Light Affects Mood and Learning through Distinct Retina-Brain Pathways.

Light exerts a range of powerful biological effects beyond image vision, including mood and learning regulation. While the source of photic information affecting mood and cognitive functions is well established, viz. intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, we reveal that the direct effects of light on learning and mood utilize distinct ipRGC output streams. ipRGCs that project to the suprachiasmatic nucleus (SCN) mediate the effects of light on learning, independently of the SCN's pacemaker function. Mood regulation by light, on the other hand, requires an SCN-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus (PHb). The PHb is integrated in a distinctive circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. Together, these results provide new insights into the neural basis required for light to influence mood and learning.

Synaptotagmin-11 facilitates assembly of a presynaptic signaling complex in post-Golgi cargo vesicles.

GABAB receptors (GBRs), the G protein-coupled receptors for GABA, regulate synaptic transmission throughout the brain. A main synaptic function of GBRs is the gating of Cav2.2-type Ca2+ channels. However, the cellular compartment where stable GBR/Cav2.2 signaling complexes form remains unknown. In this study, we demonstrate that the vesicular protein synaptotagmin-11 (Syt11) binds to both the auxiliary GBR subunit KCTD16 and Cav2.2 channels. Through these dual interactions, Syt11 recruits GBRs and Cav2.2 channels to post-Golgi vesicles, thus facilitating assembly of GBR/Cav2.2 signaling complexes. In addition, Syt11 stabilizes GBRs and Cav2.2 channels at the neuronal plasma membrane by inhibiting constitutive internalization. Neurons of Syt11 knockout mice exhibit deficits in presynaptic GBRs and Cav2.2 channels, reduced neurotransmitter release, and decreased GBR-mediated presynaptic inhibition, highlighting the critical role of Syt11 in the assembly and stable expression of GBR/Cav2.2 complexes. These findings support that Syt11 acts as a vesicular scaffold protein, aiding in the assembly of signaling complexes from low-abundance components within transport vesicles. This mechanism enables insertion of pre-assembled functional signaling units into the synaptic membrane.

Retinal innervation tunes circuits that drive nonphotic entrainment to food.

Daily changes in light and food availability are major time cues that influence circadian timing1. However, little is known about the circuits that integrate these time cues to drive a coherent circadian output1-3. Here we investigate whether retinal inputs modulate entrainment to nonphotic cues such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and the intergeniculate leaflet (IGL) through intrinsically photosensitive retinal ganglion cells (ipRGCs)4. We show that adult mice that lack ipRGCs from the early postnatal stages have impaired entrainment to time-restricted feeding, whereas ablation of ipRGCs at later stages had no effect. Innervation of ipRGCs at early postnatal stages influences IGL neurons that express neuropeptide Y (NPY) (hereafter, IGLNPY neurons), guiding the assembly of a functional IGLNPY-SCN circuit. Moreover, silencing IGLNPY neurons in adult mice mimicked the deficits that were induced by ablation of ipRGCs in the early postnatal stages, and acute inhibition of IGLNPY terminals in the SCN decreased food-anticipatory activity. Thus, innervation of ipRGCs in the early postnatal period tunes the IGLNPY-SCN circuit to allow entrainment to time-restricted feeding.

The interaction of the ribotoxin α-sarcin with complex model lipid vesicles.

Fungal ribotoxins are extracellular RNases that inactivate ribosomes by cleaving a single phosphodiester bond at the universally conserved sarcin-ricin loop of the large rRNA. However, to reach the ribosomes, they need to cross the plasma membrane. It is there where these toxins show their cellular specificity, being especially active against tumoral or virus-infected cells. Previous studies have shown that fungal ribotoxins interact with negatively charged membranes, typically containing phosphatidylserine or phosphatidylglycerol. This ability is rooted on their long, non-structured, positively charged loops, and its N-terminal ß-hairpin. However, its effect on complex lipid mixtures, including sphingophospholipids or cholesterol, remains poorly studied. Here, wild-type α-sarcin was used to evaluate its interaction with a variety of membranes not assayed before, which resemble much more closely mammalian cell membranes. The results confirm that α-sarcin is particularly sensitive to charge density on the vesicle surface. Its ability to induce vesicle aggregation is strongly influenced by both the lipid headgroup and the degree of saturation of the fatty acid chains. Acyl chain length is indeed particularly important for lipid mixing. Finally, cholesterol plays an important role in diluting the concentration of available negative charges and modulates the ability of α-sarcin to cross the membrane.

