TCRgamma silencing during alphabeta T cell development depends upon pre-TCR-induced proliferation.

During thymus development, immature T cells become committed to two distinct lineages based upon expression of alphabeta or gammadelta TCR. In the alphabeta lineage, developing thymocytes progressively extinguish transcription of the TCRgamma genes by a poorly understood process known as gamma silencing. We show that alphabeta lineage thymocytes in mice lacking a functional pre-TCR undergo limited proliferation and fail to silence TCRgamma genes during development. Stimulation of pre-TCR-deficient immature thymocytes with anti-CD3 Abs does not directly down-regulate TCRgamma transcription but restores TCRgamma silencing following proliferation. Collectively our data reveal an important role for pre-TCR induced proliferation in activating the TCRgamma silencer in alphabeta lineage thymocytes, a process that may reinforce alphabeta or gammadelta lineage commitment.

Care complexity, mood, and quality of life in liver pre-transplant patients.

RATIONALE: This study was intended to document the frequency of care complexity in liver transplant candidates, and its association with mood disturbance and poor health-related quality of life (HRQoL). METHODS: Consecutive patients fulfilling inclusion criteria, recruited in three European hospitals, were assessed with INTERMED, a reliable and valid method for the early assessment of bio-psychosocial health risks and needs. Blind to the results, they were also assessed with the Hospital Anxiety and Depression Scale (HADS). HRQoL was documented with the EuroQol and the SF36. Statistical analysis included multivariate and multilevel techniques. RESULTS: Among patients fulfilling inclusion criteria, 60 patients (75.9%) completed the protocol and 38.3% of them were identified as "complex" by INTERMED, but significant between-center differences were found. In support of the working hypothesis, INTERMED scores were significantly associated with all measures of both the SF36 and the EuroQol, and also with the HADS. A one point increase in the INTERMED score results in a reduction in 0.93 points in EuroQol and a 20% increase in HADS score. CONCLUSIONS: INTERMED-measured case complexity is frequent in liver transplant candidates but varies widely between centers. The use of this method captures in one instrument multiple domains of patient status, including mood disturbances and reduced HRQoL.

Pre-pregnancy and pregnancy predictors of obesity.

Obesity has progressively become a global epidemic that constitutes one of the biggest current health problems worldwide. Pregnancy is a risk factor for excessive weight gain. Factors that may predict development of obesity in later life mainly include gestational weight gain, pre-pregnancy nutritional status, age, parity and race. Change in lifestyle factors, such as eating habits, enrollment in physical activity, smoking and duration of lactation, in addition to the above factors, may also contribute to the development of obesity but are still not fully understood. Women who retain more body weight after pregnancy have, in general, larger pregnancy body weight gain, higher pre-pregnancy body mass index, marked weight changes in previous pregnancies, lactate slightly less and stop smoking during pregnancy to a larger extent. In addition, irregular eating habits and decreased leisure time activity after delivery influence postpartum weight retention. Taking into consideration the epidemic of obesity, with all its adverse long-term consequences, there is an increasing need to promote counseling before, during and after pregnancy on the role of diet and physical activity in reproductive health.

The Reliability of Pre-travel History to Decide on Appropriate Counseling and Vaccinations: A Prospective Study.

BACKGROUND: Although medical and travel plans gathered from pre-travel interviews are used to decide the provision of specific pre-travel health advice and vaccinations, there has been no evaluation of the relevance of this strategy. In a prospective study, we assessed the agreement between pre-travel plans and post-travel history and the effect on advice regarding the administration of vaccines and recommendations for malaria prevention. METHODS: We included prospectively all consenting adults who had not planned an organized tour. Pre- and post-travel information included questions on destination, itineraries, departure and return dates, access to bottled water, plan of bicycle ride, stays in a rural zone, and close contact with animals. The outcomes measured included: agreement between pre- and post-travel itineraries and activities; and the effect of these differences on pre-travel health recommendations, had the traveler gone to the actual versus intended destinations for actual versus intended duration and activities. RESULTS: Three hundred and sixty-five travelers were included in the survey, where 188 (52%) were males (median age 38 years). In 81(23%) travelers, there was no difference between pre- and post-travel history. Disagreement between pre- and post-travel history were the highest for stays in rural zones or with local people (66% of travelers), close contact with animals (33%), and bicycle riding (21%). According to post-travel history, 125 (35%) travelers would have needed rabies vaccine and 9 (3%) typhoid fever vaccine. Potential overprovision of vaccine was found in <2% of travelers. A change in the malaria prescription would have been recommended in 18 (5%) travelers. CONCLUSIONS: Pre-travel history does not adequately reflect what travelers do. However, difference between recommendations for the actual versus intended travel plans was only clinically significant for the need for rabies vaccine. Particular attention during pre-travel health counseling should focus on the risk of rabies, the need to avoid close contact with animals and to seek care for post-exposure prophylaxis following an animal bite.

