Validating the use of a stereoscopic robotized teleophthalmic drone slit lamp

ObjectiveTo validate the use of a mechanized remotely operated stereoscopic drone slit lamp (DSL) in assessing anterior segment pathology in ophthalmology patients compared with conventional slit lamp (CSL).MethodsPatients were recruited from eye clinics at Hotel Dieu Hospital in Kingston, Ontario, Canada. Each patient was assessed by 2 examiners. Examiners consisted of ophthalmology residents and staff attendings. Each examiner assessed the anterior chamber (AC) depth, presence or absence of cells, and/or presence of flare of the patient first using the DSL, followed by CSL. Qualitative data were collected on the ability to assess corneal integrity, infiltrates, foreign bodies, epithelial defects, and conjunctival injection using the DSL.Results48 eyes of 42 participants were examined using the DSL and CSL. No significant within-examiner differences in AC depth or cell were detected. There was substantial agreement between the DSL and CSL when assessing AC cell and flare (κ = 72.6 and κ = 60.4, respectively) and moderate agreement when assessing AC depth (κ = 42.5). The DSL compared with CSL had a sensitivity and specificity of 98.3% (95% confidence interval [CI] 94-100) and 100% (95% CI 98.7-100), respectively, for detecting AC cell. The DSL had sensitivity and specificity of 100% (95% CI 97.5-100) and 88.2% (95% CI 80.2-96.1), respectively, for detecting AC flare.ConclusionsThere was substantial agreement between the DSL and CSL when assessing AC depth, cell, and flare. Sensitivity and specificity for assessing these findings ranged from 88.2% to 100%. This DSL provides excellent capability for examination of anterior segment pathology in live patients, performing similarly to a CSL.     

Age-Dependence of the Peripheral Defocus of the Isolated Human Crystalline Lens

PurposeTo characterize the peripheral defocus of isolated human crystalline lenses and its age dependence.MethodsData were acquired on 116 isolated lenses from 99 human eyes (age range, 0.03–61 years; postmortem time, 40.1 ± 21.4 hours). Lenses were placed in a custom-built combined laser ray tracing and optical coherence tomography system that measures the slopes of rays refracted through the lens for on-axis and off-axis incidence angles. Ray slopes were measured by recording spot patterns as a function of axial position with an imaging sensor mounted on a positioning stage below the tissue chamber. Delivery angles ranged from –30° to +30° in 5° increments using a 6 mm × 6 mm raster scan with 0.5-mm spacing. Lens power at each angle was calculated by finding the axial position that minimizes the root-mean-square size of the spot pattern formed by the 49 central rays, corresponding to a 3-mm zone on-axis. The age dependence of the on-axis and off-axis optical power and the relative peripheral defocus (difference between off-axis and on-axis power) of lenses were quantified.ResultsAt all angles, lens power decreased significantly with age. Lens power increased with increasing delivery angle for all lenses, corresponding to a shift toward myopic peripheral defocus. There was a statistically significant decrease in the lens peripheral defocus with age.ConclusionsThe isolated human lens power increases with increasing field angle. The lens relative peripheral defocus decreases with age, which may contribute to the age-related changes of ocular peripheral defocus during refractive development.     

Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion

neurogenetics - Giant axonal neuropathy (GAN) is an autosomal recessive disease caused by mutations in the GAN gene encoding gigaxonin. Patients develop a progressive sensorimotor neuropathy...     

Endolysosomal TPCs regulate social behavior by controlling oxytocin secretion

Oxytocin (OT) is a prominent regulator of many aspects of mammalian social behavior and stored in large dense-cored vesicles (LDCVs) in hypothalamic neurons. It is released in response to activity-dependent Ca²⁺ influx, but is also dependent on Ca²⁺ release from intracellular stores, which primes LDCVs for exocytosis. Despite its importance, critical aspects of the Ca²⁺-dependent mechanisms of its secretion remain to be identified. Here we show that lysosomes surround dendritic LDCVs, and that the direct activation of endolysosomal two-pore channels (TPCs) provides the critical Ca²⁺ signals to prime OT release by increasing the releasable LDCV pool without directly stimulating exocytosis. We observed a dramatic reduction in plasma OT levels in TPC knockout mice, and impaired secretion of OT from the hypothalamus demonstrating the importance of priming of neuropeptide vesicles for activity-dependent release. Furthermore, we show that activation of type 1 metabotropic glutamate receptors sustains somatodendritic OT release by recruiting TPCs. The priming effect could be mimicked by a direct application of nicotinic acid adenine dinucleotide phosphate, the endogenous messenger regulating TPCs, or a selective TPC2 agonist, TPC2-A1-N, or blocked by the antagonist Ned-19. Mice lacking TPCs exhibit impaired maternal and social behavior, which is restored by direct OT administration. This study demonstrates an unexpected role for lysosomes and TPCs in controlling neuropeptide secretion, and in regulating social behavior.