Impact of Askling L-PROTOCOL on Biceps Femoris Architecture, Hamstring Flexibility and Sprint Performance.

Eccentric training has been shown to be important for hamstring strain injuries rehabilitation and prevention. The Askling L-PROTOCOL (L-P), comprising three exercises aimed at eccentric training and hamstring lengthening, was shown to improve this injuries recovery and relapse times in comparison with other traditional exercise-based protocols. However, the causes of these results remain unclear. This study looks at the impact of an 8-week L-P followed by 4 weeks of detraining on the architecture of the biceps femoris long head, hamstring flexibility and sprint performance. Twenty-eight healthy individuals were divided into two groups: an experimental group, which carried out the L-P, and a control group with no training. Muscle architecture was measured using 2D ultrasound, hamstring flexibility using goniometry and sprint performance using sports radar equipment before (M1) and after (M2) the training period and after detraining (M3). No significant changes were observed between M1 and M2 in the experimental group with regard to fascicle length (t=- 0.79, P>0.05), theoretical maximum speed (t=- 1.43, P>0.05), horizontal force (t=0.09, P>0.05), force application during sprint running (t=- 0.09, P>0.05) and horizontal power (t=- 0.97, P>0.05), but, however, changes were observed in hamstring flexibility (t=- 4.42, d=0.98, P<0.001) returning to pre-training values after detraining period (t=- 1.11, P>0.05). L-P has been shown to be an eccentric protocol of moderate intensity and easy implementation that could be interesting to include throughout a sports season.

Analysis of retention of gadolinium by brain, bone, and blood following linear gadolinium-based contrast agent administration in rats with experimental sepsis.

PURPOSE: It is important to identify populations that may be vulnerable to the brain deposition of gadolinium (Gd) from MRI contrast agents. At intervals from 24 hours to 6 weeks following injection of a linear Gd contrast agent, the brain, blood and bone content of Gd were compared between control rats and those with experimental endotoxin-induced sepsis that results in neuroinflammation and blood-brain barrier disruption. METHODS: Male rats were injected intraperitoneally with 10 mg/kg lipopolysaccharide. Control animals received no injection. Twenty-four hours later, 0.2 mmol/kg of gadobenate dimeglumine was injected intravenously. Brain, blood, and bone Gd levels were measured at 24 hours, 1 week, 3 weeks, and 6 weeks by inductively coupled plasma mass spectroscopy. RESULTS: Blood Gd decreased rapidly between 24 hours and 1 week, and thereafter was undetectable, with no significant difference between lipopolysaccharide and control rats. Brain levels of Gd were significantly higher (4.29-2.36-fold) and bone levels slightly higher (1.35-1.11-fold) in lipopolysaccharide than control rats at all time points with significant retention at 6 weeks. CONCLUSION: Experimental sepsis results in significantly higher deposition of Gd in the brain and bone in rats. While blood Gd clears rapidly, brain and bone retained substantial Gd even at 6 weeks following contrast injection.