Alpine and pre-Alpine magmatism in the root-zone of the western Central Alps

The highest grade of metamorphism and associated structural elements in orogenic belts may be inherited from earlier orogenic events. We illustrate this point using magmatic and metamorphic rocks from the southern steep belt of the Lepontine Gneiss Dome (Central Alps). The U-Pb zircon ages from an anatectic granite at Verampio and migmatites at Corcapolo and Lavertezzo yield 280-290 Ma, i.e., Hercynian ages. These ages indicate that the highest grade of metamorphism in several crystalline nappes of the Lepontine Gneiss Dome is pre-Alpine. Alpine metamorphism reached sufficiently high grade to reset the Rb-Sr and K-Ar systematics of mica and amphibole, but generally did not result in crustal melting, except in the steep belt to the north of the Insubric Line, where numerous 29 to 26 Ma old pegmatites and aplites had intruded syn- and post-kinematically into gneisses of the ductile Simplon Shear Zone. The emplacement age of these pegmatites gives a minimum estimate for the age of the Alpine metamorphic peak in the Monte Rosa nappe. The U-Pb titanite ages of 33 to 31 Ma from felsic porphyritic veins represent a minimum-age estimate for Alpine metamorphism in the Sesia Zone. A porphyric vein emplaced at 448 +/- 5 Ma (U-Pb monazite) demonstrates that there existed a consolidated Caledonian basement in the Sesia Zone.

Ly49D-mediated ITAM signaling in immature thymocytes impairs development by bypassing the pre-TCR checkpoint.

Activating and inhibitory NK receptors regulate the development and effector functions of NK cells via their ITAM and ITIM motifs, which recruit protein tyrosine kinases and phosphatases, respectively. In the T cell lineage, inhibitory Ly49 receptors are expressed by a subset of activated T cells and by CD1d-restricted NKT cells, but virtually no expression of activating Ly49 receptors is observed. Using mice transgenic for the activating receptor Ly49D and its associated ITAM signaling DAP12 chain, we show in this article that Ly49D-mediated ITAM signaling in immature thymocytes impairs development due to a block in maturation from the double negative (DN) to double positive (DP) stages. A large proportion of Ly49D/DAP12 transgenic thymocytes were able to bypass the pre-TCR checkpoint at the DN3 stage, leading to the appearance of unusual populations of DN4 and DP cells that lacked expression of intracellular (ic) TCRβ-chain. High levels of CD5 were expressed on ic TCRβ(-) DN and DP thymocytes from Ly49D/DAP12 transgenic mice, further suggesting that Ly49D-mediated ITAM signaling mimics physiological ITAM signaling via the pre-TCR. We also observed unusual ic TCRβ(-) single positive thymocytes with an immature CD24(high) phenotype that were not found in the periphery. Importantly, thymocyte development was completely rescued by expression of an Ly49A transgene in Ly49D/DAP12 transgenic mice, indicating that Ly49A-mediated ITIM signaling can fully counteract ITAM signaling via Ly49D/DAP12. Collectively, our data indicate that inappropriate ITAM signaling by activating NK receptors on immature thymocytes can subvert T cell development by bypassing the pre-TCR checkpoint.

EZ-IO(®) intraosseous device implementation in a pre-hospital emergency service: A prospective study and review of the literature.

INTRODUCTION: Intraosseous access is increasingly recognised as an effective alternative vascular access to peripheral venous access. We aimed to prospectively study the patients receiving prehospital intraosseous access with the EZ-IO(®), and to compare our results with those of the available literature. METHODS: Every patient who required an intraosseous access with the EZ-IO from January 1st, 2009 to December 31st, 2011 was included. The main data collected were: age, sex, indication for intraosseous access, localisation of insertion, success rate, drugs and fluids administered, and complications. All published studies concerning the EZ-IO device were systematically searched and reviewed for comparison. RESULTS: Fifty-eight patients representing 60 EZ-IO procedures were included. Mean age was 47 years (range 0.5-91), and the success rate was 90%. The main indications were cardiorespiratory arrest (74%), major trauma (12%), and shock (5%). The anterior tibia was the main route. The main drugs administered were adrenaline (epinephrine), atropine and amiodarone. No complications were reported. We identified 30 heterogeneous studies representing 1603 EZ-IO insertions. The patients' characteristics and success rate were similar to our study. Complications were reported in 13 cases (1.3%). CONCLUSION: The EZ-IO provides an effective way to achieve vascular access in the pre-hospital setting. Our results were similar to the cumulative results of all studies involving the use of the EZ-IO, and that can be used for comparison for further studies.

