Management of mixed acute rejection driven by a de novo donor-specific complement-binding anti-DQB1*03:01 antibody and intraepithelial CD8 T-cells in a kidney recipient: a case report.

Mixed acute rejection is a clinicopathological entity that is difficult to accurately diagnose, and so may be under-reported. Allografts are lost more often than in either humoral or cellular rejection. The diagnosis requires both histological and immunological studies on renal biopsy and blood specimens from the transplant recipient to provide the required rescue therapy to abolish the allogeneic response against the graft. We present a clinical case report of an active mixed acute rejection driven by a de novo donor-specific complement-binding anti-DQB1*03:01 antibody and intraepithelial CD8 T-cells in a patient with a kidney transplant. The patient was diagnosed, treated, and followed up as per the local institution's procedure with a full recovery of graft function. Our case emphasises the challenge of a mixed acute rejection and supports the need to improve the post-transplant outcome of recipients and their grafts.

The sensory innervation of the human nipple.

Nipples represent a highly specialized skin with capital importance in mammals for breastfeeding and additionally in humans due to sexuality. The histological studies regarding this region are scarce, so 42 human nipples were studied to describe the morphology of the nipple innervation. Our results exclude the presence of a rich innervation on nipple's skin or superficial dermis, thus definitely excluding nipple skin from the concept glabrous skin. The presence of mechanoreceptors is limited to scarce Merkel cells on the epidermis and some corpuscular capsulated and non-capsulated structures in the dermis; Merkel cells progressively decrease with ageing. No Meissner corpuscles were found and the rare Pacinian corpuscles identified were close to vascular structures and embroidered in the mammary fatty tissue. The great sensitivity observed functionally on the breast and especially in the nipple can be morphologically explained by two elements; on the one hand there is a rich smooth muscle innervation present in the deep dermis; on the other hand the mammary gland demonstrate Piezo2 expression in many glandular cells, with two differentiated patterns in the ductal and in the acinar tissue of the breast. The role of Piezo2 in the normal mammary gland is discussed.

Class I and Class II small leucine-rich proteoglycans in human cutaneous pacinian corpuscles.

Pacinian corpuscles are onion bulb-like multilayered mechanoreceptors that consist of a complicated structure of axon terminals, Schwann related cells (inner core), endoneural related cells (intermediate layer) and perineurial related cells (outer core-capsule). The cells forming those compartments are continuous and share the properties of that covering the nerve fibers. Small leucine-rich proteoglycans are major proteoglycans of the extracellular matrix and regulate collagen fibrillogenesis, cell signalling pathways and extracellular matrix assembly. Here we used immunohistochemistry to investigate the distribution of class I (biglycan, decorin, asporin, ECM2 and ECMX) and class II (fibromodulin, lumican, prolargin, keratocan and osteoadherin) small leucine-rich proteoglycans in human cutaneous Pacinian corpuscles. The distribution of these compounds was: the inner core express decorin, biglycan, lumican, fibromodulin, osteoadherin; the intermediate layer display immunoreactivity for osteoadherin; the outer core biglycan, decorin, lumican, fibromodulin and osteoadherin; and the capsule contains biglycan, decorin, fibromodulin, and lumican. Asporin, prolargin and keratocan were undetectable. These results complement our knowledge about the distribution of small leucine-rich proteoglycans in human Pacinian corpuscles, and help to understand the composition of the extracellular matrix in these sensory formations.

The development of human digital Meissner's and Pacinian corpuscles.

Meissner's and Pacinian corpuscles are cutaneous mechanoreceptors responsible for different modalities of touch. The development of these sensory formations in humans is poorly known, especially regarding the acquisition of the typical immunohistochemical profile related to their full functional maturity. Here we used a panel of antibodies (to specifically label the main corpuscular components: axon, Schwann-related cells and endoneurial-perineurial-related cells) to investigate the development of digital Meissner's and Pacinian corpuscles in a representative sample covering from 11 weeks of estimated gestational age (wega) to adulthood. Development of Pacinian corpuscles starts at 13 wega, and it is completed at 4 months of life, although their basic structure and immunohistochemical characteristics are reached at 36 wega. During development, around the axon, a complex network of S100 positive Schwann-related processes is progressively compacted to form the inner core, while the surrounding mesenchyme is organized and forms the outer core and the capsule. Meissner's corpuscles start to develop at 22 wega and complete their typical morphology and immunohistochemical profile at 8 months of life. In developing Meissner's corpuscles, the axons establish complex relationships with the epidermis and are progressively covered by Schwann-like cells until they complete the mature arrangement late in postnatal life. The present results demonstrate an asynchronous development of the Meissner's and Pacini's corpuscles and show that there is not a total correlation between morphological and immunohistochemical maturation. The correlation of the present results with touch-induced cortical activity in developing humans is discussed.

