Age-related hearing loss is not linked to cerebrospinal fluid levels of ß-amyloid or p-tau181.

INTRODUCTION: As Hearing loss and dementia affect people with the same profile, several epidemiological studies have evaluated their relationship. However, the link between age-related hearing loss and Alzheimer's disease is still unclear. METHODS: We selected subjects with no history of exposure to loud noises, blasts, head trauma with hearing loss, or sudden sensorineural hearing loss from a cohort intended to study preclinical phases of Alzheimer's disease. Participants are volunteers over 55 years without cognitive impairment. We correlated the results of an objective auditory evaluation with brain amyloid and p-tau181 levels and with the outcomes of a comprehensive neuropsychological assessment. RESULTS: Fifty-five subjects at different stages of the Alzheimer's disease continuum were evaluated. There were no statistically significant correlations between amyloid-ß and p-tau levels and any of the objective auditory measures. A weak but significant correlation was found between amyloid-ß values and the Hearing Handicap Inventory for the Elderly. The neuropsychological domains more correlated to hearing loss were executive function and processing speed. DISCUSSION: Age-related hearing loss is not linked to any pathological markers of Alzheimer's disease nor to neuropsychological domains typically affected in this disease. The Hearing Handicap Inventory for the Elderly has an important component of subjectivity and further studies are needed to explore its relationship with amyloid-ß levels.

Axonal and Glial PIEZO1 and PIEZO2 Immunoreactivity in Human Clitoral Krause's Corpuscles.

Krause's corpuscles are typical of cutaneous mucous epithelia, like the lip vermillion or the glans clitoridis, and are associated with rapidly adapting low-threshold mechanoreceptors involved in gentle touch or vibration. PIEZO1 and PIEZO2 are transmembrane mechano-gated proteins that form a part of the cationic ion channels required for mechanosensitivity in mammalian cells. They are involved in somatosensitivity, especially in the different qualities of touch, but also in pain and proprioception. In the present study, immunohistochemistry and immunofluorescence were used to analyze the occurrence and cellular location of PIEZO1 and PIEZO2 in human clitoral Krause's corpuscles. Both PIEZO1 and PIEZO2 were detected in Krause's corpuscles in both the axon and the terminal glial cells. The presence of PIEZOs in the terminal glial cells of Kraus's corpuscles is reported here for the first time. Based on the distribution of PIEZO1 and PIEZO2, it may be assumed they could be involved in mechanical stimuli, sexual behavior, and sexual pleasure.

Acid-Sensing Ion Channels' Immunoreactivity in Nerve Profiles and Glomus Cells of the Human Carotid Body.

The carotid body is a major peripheral chemoreceptor that senses changes in arterial blood oxygen, carbon dioxide, and pH, which is important for the regulation of breathing and cardiovascular function. The mechanisms by which the carotid body senses O2 and CO2 are well known; conversely, the mechanisms by which it senses pH variations are almost unknown. Here, we used immunohistochemistry to investigate how the human carotid body contributes to the detection of acidosis, analyzing whether it expresses acid-sensing ion channels (ASICs) and determining whether these channels are in the chemosensory glomic cells or in the afferent nerves. In ASIC1, ASIC2, and ASIC3, and to a much lesser extent ASIC4, immunoreactivity was detected in subpopulations of type I glomus cells, as well as in the nerves of the carotid body. In addition, immunoreactivity was found for all ASIC subunits in the neurons of the petrosal and superior cervical sympathetic ganglia, where afferent and efferent neurons are located, respectively, innervating the carotid body. This study reports for the first time the occurrence of ASIC proteins in the human carotid body, demonstrating that they are present in glomus chemosensory cells (ASIC1 < ASIC2 > ASIC3 > ASIC4) and nerves, presumably in both the afferent and efferent neurons supplying the organ. These results suggest that the detection of acidosis by the carotid body can be mediated via the ASIC ion channels present in the type I glomus cells or directly via sensory nerve fibers.

Sensory innervation of the human male prepuce: Meissner's corpuscles predominate.