C-terminal phosphorylation regulates the kinetics of a subset of melanopsin-mediated behaviors in mice.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and mediate several non-image-forming visual functions, including circadian photoentrainment and the pupillary light reflex (PLR). ipRGCs act as autonomous photoreceptors via the intrinsic melanopsin-based phototransduction pathway and as a relay for rod/cone input via synaptically driven responses. Under low light intensities, where only synaptically driven rod/cone input activates ipRGCs, the duration of the ipRGC response will be determined by the termination kinetics of the rod/cone circuits. Little is known, however, about the termination kinetics of the intrinsic melanopsin-based phototransduction pathway and its contribution to several melanopsin-mediated behaviors. Here, we show that C-terminal phosphorylation of melanopsin determines the recovery kinetics of the intrinsic melanopsin-based photoresponse in ipRGCs, the duration of the PLR, and the speed of reentrainment. In contrast, circadian phase alignment and direct effects of light on activity (masking) are not influenced by C-terminal phosphorylation of melanopsin. Electrophysiological measurements demonstrate that expression of a virally encoded melanopsin lacking all C-terminal phosphorylation sites (C terminus phosphonull) leads to a prolonged intrinsic light response. In addition, mice expressing the C terminus phosphonull in ipRGCs reentrain faster to a delayed light/dark cycle compared with mice expressing virally encoded WT melanopsin; however, the phase angle of entrainment and masking were indistinguishable. Importantly, a sustained PLR in the phosphonull animals is only observed at brighter light intensities that activate melanopsin phototransduction, but not at dimmer light intensities that activate only the rod/cone pathway. Taken together, our results highlight how the kinetics of the melanopsin photoresponse differentially regulate distinct light-mediated behaviors.

Carpal Instability Nondissociative Following Acute Wrist Fractures.

PURPOSE: Carpal malalignment following intra-articular fractures has been reported in the literature, with no clear description of possible ligamentous injury leading to the radiological appearance. This study presents a series of patients that developed carpal instability nondissociative (CIND) following acute wrist fractures. The mechanism of injury is postulated by using a cadaveric laboratory investigation. METHOD: Twelve patients with average age of 32 years were identified with CIND, between 2013 and 2018. Ten patients with a normal carpal alignment in the initial postoperative radiographs exhibited CIND-palmar radiographically at different postoperative periods, and 2 patients showed CIND-dorsal in the initial postoperative x-rays. Four cadaveric specimens were used to validate this injury pattern. RESULTS: In cadaveric dissections, CIND-palmar could be reproduced by applying an axial loading and dorsal shearing force on a wrist with sequential sectioning of dorsal and palmar extrinsic wrist ligaments. For the intra-articular fractures with CIND-dorsal, the cause is likely a result of volar radiocarpal extrinsic ligament injury combined with intra-articular incongruity of the scaphoid fossa. Eight out of the 12 patients had severe wrist pain and underwent additional surgery. Three patients with reducible CIND-palmar had open capsular repair, and 5 patients with fixed nonreducible malalignment were treated with radioscapholunate arthrodesis. At an average follow-up of 2.3 years, pain relief was noted, together with an improvement in grip strength and range of movement. Radiographically, the wrist alignment was corrected and maintained. CONCLUSIONS: This article highlights the existence of possible concomitant radiocarpal ligament lesions and residual articular incongruity, associated with acute intra-articular fractures and radiocarpal fracture-dislocations, that destabilize the proximal carpal row into a pattern of nondissociative carpal instability. Early detection of this condition may preserve wrist function by capsular repair, whereas cases with fixed deformity and residual joint incongruity may be best managed with a limited radiocarpal arthrodesis. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

Annotated Dataset for Anomaly Detection in a Data Center with IoT Sensors.

The relative simplicity of IoT networks extends service vulnerabilities and possibilities to different network failures exhibiting system weaknesses. Therefore, having a dataset with a sufficient number of samples, labeled and with a systematic analysis, is essential in order to understand how these networks behave and detect traffic anomalies. This work presents DAD: a complete and labeled IoT dataset containing a reproduction of certain real-world behaviors as seen from the network. To approximate the dataset to a real environment, the data were obtained from a physical data center, with temperature sensors based on NFC smart passive sensor technology. Having carried out different approaches, performing mathematical modeling using time series was finally chosen. The virtual infrastructure necessary for the creation of the dataset is formed by five virtual machines, a MQTT broker and four client nodes, each of them with four sensors of the refrigeration units connected to the internal IoT network. DAD presents a seven day network activity with three types of anomalies: duplication, interception and modification on the MQTT message, spread over 5 days. Finally, a feature description is performed, so it can be used for the application of the various techniques of prediction or automatic classification.