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity.

The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch-gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell-neurite complexes, Meissner-like corpuscles and lanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry to investigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20+ , chromogranin A+ and synaptophisin+ ) Merkel cells. Most of them were in close contact with Piezo2- nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2+ , but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non-nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low-threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.

Pacinian Corpuscles in Human Lymph Nodes.

The occurrence of Pacinian corpuscles associated to lymph nodes is an anatomical rarity and very scarce information exists in this regard. Here we examined immunohistochemically four Pacinian corpuscles found in the close vicinity of the hiliar blood vessels of lymph nodes (2 cervical, 1 axillary, and 1 inguinal) during routine surgical pathology. Pacinian corpuscles were normally arranged and displayed a pattern of protein distribution as follows: the axon was positive for neurofilament proteins and neuron specific enolase, the inner core cells showed intense S100 protein and vimentin immunostaining while they were negative for glial fibrillary acidic protein, type IV collagen and glucose transporter 1; vimentin, type IV collagen, and glucose transporter 1 were also observed also in the outer-core and the capsule. These results are in agreement with those reported for cutaneous Pacinian corpuscles, demonstrating that the immunohistochemical profile of these corpuscles is independent of its anatomical localization. The possible functional significance of Pacinian corpuscles in lymph nodes is discussed. Anat Rec, 300:2233-2238, 2017. © 2017 Wiley Periodicals, Inc.

Endoneurial-CD34 positive cells define an intermediate layer in human digital Pacinian corpuscles.

The endoneurial and/or perineurial origin of the outer core; i.e. the concentric and continuous lamellae located outside the complex formed by the axon and the Schwann-related cells, in human Pacinian corpuscles is still debated. Here we used immunohistochemistry coupled with a battery of antibodies to investigate the expression of perineurial (Glucose transporter 1 and epithelial membrane antigen) or endoneurial (CD34 antigen) markers in human digital Pacinian corpuscles. CD34 immunoreactivity was restricted to one layer immediately outside the inner core, whereas the proper outer core displayed antigens typical of the perineurial cells. These results demonstrate an intermediate endoneurial layer that divides the Pacinian corpuscles into two distinct compartments: the avascular inner neural compartment (formed by the axon and the Schwann-related cells that form the inner core), and the outer non-neural compartment (formed by the outer core). The functional relevance of these findings, if any, remains to be clarified.

ASIC2 is present in human mechanosensory neurons of the dorsal root ganglia and in mechanoreceptors of the glabrous skin.

Mechanosensory neurons lead to the central nervous system touch, vibration and pressure sensation. They project to the periphery and form different kinds of mechanoreceptors. The manner in which they sense mechanical signals is still not fully understood, but electrophysiological experiments have suggested that this may occur through the activation of ion channels that gate in response to mechanical stimuli. The acid-sensing ion channels (ASICs), especially ASIC2, may function as mechanosensors or are required for mechanosensation, and they are expressed in both mechanosensory neurons and mechanoreceptors. Here, we have used double immunohistochemistry for ASIC2 together with neuronal and glial markers associated with laser confocal microscopy and image analysis, to investigate the distribution of ASIC2 in human lumbar dorsal root ganglia, as well as in mechanoreceptors of the hand and foot glabrous skin. In lumbar dorsal root ganglia, ASIC2 immunoreactive neurons were almost all intermediate or large sized (mean diameter ≥20-70 µm), and no ASIC2 was detected in the satellite glial. ASIC2-positive axons were observed in Merkel cell-neurite complexes, Meissner and Pacinian corpuscles, all of them regarded as low-threshold mechanoreceptors. Moreover, a variable percent of Meissner (8 %) and Pacinian corpuscles (27 %) also displayed ASIC2 immunoreactivity in the Schwann-related cells. These results demonstrate the distribution of ASIC2 in the human cutaneous mechanosensory system and suggest the involvement of ASIC2 in mechanosensation.

The sensory innervation of the human pharynx: searching for mechanoreceptors.