Oxytocin (OT) was initially described as a hormone regulating parturition (1, 2) and lactation (3), but it is now also well-recognized as a prosocial hormone regulating maternal behavior (4, 5), social recognition (6–8), and social interactions (9–14). OT is stored in large dense-core vesicles (LDCV) in the magno- and parvocellular secretory neurons of the paraventricular nuclei (PVN) and the supraoptic nuclei (SON) of the hypothalamus. This neuropeptide is released from hypothalamic neurons into different brain structures, and via the pituitary gland into the systemic bloodstream. OT neurons are multifunctional multisensory cells that respond to a wide variety of stimuli to fulfil their numerous roles described above (for review see ref. 15). However, the regulatory mechanisms underlying OT secretion are still unclear. Although OT secretion is known to be independently regulated in different neuronal compartments such as axons, soma, and dendrites (8, 16–20), the intracellular signaling pathways underlying secretion in these complex multitask neurons are still unclear.OT release from both somatodendritic sites (16) and neurohypophysial axonal terminals (21) have been proposed to be dependent on Ca²⁺ release from intracellular stores in addition to Ca²⁺ influx via voltage-dependent Ca²⁺ channels. Indeed release of OT from pituitary axonal terminals and hypothalamus was shown to be highly dependent on the expression of cluster of differentiation 38 (CD38) (21, 22), a transmembrane multifunctional enzyme that catalyzes the synthesis of the Ca²⁺ mobilizing messenger, cyclic ADP-ribose (cADPR). cADPR which promotes Ca²⁺ release via ryanodine receptors (RyRs) from the endoplasmic reticulum (ER) (23) caused a large increase in OT release from isolated oxytocinergic nerve endings (21). However, CD38 also may catalyze the synthesis of another major Ca²⁺ mobilizing messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), which specifically mobilizes Ca²⁺ from acidic organelles such as lysosomes (24, 25) via two-pore channels (TPCs) (26). However, in contrast to cADPR, NAADP was found not to directly stimulate OT release (21).Somatodendritic OT secretion has also been shown to exhibit the important property of priming, which greatly increases the extent of exocytosis of OT-containing LCDVs (16). Priming in neuroendocrine cells is the phenomenon whereby an initial signal prepares cells for an anticipated subsequent trigger, sometimes involving the autocrine action of the peptide released (8, 16, 27). It is of fundamental significance in the neuroendocrine system where such a mechanism mediates such phenomena as the OT-controlled milk-ejection reflex and the LH surge at ovulation (28). In hypothalamic neurons, this initial priming signal can be OT itself (self-priming) or other hormones or neurotransmitters which activate metabotropic cell surface receptors to mobilize Ca²⁺ from intracellular stores. This results in a substantial augmentation of the secretory response to subsequent cell activation and is thought to occur by recruiting a reserve pool of LCDVs to the plasma membrane, increasing their probability of release. It had been previously suggested that Ca²⁺ release from Ca²⁺ storage organelles primes vesicles for sustained OT release since pharmacological release of Ca²⁺ from the ER by the sarcoendoplasmic reticulum Ca²⁺ ATPase (SERCA) inhibitor thapsigargin and consequential Ca²⁺ entry promoted priming effects (16, 29, 30).Lysosomes are recognized as important organelles in autophagic macromolecular degradation and membrane repair, but they also contain a high concentration of Ca²⁺ that could be mobilized for cell signaling (24, 25, 31, 32). Electron microscopy has shown the presence of lysosomes in axon endings, dendrites, cell-bodies, and Herring bodies of OT neurons located in areas rich in LDCVs (33–35), but so far, their role in hypothalamic neurons as a source of Ca²⁺ has remained unexplored. In various cell types, endosomes and lysosomes release Ca²⁺ through the activation of the endolysosomal TPCs, modulated by NAADP (26, 36–39) and phosphatidylinositol-3, 5-bisphosphate (PI(3, 5)P₂) (40, 41). TPCs belong to an ancient cation channel family present in numerous species with three known isoforms (TPC1, TPC2, and TPC3). In humans and rodents, only TPC1 and TPC2 are expressed, displaying different ionic selectivity in part depending on how they are activated: NAADP favoring Ca²⁺ permeation (42, 43), while PI(3, 5)P₂ favors Na⁺ permeation (40, 43–45). TPCs have been implicated in many aspects of cell signaling, autophagy, and vesicular trafficking in various cell types (42, 46, 47), but despite the growing interest in these channels, their roles in the central nervous system remain largely unexplored (for review, see ref. 22).Here on the basis that CD38 is a major regulator of OT secretion (21), we have examined the role of endolysosomal TPCs as the principal targets of the NAADP branch of the CD38 signaling pathway and found that they play critical roles in the regulation of OT secretion and thus control social behavior.     