[Activity based costs of different units in a high complexity Chilean hospital]. / Los costos basados en actividades de Unidades Médico Quirúrgica y de Cuidados Medios en un hospital público.

BACKGROUND: Hospitals must have management tools that allow them to fulfil all their requirements with the allocated resources. AIM: To evaluate the number of bed-days according to the discharge diagnosis in a High Complexity Hospital in Chile. MATERIAL AND METHODS: An activity Based Cost (ABC) calculation was used. The stages were gathering of procedures, identification of the resources used, analysis of discharge diagnosis, definition of cost objects, resource cost drivers, cost of procedures, procedures cost drivers and cost of the cost objects that corresponds to bed-day by each medical specialty. Costs were calculated for Medical-Surgical and Intermediate Care units. RESULTS: There were significant differences in costs according to medical specialty when comparing the costs obtained using the Management information system (WinSig) and ABC. Respiratory, Renal and Circulatory-Cardiovascular specialties accounted for the most expensive bed-days. CONCLUSIONS: This study identified bed-day costs and provides disaggregated information about the causes of cost differences between medical specialties.

Effects of the Functional Heel Drop Exercise on the Muscle Architecture of the Gastrocnemius.

CONTEXT: The architectural characteristics of a muscle determine its function. OBJECTIVE: To determine the architectural adaptations of the lateral gastrocnemius (LG) and medial gastrocnemius (MG) muscles after a functional eccentric strength training protocol consisting of heel drop exercises, followed by a subsequent detraining period. DESIGN: Pretest and posttest. SETTING: Training rooms and laboratory. PARTICIPANTS: The participants (N = 45) who were randomly divided into an experimental group (EG, n = 25) and a control group (CG, n = 20). INTERVENTIONS: The 13-week intervention included participants (N = 45) who were randomly divided into an EG (n = 25) and a CG (n = 20). The EG performed a week of control and training, 8 weeks of eccentric training, and 4 weeks of detraining. The CG did not perform any type of muscular training. The architectural characteristics of the LG and MG muscles were evaluated at rest in both groups using 2-D ultrasound before (pretest-week 1) and after (posttest-week 9) the training, and at the end of the detraining period (retest-week 13). MAIN OUTCOME MEASURES: One-way repeated measures analysis of variance was used to determine training-induced changes in each of the variables of the muscle architecture. RESULTS: After the training period, the members of the EG experienced a significant increase in the fascicle length of LG (t = -9.85, d = 2.78, P < .001) and MG (t = -8.98, d = 2.54, P < .001), muscle thickness (t = -6.71, d = 2.86, P < .001) and (t = -7.85, d = 2.22, P < .001), and the pennation angle (t = -10.21, d = 1.88, P < .05) and (t = -1.87, d = 0.53, P < .05), respectively. After the detraining period, fascicle length, muscle thickness, and pennation angle showed a significant decrease. In the CG, no significant changes were observed in any of the variables. CONCLUSIONS: The heel drop exercise seems to generate adaptations in the architectural conditions of LG and MG, which are also reversible after a detraining period. These results may have practical implications for injury prevention and rehabilitation programs.

Light as a central modulator of circadian rhythms, sleep and affect.

Light has profoundly influenced the evolution of life on earth. As widely appreciated, light enables us to generate images of our environment. However, light - through intrinsically photosensitive retinal ganglion cells (ipRGCs) - also influences behaviours that are essential for our health and quality of life but are independent of image formation. These include the synchronization of the circadian clock to the solar day, tracking of seasonal changes and the regulation of sleep. Irregular light environments lead to problems in circadian rhythms and sleep, which eventually cause mood and learning deficits. Recently, it was found that irregular light can also directly affect mood and learning without producing major disruptions in circadian rhythms and sleep. In this Review, we discuss the indirect and direct influence of light on mood and learning, and provide a model for how light, the circadian clock and sleep interact to influence mood and cognitive functions.

Isotopes in teeth and a cryptic population of coastal freshwater seals.

