was developed to quantify parenchyma volume in 13 hemispheric regions. This study utilized SABRE and tissue segmentation to examine whether regional brain atrophy in MS is mostly due to GM or WM loss, correlated with disease duration, and moderated by disease course. We studied 68 MS patients and 39 normal controls with 1.5 T brain MRI. As expected, MS diagnosis was associated with significantly lower (P < 0.001) regional brain parenchymal fractions (RBPFs). While significant findings emerged in 11 GM comparisons, only four WM comparisons were significant. The largest mean RBPF percent differences between groups (MS < NC) were in the posterior basal ganglia/thalamus region (-19.3%), superior frontal (-15.7%), and superior parietal (-14.3%) regions. Logistic regression analyses showed GM regions were more predictive of MS diagnosis than WM regions. Eight GM RBPFs were significantly correlated (P < 0.001) with disease duration compared to only one WM region. Significant trends emerged for differences in GM, but not WM between secondary progressive (SP) and relapsing-remitting MS patients. Percent differences in GM between the two groups were largest in superior frontal (-9.9%), medial superior frontal (-6.5%), and superior parietal (-6.1%) regions, with SP patients having lower volumes. Overall, atrophy in MS is diffuse and mostly related to GM loss particularly in deep GM and superior frontal-parietal regions.

Interpreting patient/informant discrepancies of reported cognitive symptoms in MS.

Although numerous studies have shown that brain-damaged patients tend to underestimate neuropsychological (NP) impairment when self-ratings are compared to informant ratings, the meaning of such discrepancies is not well studied in multiple sclerosis (MS). We compared patient self- and informant-report questionnaire ratings of NP functioning in 122 MS patients and 37 age- and education-matched normal controls. In addition to completing the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ), participants underwent NP testing and assessment of depression, personality, and neuropsychiatric symptoms. Based on the normal distribution of discrepancy scores, patients were classified according to whether they overestimated or underestimated their cognitive ability, relative to informant ratings. ANOVAs comparing test scores derived from overestimators, underestimators, and accurate estimators were significant for multiple measures of cognitive function, depression, personality, and neuropsychiatric symptoms. Overestimators were characterized by less depression and conscientiousness, and greater degrees of cognitive impairment, euphoric behavioral disinhibition, and unemployment as compared to underestimators. We conclude that patient/informant discrepancy scores on the MSNQ are associated with the aforementioned neuropsychiatric features, and that the MSNQ has potential utility for predicting euphoria and disinhibition syndromes in MS.

[Laser assisted intracytoplasmic sperm injection: a more effective and faster technique of immobilization of spermatozoa than traditional one]. / Impiego del laser per l'immobilizzazione degli spermatozoi: un'alternativa efficace e più rapida alla tecnica tradizionale.

AIM: Intracytoplasmic sperm injection (ICSI) is employed routinely in the assisted reproductive technique, in particular in case of male factor infertility. Recently, some options have been introduced in the micromanipulation system employed in ICSI, improving the performance of this technique. One of these is a no-contact laser, mostly used for the assisted hatching and the blastomere biopsy in preimplantation genetic diagnosis. One of the most important step of the ICSI technique is the sperm immobilization. Normally, this is performed by the operator and needs some time. METHODS: A one-year perspective-comparative study has been carried out and the results obtained with the traditional technique of immobilization of spermatozoa have been compared with those obtained with the laser technique (spermatozoa previously immobilized by no-contact laser). We have evaluated 3 parameters: 1) fertilization rate; 2) cleavage rate and 3) time needed to immobilize sperm. RESULTS: Some interesting findings have been observed: the embryo quality, fertilization rate and cleavage rate seem the same in both groups. The most interesting finding is the drastic reduction of the time needed for microinjection when the laser technique is used. CONCLUSIONS: This technique will reduce the total time needed to perform the ICSI, decreasing the time of exposure of the gametes outside the incubator and reducing the possibility of irreversible damage.

A social cognitive perspective on religious beliefs: their functions and impact on coping and psychotherapy.

Religious beliefs are an important part of clients' culture, whether acknowledged or not. Psychological theories about social and cognitive processes can help mental-health professionals better understand the function of religious beliefs in coping and their role in therapy. Religious individuals are likely to use heuristics to form rapid judgments rather than engage in formal information-gathering processes. The confirmatory and in-group/out-group biases support such judgments and shield them from disconfirmatory evidence. Religious beliefs provide order and understanding to an otherwise chaotic and unpredictable world. Many religions advocate forgiveness, which is often helpful in resolving conflicts. Another beneficial religious belief is an ever-present spiritual attachment figure. Negative effects of religion include its exercising aversive control to maintain conformity and its promoting an external locus of control. In contrast, mental-health professionals belong to a tradition of free inquiry and self-development, and guide clients to acquire competencies necessary to change and direct their lives. Therapist attitudes are far less likely to include allegiance to religion than are those of the public and psychiatric patients. Rather than being biased against religion or trying to debate religion, therapists need to engage in problem solving with clients in the context of this example of sociocultural factors.

Assessment of visual-motor coordination in 6- to 11-yr.-olds.