Meissner's corpuscles are the most abundant sensory corpuscles in the glabrous skin of the male prepuce. They are type I, rapidly adapting, low-threshold mechanoreceptors, and their function is linked to the expression of the mechanoprotein piezo-type mechanosensitive ion channel component 2 (PIEZO2). Stimulation of genital Meissner's corpuscles gives rise to sexual sensations. It has been recently demonstrated that digital Meissner's corpuscles, Meissner-like corpuscles, and genital end bulbs have an endoneurium-like capsule surrounding their neuronal elements; that is, the axon and glial lamellar cells, and their axons, display PIEZO2 immunoreactivity. It is unknown whether this is also the case for preputial Meissner's corpuscles. Furthermore, the expression of certain proteins that have been found in Meissner's corpuscles at other anatomical locations, especially in the digits, has not been investigated in preputial Meissner's corpuscles. Here, we used immunohistochemistry to investigate the expression of axonal (neurofilament, neuron-specific enolase), glial (S100 protein, glial fibrillary acidic protein, vimentin), endoneurial (CD34), and perineurial (glucose transporter 1) markers in the preputial and digital Meissner's corpuscles of male participants aged between 5 and 23 years. Furthermore, we investigated the occurrence of the mechanoprotein PIEZO2 in male preputial Meissner's corpuscles. Human male prepuce contains numerous Meissner's corpuscles, which may be grouped or isolated and are regularly distributed in the dermal papillae. Lamellar glial cells display strong expression of S100 protein and vimentin but lack expression of glial fibrillary acidic protein. In addition, they show axonal PIEZO2 expression and have an endoneurial capsule, but no perineurial. Our results indicate that human male preputial Meissner's corpuscles share the immunohistochemical profile of digital Meissner's corpuscles, which is considered to be necessary for mechanotransduction. These data strongly suggest that the structure and function of Meissner's corpuscles are independent of their anatomical location.

Verification and characterisation of human digital Ruffini's sensory corpuscles.

Ruffini's corpuscles are present as long fusiform encapsulated sensory structures in different tissues including the skin. Although physiological analyses strongly suggest their existence in glabrous digital skin, such localisation remains unconfirmed. Here, we have investigated the occurrence of typical Ruffini's corpuscles in 372 sections of human digital skin obtained from 186 subjects of both sexes and different ages (19-92 years). S100 protein, neuron-specific enolase and neurofilament proteins were detected, and the basic immunohistochemical profile of these corpuscles was analysed. Fewer than 0.3 Ruffini's corpuscles/mm2 were detected, with density distribution across the fingers being F4 > F3 > F2 > F1 > F5 and absolute values being F2 > F1 > F3 > F4 > F5. Axons displayed neuron-specific enolase immunoreactivity, glial cells forming the core contained S100 protein, and the capsule was positive for CD34 but not Glut1, demonstrating an endoneurial origin. Present results demonstrate the existence of Ruffini's corpuscles in human glabrous digital skin at very low densities. Moreover, the identified Ruffini's corpuscles share the basic immunohistochemical characteristics of other dermal sensory corpuscles.

Glans clitoris innervation: PIEZO2 and sexual mechanosensitivity.

The clitoris is a leading player in female sexual arousal, if not the main protagonist. Despite this role, studies performed on this structure with specific neuroanatomical techniques are few. This study focuses on glans clitoris innervation, with special emphasis on sensory corpuscles and the presence of the mechanotransducer protein PIEZO2 in these structures. Six glans clitoris samples were obtained at autopsy covering an age spectrum between 52 and 83 years old. Several types of nerve terminations including free nerve endings, genital endbulbs as well as Meissner-like corpuscles and Pacinian corpuscles, but not Ruffini corpuscles, were found. Although corpuscular morphology in the glans clitoris was subtly different from the cutaneous digital counterparts, their basic composition was comparable for both Pacinian and Meissner-like corpuscles. Genital endbulbs showed heterogeneous morphology, and the axons usually exhibited a typical "wool ball" or "yarn ball" aspect. Some of them were lobulated and variably encapsulated by endoneurial elements (65%); from the capsule originate septa that divides the genital endbulbs, suggesting that they are found in clusters rather than as single corpuscles. In addition, most corpuscles in the glans clitoris showed axonal PIEZO2 immunoreactivity, thus, suggesting a mechanical role and molecular mechanisms of mechanosensibility similar to those of digital Meissner's corpuscles. Our results demonstrate that sensory corpuscles of the glans clitoris are similar to those of other glabrous skin zones, as most genital organs are characterized by clusters of corpuscles and the occurrence of the mechanoprotein PIEZO2 in the axons. These findings strongly suggest that PIEZO2 participates in erotic and sexual mechanical sensing.

The capsule of human Meissner corpuscles: immunohistochemical evidence.