Human activities threaten the biodiversity of aquatic mammals across the globe. Conservation of these species hinges on the ability to delineate movements and foraging behaviors of animals, but gaining such insights is hampered by difficulties in tracing individuals over their lives. We determined isotope ratios in teeth (87 Sr/86 Sr, 13 C/12 C, and 18 O/16 O) to examine lifelong movement and resource-use patterns of a unique freshwater population of a wide-ranging pinniped species (harbor seal [Phoca vitulina]) that resides in Iliamna Lake, Alaska (U.S.A.). This population's potentially unique migratory behavior and use of different trophic resources are unknown. The isotope ratios we measured in teeth showed that seals were born in the lake, remained lifelong residents, and relied principally on resources produced from in the lake, even when seasonally abundant and nutrient-dense spawning anadromous fish (i.e., sockeye salmon [Oncorhynchus nerka]) were available in the lake. Our results illustrate how serial isotope records in teeth, particularly 87 Sr/86 Sr ratios, can be used to quantify how coastal mammal populations exploit both freshwater and marine ecosystems. Understanding lifelong patterns of habitat and resource use is essential information when designing effective conservation plans for threatened coastal mammals. We present the Iliamna Lake harbor seals as a unique case study into how isotope records within teeth can help reveal the cryptic ecology of such a population residing in an intact ecosystem. The results also provide critical baseline information for the Kvichak River system, which is facing an uncertain future due to proposed large-scale industrial development and a rapidly changing climate.

Isotopos Dentales y una Población Críptica de Focas Costeras de Agua Dulce Resumen Las actividades humanas amenazan a la diversidad de mamíferos acuáticos en todo el mundo. La conservación de estas especies depende de la habilidad para delinear los movimientos y los comportamientos de búsqueda de alimento de los animales, pero la obtención de dicha información está obstaculizada por las dificultades en el rastreo de individuos a lo largo del transcurso de sus vidas. Determinamos la proporción de isotopos dentales (87 Sr/86 Sr, 13 C/12 C y 18 O/16 O) para examinar el movimiento a lo largo de la vida y los patrones de uso de recursos de una población única de una especie de pinnípedos de agua dulce con una distribución amplia (foca común [Phoca vitulina]), la cual reside en el lago Iliamna, Alaska (E.U.A.). Se desconocen el comportamiento migratorio potencialmente único de esta población y el uso que le dan a los diferentes recursos tróficos. La proporción de isotopos que medimos en los dientes mostró que las focas nacieron en el lago, permanecieron como residentes de toda la vida y dependieron principalmente de los recursos producidos en el lago, incluso cuando estaban disponibles en aquel lugar por razones reproductivas los peces anádromos abundantes estacionalmente y con densidad de nutrientes (es decir, el salmón rojo [Oncorhynchus nerka]). Nuestros resultados ilustran cómo los registros seriales de isotopos dentales, particularmente la proporción 87 Sr/86 Sr, pueden usarse para cuantificar cómo las poblaciones de mamíferos costeros explotan tanto los ecosistemas marinos como los de agua dulce. El entendimiento de los patrones ontogénicos del uso de recursos y de hábitat es esencial cuando se diseñan planes efectivos de conservación para los mamíferos costeros en peligro. Presentamos a las focas comunes del lago Iliamna como un estudio de caso único sobre cómo los registros de isotopos dentales pueden ayudar a revelar la ecología críptica de dicha población que reside en un ecosistema intacto. Los resultados también proporcionan información importante de línea base para el sistema el río Kvichak, el cual está enfrentando un futuro incierto debido a la propuesta de un desarrollo industrial de gran escala y al rápido clima cambiante.

Detecting riparian habitat preferences in "savanna" chimpanzees and associated Fauna with strontium isotope ratios: Implications for reconstructing habitat use by the chimpanzee-human last common ancestor.