Control of negative inotropic vagal preganglionic neurons in the dog: synaptic interactions with substance P afferent terminals in the nucleus ambiguus?

Previous research from this laboratory has shown that substance P-immunoreactive (SP) terminals synapse upon negative chronotropic vagal preganglionic neurons (VPNs), but not upon negative dromotropic VPNs, of the ventrolateral nucleus ambiguus (NA-VL). Moreover, SP agonists injected into NA-VL cause bradycardia without decreasing AV conduction. In the current study, we have: (1) defined the electron microscopic characteristics of the SP neurons of NA-VL in dog; and (2) tested the hypothesis that SP nerve terminals synapse upon negative inotropic VPNs of NA-VL, retrogradely labeled from the cranial medial ventricular (CMV) ganglion. Numerous SP terminals and a few SP neurons were observed in the vicinity of retrogradely labeled neurons. SP terminals were observed forming synapses with unlabeled dendrites and with SP dendrites, but never with the retrogradely labeled neurons. Together, these results and earlier findings suggest that SP agonists may be able to induce bradycardia without decreasing AV conduction or ventricular contractility.     

Atrophy of the supraspinatus belly Assessment by MRI in 55 patients with rotator cuff pathology

A study of 5 fresh cadaveric shoulders demonstrated that an oblique-sagittal plane which crosses the scapula through the medial border of the coracoid process offers a view of the supraspinatus fossa mostly limited by bone.This view could easily be reproduced by MRI and we called it the Y-shaped view. It allowed a reliable measurement of supraspinatus muscle atrophy by the calculation of the occupation ratio (R) which is the ratio between the surface of the cross-section of the muscle belly and that of the fossa.This ratio was calculated in a prospective study based on 55 shoulders divided into 3 groups with different rotator cuff status: group I, 15 controls; group II, 10 degenerative cuffs, without tears; group III, 30 operated tears. There was no difference between groups I (mean ratio 0.7) and II (mean ratio 0.62), but the ratio was decreased in group III (mean ratio 0.44), in which the extent of the tear in both the sagittal and coronal planes aggravated the muscle atrophy. We propose a three-stage classification to improve indications for rotator cuff tear treatment.     

Effects of α2-Adrenoceptor Agonists on Perinatal Excitotoxic Brain Injury: Comparison of Clonidine and Dexmedetomidine

Background: A growing number of children have severe neurologic impairment related to very premature birth. Experimental data suggest that overstimulation of cerebral N-methyl-d-aspartate (NMDA) receptors caused by excessive glutamate release may be involved in the genesis of perinatal hypoxic-ischemic brain injury. [alpha]2-Adrenoceptor agonists are protective in models of brain ischemia in adults. The authors sought to determine whether they prevent perinatal excitotoxic neuronal damage.