Bone metabolism and risk of secondary hyperparathyroidism 12 months after gastric banding in obese pre-menopausal women.

OBJECTIVE: To evaluate, during the first postoperative year in obese pre-menopausal women, the effects of laparoscopic gastric banding on calcium and vitamin D metabolism, the potential modifications of bone mineral content and bone mineral density, and the risk of development of secondary hyperparathyroidism. SUBJECTS: Thirty-one obese pre-menopausal women aged between 25 and 52 y with a mean body mass index (BMI) of 43.6 kg/m(2), scheduled for gastric banding were included. Patients with renal, hepatic, metabolic and bone disease were excluded. METHODS: Body composition and bone mineral density (BMD) were measured at baseline, 6 and 12 months after gastric banding using dual-energy X-ray absorptiometry. Serum calcium, phosphate, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bilirubin, urea, creatinine, uric acid, proteins, parathormone, vitamin D(3), IGF-1, IGF-BP3 and telopeptide, as well as urinary telopeptide, were measured at baseline and 1, 3, 6, 9 and 12 months after surgery. RESULTS: After 1 y vitamin D3 remained stable and PTH decreased by 12%, but the difference was not significant. Serum telopeptide C increased significantly by 100% (P<0.001). There was an initial drop of the IGF-BP3 during the first 6 months (P<0.05), but the reduction was no longer significant after 1 y. The BMD of cortical bone (femoral neck) decreased significantly and showed a trend of a positive correlation with the increase of telopeptides (P<0.06). The BMD of trabecular bone, at the lumbar spine, increased proportionally to the reduction of hip circumference and of body fat. CONCLUSION: There is no evidence of secondary hyperparathyroidism 1 y after gastric banding. Nevertheless biochemical bone markers show a negative remodelling balance, characterized by an increase of bone resorption. The serum telopeptide seems to be a reliable parameter, not affected by weight loss, to follow up bone turnover after gastroplasty.

Urinalysis and pre-renal acute kidney injury: time to move on.

Urinary indices are classically believed to allow differentiation of transient (or pre-renal) acute kidney injury (AKI) from persistent (or acute tubular necrosis) AKI. However, the data validating urinalysis in critically ill patients are weak. In the previous issue of Critical Care, Pons and colleagues demonstrate in a multicenter observational study that sodium and urea excretion fractions as well as urinary over plasma ratios performed poorly as diagnostic tests to separate such entities. This study confirms the limited diagnostic and prognostic ability of urine testing. Together with other studies, this study raises more fundamental questions about the value, meaning and pathophysiologic validity of the pre-renal AKI paradigm and suggests that AKI (like all other forms of organ injury) is a continuum of injury that cannot be neatly divided into functional (pre-renal or transient) or structural (acute tubular necrosis or persistent).

Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease.

Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

Pre-hospital tracheal intubation in patients with traumatic brain injury: systematic review of current evidence.

BACKGROUND: We reviewed the current evidence on the benefit and harm of pre-hospital tracheal intubation and mechanical ventilation after traumatic brain injury (TBI). METHODS: We conducted a systematic literature search up to December 2007 without language restriction to identify interventional and observational studies comparing pre-hospital intubation with other airway management (e.g. bag-valve-mask or oxygen administration) in patients with TBI. Information on study design, population, interventions, and outcomes was abstracted by two investigators and cross-checked by two others. Seventeen studies were included with data for 15,335 patients collected from 1985 to 2004. There were 12 retrospective analyses of trauma registries or hospital databases, three cohort studies, one case-control study, and one controlled trial. Using Brain Trauma Foundation classification of evidence, there were 14 class 3 studies, three class 2 studies, and no class 1 study. Six studies were of adults, five of children, and three of both; age groups were unclear in three studies. Maximum follow-up was up to 6 months or hospital discharge. RESULTS: In 13 studies, the unadjusted odds ratios (ORs) for an effect of pre-hospital intubation on in-hospital mortality ranged from 0.17 (favouring control interventions) to 2.43 (favouring pre-hospital intubation); adjusted ORs ranged from 0.24 to 1.42. Estimates for functional outcomes after TBI were equivocal. Three studies indicated higher risk of pneumonia associated with pre-hospital (when compared with in-hospital) intubation. CONCLUSIONS: Overall, the available evidence did not support any benefit from pre-hospital intubation and mechanical ventilation after TBI. Additional arguments need to be taken into account, including medical and procedural aspects.