OBJECTIVES: Riparian or gallery forests are critical habitats for numerous plants and animals today. Paleoanthropologically, reliance on such habitats informs behavioral and ecological reconstructions; for example, gallery forest habitats likely played a critical role in the transition from ape to hominin in the early Pliocene and may represent a preferred habitat for the last common ancestor of chimpanzees and humans. Direct indicators for gallery forest habitats preference are lacking. The objective of this article is to assess whether strontium isotope ratios are a reliable indicator of habitat preference for fauna living in and around gallery forests. MATERIALS AND METHODS: We report bioavailable strontium isotope ratios from the Mugiri River, its tributaries, and its gallery forest (Toro-Semliki Wildlife Reserve, southwestern Uganda), and compare them to surrounding savanna-grassland values. We compare these environmental values to strontium isotopes ratios in faunal tooth enamel to determine if habitat preferences are accurately reflected. RESULTS: Gallery forest and savanna-grassland vegetations have significantly different strontium isotope ratio profiles. We trace these isotopic differences to the influence of the Mugiri tributaries, which originate on Paleoproterozoic gneiss deposits on top of the surrounding escarpments. These isotopic differences in vegetation are mirrored in the tissues of fauna with habitat preferences for either the gallery forest or the surrounding grasslands. DISCUSSION: This research demonstrates the potential of strontium isotope ratios to identify habitat preferences in modern or fossil fauna under proper geologic variability. It provides a methodological model for future studies seeking to reconstruct habitat preferences in early hominins.

Liver transplantation in adults with acute liver failure: Outcomes from the Argentinean Transplant Registry.

INTRODUCTION AND AIM: Liver transplantation (LT) for acute liver failure (ALF) still has a high early mortality. We aimed to evaluate changes occurring in recent years and identify risk factors for poor outcomes. MATERIAL AND METHODS: Data were retrospectively obtained from the Argentinean Transplant Registry from two time periods (1998-2005 and 2006-2016). We used survival analysis to evaluate risk of death. RESULTS: A total of 561 patients were listed for LT (69% female, mean age 39.5±16.4 years). Between early and later periods there was a reduction in wait-list mortality from 27% to 19% (p<0.02) and 1-month post-LT survival rates improved from 70% to 82% (p<0.01). Overall, 61% of the patients underwent LT and 22% died on the waiting list. Among those undergoing LT, Cox regression analysis identified prolonged cold ischemia time (HR 1.18 [1.02-1.36] and serum creatinine (HR 1.31 [1.01-1.71]) as independent risk factors of death post-LT. Etiologies of ALF were only available in the later period (N=363) with indeterminate and autoimmune hepatitis accounting for 28% and 26% of the cases, respectively. After adjusting for age, gender, private/public hospital, INR, creatinine and bilirubin, and considering LT as the competing event, indeterminate etiology was significantly associated with death (SHR 1.63 [1.06-2.51] and autoimmune hepatitis presented a trend to improved survival (SHR 0.61 [0.36-1.05]). CONCLUSIONS: Survival of patients with ALF on the waiting list and after LT has significantly improved in recent years. Indeterminate cause and autoimmune hepatitis were the most frequent etiologies of ALF in Argentina and were associated with mortality.

Willingness to adopt wearable devices with behavioral and economic incentives by health insurance wellness programs: results of a US cross-sectional survey with multiple consumer health vignettes.

BACKGROUND: The number of health-related wearable devices is growing but it is not clear if Americans are willing to adopt health insurance wellness programs based on wearables and the incentives with which they would be more willing to adopt. METHODS: In this cross-sectional study we used a survey methodology, usage vignettes and a dichotomous scale to examine U.S. residents' willingness to adopt wearables (WTAW) in six use-cases where it was mandatory to use a wearable device and share the resulting data with a health insurance company. Each use-case was tested also for the influence of additional economic incentives on WTAW. RESULTS: A total of 997 Americans across 46 states participated in the study. Most of them were 25 to 34 years old (40.22%), 57.27% were female, and 74.52% were white. On average, 69.5% of the respondents were willing to adopt health-insurance use-cases based on wearable devices, though 77.8% of them were concerned about issues related to economic benefits, data privacy and to a lesser extent, technological accuracy. WTAW was 11-18% higher among consumers in use-cases involving health promotion and disease prevention. Furthermore, additional economic incentives combined with wearables increased WTAW overall. Notably, financial incentives involving providing healthcare credits, insurance premium discount, and/or wellness product discounts had particularly greater effectiveness for increasing WTAW in the consumer use-cases involving participation: for health promotion (RR = 1.06 for financial incentive, 95% CI: 1.01-1.11; P = 0.018); for personalized products and services (RR = 1.11 for financial incentive, 95% CI: 1.01-1.21; P = 0.018); and for automated underwriting discount at annual renewal (RR = 1.28 for financial incentive, 95% CI: 1.20-1.37; P < 0.001). CONCLUSIONS: Under the adequate economic, data privacy and technical conditions, 2 out of 3 Americans would be willing to adopt health insurance wellness programs based on wearable devices, particularly if they have benefits related to health promotion and disease prevention, and particularly with financial incentives.