The concurrent and content validity of the Rey-Osterrieth Complex Figure Test and the Beery Developmental Test of Visual-Motor Integration-Third Revision were investigated through correlational analysis. 432 children, ages 6 to 11 years, were administered both tests. Across age groups participants performed better on both measures, providing support for the similarity of the measures and their sensitivity to the development of visuomotor integration. Although analysis indicated considerable overlap in the content of the two scales, the shared variance ranged from 7% to 31%, depending on the age of the child. The Rey-Osterrieth figure is composed of overlapping squares, rectangles, triangles, and various other shapes. Given this complex combination, scores on this test reflect the examinees' visual organization and motor planning skills. On the other hand, the Beery test consists of a series of shapes which progress from simple figures to more complex ones. Because the figures become more difficult to copy, the score on this test reflects the examinees' developmental level of visuomotor ability. Despite these differences in test stimuli and interpretation of performance, the present study showed considerable shared variance in the scores of the examinees who took both tests. Finally, local norms for the Rey-Osterrieth figure using the scoring approach of E. M. Taylor (1959, adapted from Osterrieth, 1944) and including standard scores are presented for children ages 6 to 11 years.

Lipoperoxidation and antioxidant enzymes activity in pregnancy complicated with hypertension.

OBJECTIVE: To assess maternal circulating levels of lipid peroxidation breakdown products and antioxidant enzymes activity in pregnancies complicated with hypertension. STUDY DESIGN: Ten women with uncomplicated pregnancies and nine women with hypertension antedating pregnancy were prospectively sampled. Eight women, who had developed preeclampsia, were also cross-sectionally included. Twenty healthy non pregnant volunteers were the control group. Thiobarbituric acid reactive substances (TBA-RS), as lipid peroxidation products, and the activity of catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase (SOD), as antioxidant enzymes, were assayed in red blood cell hemolysates. A prooxidant/antioxidant (P/A) ratio (TBA-RS/CAT + GPX + SOD) was determined from the mean value of the volunteers. RESULTS: In women with chronic hypertension, TBA-RS levels were higher than those in normal pregnant women, whereas antioxidant enzymes activities were either stable or decreased. Therefore the P/A ratio was progressively lower in the second and third trimester. Similar result were found in patients with preeclampsia. CONCLUSIONS: Normal gestation induces an increase of lipid peroxidation products, whereas antioxidant activity seems stable. In pregnancies complicated by chronic hypertension, a deficiency of the oxidative system balance is detectable, which consistently progresses in the second and third trimester, strongly suggesting a failure of the protective mechanisms.

[Analytic study of the reliability of an integrated mineralometric and biochemical system in the dynamic evaluation of the bone mineral content after menopause]. / Studio analitico sull'affidabilità di un sistema integrato mineralometrico e biochimico nella valutazione dinamica del contenuto minerale osseo dopo la menopausa.

OBJECTIVE: The purpose of the present study was to determine the accuracy of Osteometer diagnostic test to estimate the rate of postmenopausal bone loss (% per year) by means of combined evaluation of mineralometric and biochemical data of bone turnover. STUDY DESIGN: This was a one-year analytic study of 58 post-menopausal, apparently health, women whose last spontaneous menstrual period was at least 12 months before study entry. Bone mineral content in the forearm and biochemical indicators of calcium metabolism in urine and serum were periodically assessed. MAIN OUTCOME MEASURES: Bone Mineral Content (BMC), plasmatic estradiol, FSH, LH, Fasting Urine Hydroxyproline/Creatinine (FU Hpr/Cr), Fasting Urine Calcium/Creatinine (FU Ca/Cr), serum bone Gla protein (sBGP), serum Alkaline Phosphatase (sAP) were measured in all subjects. RESULTS: One year after the first evaluation (BMC measurement and biochemical markers of bone turnover evaluation), percent changes of bone mineral content was compared to estimation of annual bone loss by Osteometer diagnostic test. The data show that at first evaluation it was predicted an annual bone loss of 1.2 +/- 0.3%. Periodically monitored after 1 year the same patients reported a mean decrease of 0.8 +/- 0.1% of bone mineral content. If so, no statistically differences were found between data predicted and data evaluated at control one year after. DISCUSSION: The use of Osteometer Diagnostic test, using BMC measurements of forearm and biochemical parameters, represents a safe and simply method to detect post-menopausal women and its permits to identify fast bone mass looser among post-menopausal women.

Lipid peroxidation products and antioxidant enzymes in red blood cells during normal and diabetic pregnancy.

Oxygen free radicals produced during normal aerobic metabolism have been implicated in several pathophysiological mammalian processes. The importance of free radical-mediated fatty acid oxidation has received much attention. The generation of active oxygen species may lead to lipid peroxidation and formation of reactive products, which may be involved in severe damage of cell molecules and structures. Free radical metabolism in pregnancy and in diabetes mellitus is still unclear. To add new insights to the question, changes in lipid peroxidation products and activities of three antioxidant enzymes: catalase (CAT), glutathione peroxidase (GPX) and superoxide dismutase (SOD) in maternal red blood cells haemolysates were evaluated in pregnant women with insulin-dependent diabetes mellitus (IDDM-PW) and in healthy pregnant women (HPW). Healthy non-pregnant women were the control group for IDDM-PW and HPW, respectively. Pregnancy provoked an increase of lipoperoxidation products and an high SOD activity since early pregnancy, while CAT and GPX activities did not change during gestation. IDDM-PW showed higher content of lipoperoxidation breakdown products and lower SOD activity at each trimester, if compared with HPW; moreover, a slight increase of CAT and SOD activity is reported during late diabetic pregnancy. IDDM-PW were in very good metabolic control at time of sampling. The variations reported suggest an easier membrane lipoperoxidability and, consequently, an easier membrane damage during diabetic gestation.