The coordinate neural regulation of the upper airways muscles is basic to control airway size and resistance. The superior constrictor pharyngeal muscle (SCPM) forms the main part of the lateral and posterior walls of the pharynx and typically is devoid of muscle spindles, the main type of proprioceptor. Because proprioception arising from SCPM is potentially important in the physiology of the upper airways, we have investigated if there are mechanical sensory nerve endings substitute for the muscle spindles. Samples of human pharynx were analyzed using immunohistochemistry associated to general axonic and Schwann cells markers (NSE, PGP 9.5, RT-97, and S100P), intrafusal muscle fiber markers, and putative mechanical sense proteins (TRPV4 and ASIC2). Different kinds of sensory corpuscles were observed in the pharynx walls (Pacini-like corpuscles, Ruffini-like corpuscles, spiral-wharves nerve structures, and others) which are supplied by sensory nerves and express putative mechanoproteins. No evidence of muscle spindles was observed. The present results demonstrate the occurrence of numerous and different morphotypes of sensory corpuscles/mechanoreceptors in human pharynx that presumably detect mechanical changes in the upper airways and replace muscle spindles for proprioception. Present findings are of potential interest for the knowledge of pathologies of the upper airways with supposed sensory pathogenesis.

Current concepts on the management of tooth wear: part 4. An overview of the restorative techniques and dental materials commonly applied for the management of tooth wear.

This final article of the four part series on the current concepts of tooth wear will provide the reader with an evaluation of the data available in the contemporary literature with regards to the survival analysis of differing restorative materials, and their respective methods of application to treat tooth wear. It is vital that the dental operator is familiar with the role of differing materials which may be used to restore the worn dentition, some of which may prove to be more suitable for the management of particular patterns of tooth wear than others. The active management of tooth wear unfortunately commits the patient to a lifelong need for considerable maintenance, and it is imperative that this is understood from the outset.

Current concepts on the management of tooth wear: part 3. Active restorative care 2: the management of generalised tooth wear.

Paper 3 of this series on the current concepts of tooth wear management will focus on the provision of active restorative intervention for cases presenting with generalised tooth wear. The use of both contemporary adhesive and traditional conventional techniques applied to treat cases of generalised tooth wear will be discussed, including a consideration of the merits and drawbacks of each approach respectively.

Current concepts on the management of tooth wear: part 1. Assessment, treatment planning and strategies for the prevention and the passive management of tooth wear.

The aim of this series of four articles on tooth wear management is to provide the reader with the necessary information in order to be able to successfully manage cases of tooth wear, regardless of the cause, severity and location of the wear pattern seen. The content will largely focus on contemporary clinical techniques, illustrated where possible by case examples. Emphasis will be placed on 'additive adhesive techniques' utilising fixed prosthodontic protocols; however, cases of tooth wear amongst partially dentate patients involving the use of removable prostheses will also be described. The importance of patient consent and contingency planning will also be discussed. Paper 1 will describe the assessment of the wear patient, including the rationale for the planning of dental care. Also discussed will be the administration of preventative and passive management strategies for cases displaying tooth wear.

Current concepts on the management of tooth wear: part 2. Active restorative care 1: the management of localised tooth wear.

This second of the four part series of articles on the current concepts of tooth wear management will focus on the provision of active restorative care, where the implementation of a preventative, passive approach may prove insufficient to meet the patient's expectations, or indeed prove to be sufficiently adequate to address the extent of the underlying pathology to the desired level of clinical satisfaction. The active restorative management of cases presenting with localised tooth wear (of either the anterior, posterior, maxillary or mandibular variety) will be considered in depth in this paper, including a description of the commonly applied techniques and treatment strategies, where possible illustrated by case examples.

Differential localization of Acid-sensing ion channels 1 and 2 in human cutaneus pacinian corpuscles.

Acid-sensing ion channels (ASICs) are the members of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily which mediate different sensory modalities including mechanosensation. ASICs have been detected in mechanosensory neurons as well as in peripheral mechanoreceptors. We now investigated the distribution of ASIC1, ASIC2, and ASIC3 proteins in human cutaneous Pacinian corpuscles using immunohistochemistry and laser confocal-scanner microscopy. We detected different patterns of expression of these proteins within Pacinian corpuscles. ASIC1 was detected in the central axon co-expressed with RT-97 protein, ASIC2 was expressed by the lamellar cells of the inner core co-localized with S100 protein, and ASIC3 was absent. These results demonstrate for the first time the differential distribution of ASIC1 and ASIC2 in human rapidly adapting low-threshold mechanoreceptors, and suggest specific roles of both proteins in mechanotransduction.

The lamellar cells in human Meissner corpuscles express TrkB.