Meissner corpuscles are cutaneous mechanoreceptors that are usually located in the dermal papillae of human glabrous skin. Structurally, these sensory corpuscles consist of a mechanoreceptive sensory neuron surrounded by non-myelinating lamellar Schwann-like cells. Some authors have described a partially developed fibroblastic capsule of endoneurial or perineurial origin around Meissner corpuscles; however, others have noted that these structures are non-encapsulated. As there is continuity between the periaxonic cells forming the sensory corpuscles and the cells of the nerve trunks, we used immunohistochemistry to examine the expression of endoneurial (CD34 antigen) or perineurial [Glucose transporter 1 (Glut1)] markers in human cutaneous Meissner corpuscles. We also investigated the immunohistochemical patterns of nestin and vimentin (the main intermediate filaments of the cytoskeleton of endoneurial and perineurial cells, respectively) in Meissner corpuscles. The most important finding from this study was that CD34-positive cells formed a partial/complete capsule of endoneurial origin around most Meissner corpuscles, without signs of other perineurial Glut1-positive elements. However, the cytoskeletal proteins of the capsular CD34-positive cells did not include either nestin or vimentin, so the cytoskeletal composition of these cells remains to be established. Finally, the intensity of the immunoreactivity for CD34 in the capsule decreased with ageing, sometimes becoming completely absent in the oldest individuals. In conclusion, we report the first immunohistochemical evidence of the capsule of Meissner corpuscles in humans and demonstrate the endoneurial origin of the capsule.

Peripheral Mechanobiology of Touch-Studies on Vertebrate Cutaneous Sensory Corpuscles.

The vertebrate skin contains sensory corpuscles that are receptors for different qualities of mechanosensitivity like light brush, touch, pressure, stretch or vibration. These specialized sensory organs are linked anatomically and functionally to mechanosensory neurons, which function as low-threshold mechanoreceptors connected to peripheral skin through Aß nerve fibers. Furthermore, low-threshold mechanoreceptors associated with Aδ and C nerve fibers have been identified in hairy skin. The process of mechanotransduction requires the conversion of a mechanical stimulus into electrical signals (action potentials) through the activation of mechanosensible ion channels present both in the axon and the periaxonal cells of sensory corpuscles (i.e., Schwann-, endoneurial- and perineurial-related cells). Most of those putative ion channels belong to the degenerin/epithelial sodium channel (especially the family of acid-sensing ion channels), the transient receptor potential channel superfamilies, and the Piezo family. This review updates the current data about the occurrence and distribution of putative mechanosensitive ion channels in cutaneous mechanoreceptors including primary sensory neurons and sensory corpuscles.

Hyperplastic sensory corpuscles in nevus sebaceus of labia minora pudendi. A case report.

A vulvar case of nevus sebaceus is presented. During the routine histopatological examination, attention was drawn by several corpuscular structures. Immunohistochemistry demonstrated that they were sensory corpuscles, identified respectively as Meissner-like and glomerular corpuscles. Nevertheless, compared with typical Meissner corpuscles from digital glabrous skin, Meissner-like corpuscles identified here were bigger, the axon showed an irregular course, and the lamellar cells were smaller. Regarding the glomerular corpuscles they were bigger but with a normal arrangement of the corpuscular constituents. These findings suggest that these cutaneous sensory corpuscles are part of the nevus sebaceus hamartoma.

Response to combined antiretroviral therapy according to gender and origin in a cohort of naïve HIV-infected patients: GESIDA-5808 study.

BACKGROUND: We analyzed differences in response to combined antiretroviral therapy (cART) according to sex and geographic origin in a retrospective comparative study of Spanish-born and immigrant patients initiating cART. METHODS: The primary endpoint was time to treatment failure (TTF), defined as virological failure, death, opportunistic infection, interruption of cART, or loss to follow-up. Late diagnosis was defined as a CD4+ cell count ≤ 200 cells/mm3 and/or AIDS at initiation of cART. Survival was analyzed using Kaplan-Meier analysis and Cox regression. RESULTS: We followed 1,090 patients, of whom 318 were women (45.6% immigrant women [IW]). At initiation of treatment, women had a higher CD4+ count than men (217 vs 190 cells/mm3), a lower viral load (4.7 vs 5 log), and fewer were late starters (49% vs 59%). The adjusted risk of TTF between women and men was not significantly different (hazard ratio [HR], 1.10; 95% CI, 0.79-1.53). TTF was shorter among IW than Spanish-born women (124 weeks [95% CI, 64-183] vs 151 [95% CI, 127-174]) and loss to follow-up was double that of Spanish-born women (25.5% vs 11.6%). CONCLUSIONS: Although response to cART was similar for both sexes, men started treatment later. IW were more frequently lost to follow-up and switched treatment. Measures to improve medical follow-up after initiation of cART should be promoted among this minority group.