Methods: Five-day-old mice were allocated at random to clonidine (4-400 [mu]g/kg), dexmedetomidine (1-30 [mu]g/kg), or saline injected intraperitoneally before an intracerebral stereotactic injection of the NMDA receptor agonist ibotenate; cortical and white matter lesions were quantified 5 days later by histopathologic examination. Cortical neuron cultures exposed to 300 [mu]m NMDA were used to evaluate the effects of clonidine or dexmedetomidine on neuronal death assessed by counting the number of pycnotic nuclei after fluorescent chromatin staining.

Results: In vivo, both clonidine and dexmedetomidine induced significant concentration-dependent reductions in the size of ibotenate-induced lesions in the cortex and white matter. In vitro, the number of neurons damaged by NMDA exposure was significantly decreased by both dexmedetomidine (-28 +/- 12% at 10 [mu]m;P < 0.01) and clonidine (-37 +/- 19% at 100 [mu]m;P < 0.01) as compared with controls. In both models, the selective [alpha]2-adrenoceptor antagonist yohimbine abolished the neuroprotective effect of clonidine and dexmedetomidine.     

Peak systolic over protodiastolic ratio as an objective substitute for the uterine artery notch

Objective To measure the inter-rater agreement for the identification of a uterine artery notch, as well as the association between an observed notch and the peak systolic over protodiastolic (A/C) ratio.
Design Cohort study.
Setting Tertiary care university hospital.
Population and methods Six hundred and sixty-five nulliparous women in whom 1022 examinations of uterine artery velocity waveforms were performed by pulsed Doppler at 18 and at 26 weeks of gestation. Agreement between two independent raters was analysed using Cohen's kappa statistics. A/C ratios of flow velocity waveforms with or without a notch were compared. The agreement between A/C values and the presence of a notch was estimated by measuring the surface under the receiver operating characteristic (ROC) curve.
Results Inter-rater agreement for the identification of a notch was 074 (95% CI 0.64–0.83) at 18 weeks and 0.72 (95% CI 0.64–0.80) at 26 weeks. NC ratios were higher when a notch was present (   P < 0.0001  ). The area under the ROC curve was 0.86 (95% CI 0.81491) for the placental uterine artery and 0.93 (95% CI 0.90–0.96) for the nonplacental artery. An A/C value 2.5 in any uterine artery had a sensitivity of 88% and a specificity of 86% to detect a notch.
Conclusion Although there is no definitive definition of the notch, its detection is reproducible within a center. However, published prevalences between centers in unselected populations vary. The measure of the NC ratio can serve as an objective substitute.     

Évolution inhabituellement prolongée d’une dactylite tuberculeuse avec atteinte osseuseUnusually prolonged course of tuberculous dactylitis with osteitis

We report a case of tuberculous dactylitis that was unusual in 2 regards: the bone was infected, and the course was prolonged and atypical, with a spontaneous clinical remission followed by a recurrence that led to the diagnosis.     

Number processing after stroke: anatomoclinical correlations in oral and written codes.

Calculation and number-processing abilities were studied in 49 patients with chronic single vascular brain lesions by means of a standardized multitask assessment battery (EC301), as well as through other tasks, testing functions thought to be implicated in calculation such as language, visuo-perceptive abilities, verbal and spatial working memory, planning, and attention. The results show that (1) lesions involving parietal areas-particularly left parietal lesions-are prone to alter calculation processing. A more detailed analysis showed that patients with lesions involving left parietal areas were impaired in both digital (i.e., comprehension and production of numbers written in Arabic code) and oral (i.e., comprehension and production of numbers heard or expressed orally) processing while lesions involving right parietal areas lead to an impairment in digital processing only. However, linguistically related alphanumerical processing (i.e., comprehension and production of numbers written orthographically) was not influenced by parietal lesions. (2) Semantic representations (knowledge of the magnitude related to a given number) as well as rote arithmetical knowledge are also impaired following damage to parietal and particularly left parietal lesions, suggesting that these areas are also implicated in magnitude comparisons and in the retrieval of arithmetical facts. (3) Performance in calculation is highly correlated with language. (4) Moreover, we found a highly significant correlation between performances in oral calculation and verbal working memory, and between written-digit calculation and visuospatial working memory. Performances in regard to visuo-perceptive abilities, planning, and attention were less consistently correlated with calculation. These results stress the close correlation, but relative independence between calculation and language, as well as a dissociated sensitivity of oral and digital processing to brain lesions.