Cutaneous Meissner corpuscles depend for development and survival exclusively on the NT system TrkB/BDNF/NT-4 unlike other types of sensory corpuscles and nerve endings, which have very complex neuronal and growth factor dependence. However, the pattern of expression of TrkB in human Meissner corpuscles is not known. The experiments in these studies were designed to pursue further findings that suggest that BDNF and NT-4 have critical roles in the development and maintenance of Meissner corpuscles by analyzing the pattern of expression of TrkB, their high-affinity receptor, in human glabrous skin. These experiments showed that TrkB is expressed in different patterns by the lamellar cells of Meissner corpuscles and not by the axon. The studies also show that while the percentage of Meissner corpuscles that express TrkB remains constant from birth till 50-year old cases, it decreases approximately 3-fold in subjects older than 50 years. These results are important since the study of Meissner corpuscles from cutaneous biopsies to diagnose some neurological diseases has rapidly become of high interest and therefore the proteins expressed in these corpuscles are potential diagnostic tools.

El aspecto clínico de la enfermedad celíaca se amplía / Celiac disease: new clinical aspects

Se hace una revisión de las alteraciones neurológicas frecuentemente asociadas con la enfermedad celíaca descritas en la literatura. Entre las mismas destaca la elevada prevalencia de crisis convulsivas febriles y epilepsia, tanto generalizada como asociada a calcificaciones cerebrales occipitales bilaterales. También es relevante la asociación con síndromes espino-cerebelosos con ataxia, alteraciones psiquiátricas y de conducta, neuropatía periférica, miopatía inflamatoria, cefalea tanto tensional como migrañosa, síncope vagal, hipotonía muscular y vasculitis cerebral. Se revisa la posible etiopatogenia de tales alteraciones que en dependencia del tipo de manifestación obedecería a factores genéticos, mecanismos inmunológicos o tóxicos o por deficiencia vitamínica o alteración de las aminas biógenas en relación con una alteración malabsortiva intestinal (AU)

Number of roots and canals in maxillary first premolars: study of an Andalusian population.

A study of 150 extracted maxillary first premolars from citizens of Seville, Andalusía, southern Spain, revealed 60 teeth with one root (40.0%), 85 teeth with two roots (56.7%) and five teeth with three roots (3.3%). The distribution of root canal shapes in the sample showed that all teeth with two or three roots had type I root canals (each canal had one apical foramen). Conversely, most of the single-rooted maxillary first premolars had root canal shape type II (two canals converging in the same apical foramen). Only 1.3% of the teeth had a unique orifice in the pulp chamber and only one root canal. These results emphasized the importance of good knowledge of the root canal morphology and the need for a careful radiographic examination as part of competent root canal therapy of maxillary first premolars.

Effect in vitro of Tifell (formocresol-eugenol) on macrophage adhesion.

The purpose of this study was to investigate the effect in vitro on macrophage adhesion of Tifell (formocresoleugenol), used as an intracanal medicament and in therapeutic pulpotomies in primary teeth, Macrophages were obtained from Wistar rats. As a test of macrophage phagocytic function the adherence capacity of macrophages to a plastic surface was determined. Assays were carried out in Eppendorf tubes after 15 min of incubation at 37 degrees C in a humidified atmosphere of 5% carbon dioxide. The adherence index (AI) was calculated. Results showed that Tifell decreased significantly (P < 0.05) the AI of macrophages. Half maximal inhibition of AI was obtained at 1:334.5 Tifell dilution (AI = 27.75; P < 0.05). Taking into account that substrate adherence is the first step in the phagocytic action of macrophages and in antigen presentation, Tifell could inhibit macrophage function and modulate immune and inflammatory responses in dental pulp and periapical tissues.

A case of combined dental development abnormalities: importance of a thorough examination.

This report describes a case of combined dental development abnormalities. A patient with a previous ectopically erupted supernumerary maxillary canine presented a new ectopically erupted supernumerary premaxillary tooth with dens invaginatus (Oehlers' type 2) and an aberrant coronal morphology, including a pit in the distal portion of the palatal surface. This tooth would have been diagnosed earlier if a panoramic radiograph had been taken at the first visit 5 months before. This case represents a good example of combined dental development abnormalities, i.e., a numerical anomaly (the supernumerary tooth), an alteration of dental position (the ectopic eruption), an alteration of dental morphology (the aberrant coronal shape), and the invagination. This case highlights the importance of a thorough examination, including complementary radiography, of patients with a dental anomaly.