Hypersensitivity to alemtuzumab. A safe and effective desensitization protocol: A case report.

We describe a successful desensitization to alemtuzumab in one patient diagnosed with T-cell prolymphocytic leukaemia. Alemtuzumab treatment was initiated during infusion number 18, the patient showed cutaneous eruption with a miliary pattern, despite premedication with corticosteroids and antihistamines. The eruption returned with successive alemtuzumab infusions (infusions 19, 20 and 21), remained present for longer and was more severe with each infusion. The patient was referred to our Allergy Unit as it was necessary to maintain alemtuzumab treatment. Total immunoglobulin E level was 3 UI/ml and specific immunoglobulin E against more common pneumo-allergens, food, latex and hamster were inferior to 0.35 UI/ml. Prick test using the undiluted drug (30 mg/ml) and intradermal tests using serial dilutions (1/10, 1/100) were performed. The result of alemtuzumab skin prick test was 4 mm. The intradermal skin test result was positive at 1/100 dilution (papule: 8 mm; erythema: 12 mm). The basophil activation test with alemtuzumab was performed concluding that 10% of the basophils were activated by alemtuzumab. The patient underwent alemtuzumab desensitization according to a 12-step protocol that resolved to be safe and efficacious. Our experience may be helpful for similar clinical cases where the therapeutic options are very limited and a life-threatening condition such T-cell prolymphocytic leukaemia is present. In addition, a careful risk/benefit ratio should be considered and accurate informed consent is mandatory.

Architecture of retinal projections to the central circadian pacemaker.

The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.

Pulse wave velocity reference values in 3,160 adults referred to a hypertension clinic for 24-hour ambulatory blood pressure monitoring.

Background: Carotid-femoral pulse wave velocity (PWV) is a direct measure of aortic stiffness used in the stratification of cardiovascular risk. Its clinical application in Latin America has been limited by the absence of reference values. The objective of this study was to establish PWV reference values among adults referred to a specialized cardiology center for 24-hour ambulatory blood pressure monitoring (ABPM) in Medellín, Colombia.Methods: A descriptive study of 3,160 records of adult (older than 18 years) patients without pharmacological treatment assessed for PWV using a Mobil-O-Graph® 24-hour PWA device (IEM, Stolberg, Germany) and 24-hour ABPM with hemodynamic parameters based on suspected hypertension or hypotension was conducted. Patient records were categorized by decade of age and sub-divided based on the following 24-hour ABPM categories: normal (< 130/80 mmHg), grade I hypertension (between 130-150/80-90 mmHg), and grade II hypertension (> 150/90 mmHg).Results: PWV increased with age (r = 0,894; p < 0,001) and blood pressure category (ρ = 0,081; p < 0,001); the age-related increase was more pronounced among the patients in the higher blood pressure categories. Measures of central tendency and dispersion regarding PWV are presented, and reference values are proposed from the 90th percentile based on the age and 24-hour ABPM categories.Conclusions: PWV is directly related to age and blood pressure and can be predicted using a simple equation that includes these two variables. To stratify the cardiovascular risk of patients and make clinical decisions, the 90th percentile based on the age and 24-hour ABPM categories is recommended as a cut-off.