Human digital merkel cells display pannexin1 immunoreactivity.

Pannexins are channel proteins displaying functional similarities to gap junctions in vertebrates and are regarded as transmembrane ATP-releasing channels. A member of this family, denominate pannexin1, has been detected in the epidermis and cutaneous adnexal structures. Here we used immunohistochemistry to investigate whether human digital Merkel cells express this protein since ATP is postulated as a neurotransmitter in the Merkel cell-axon complexes low-threshold mecahoreceptors. Pannexin1 immunoreactivity was found in cytokeratine 20-, chromogranin A- and synaptophysin-positive cells placed at the basal layer of the epidermis. Cell displaying pannexin1 immunoreactivities were thus identified as Merkel cells and showed close contact with nerve profiles. Light pannexin1 immunoreactivity in dermal blood vessels was also verified. Present results demonstrate for the first time the expression of pannexin1 in human digital Merkel cells supporting the idea that ATP can be involved directly or indirectly in the mechanotransductional process at Merkel-axon complexes.

Merkel Cell Carcinoma Display PIEZO2 Immunoreactivity.

As an essential component of mechano-gated ion channels, critically required for mechanotransduction in mammalian cells, PIEZO2 is known to be characteristically expressed by Merkel cells in human skin. Here, we immunohistochemically investigated the occurrence of Piezo channels in a case series of Merkel cell carcinoma. A panel of antibodies was used to characterize Merkel cells, and to detect PIEZO2 expression. All analyzed tumors displayed PIEZO2 in nearly all cells, showing two patterns of immunostaining: membranous and perinuclear dot-like. PIEZO2 co-localized with cytokeratin 20, chromogranin A, synaptophysin and neurofilament. Moreover, neurofilament immunoreactive structures resembling nerve-Merkel cell contacts were occasionally found. PIEZO2 was also detected in cells of the sweat ducts. The role of PIEZO2 in Merkel cell carcinoma is still unknown, but it could be related with the mechanical regulation of the tumor biology or be a mere vestige of the Merkel cell derivation.

Synaptophysin is a selective marker for axons in human cutaneous end organ complexes.

BACKGROUND: Small clear synaptic-like vesicles fill axon terminals of mechanoreceptors. Their functional significance is controversial and probably includes release of neurotransmitters from afferent axon terminals. Synaptophysin, a major protein of the synaptic vesicle membrane, is present in presynaptic endings of the central and peripheral nervous systems. It is also expressed in mechanosensory neurons which extend into skin forming sensory corpuscles. Nevertheless, synaptophysin occurrence in these structures has never been investigated. METHODS: Here we used immunohistochemistry to detect synaptophysin in adult human dorsal root ganglia, cutaneous Meissner and Pacinian corpuscles and Merkel cell-neurite complexes from foetal to elderly period. Moreover, we analyzed whether synaptophysin co-localizes with the mechano-gated protein PIEZO2. RESULTS: Synaptophysin immunoreactivity was observed in primary sensory neurons (36 ± 6%) covering the entire soma size ranges. Axons of Meissner's and Pacinian corpuscles were positive for synaptophysin from 36 and 12 weeks of estimated gestational age respectively, to 72 years old. Synaptophysin was also detected in Merkel cells (from 14 weeks of estimated gestational age to old age). Additionally in adult skin, synaptophysin and PIEZO2 co-localized in the axon of Meissner and Pacinian corpuscles, Merkel cells as well as in some axons of Merkel cell-neurite complexes. CONCLUSION: Present results demonstrate that a subpopulation of primary sensory neurons and their axon terminals forming cutaneous sensory corpuscles contain synaptophysin, a typical presynaptic vesicle protein. Although the functional relevance of these findings is unknown it might be related to neurotransmission mechanisms linked to mechanotransduction.

The Human Cutaneous Sensory Corpuscles: An Update.

Sensory corpuscles of human skin are terminals of primary mechanoreceptive neurons associated with non-neuronal cells that function as low-threshold mechanoreceptors. Structurally, they consist of an extreme tip of a mechanosensory axon and nonmyelinating peripheral glial cells variably arranged according to the morphotype of the sensory corpuscle, all covered for connective cells of endoneurial and/or perineurial origin. Although the pathologies of sensitive corpuscles are scarce and almost never severe, adequate knowledge of the structure and immunohistochemical profile of these formations is essential for dermatologists and pathologists. In fact, since sensory corpuscles and nerves share a basic structure and protein composition, a cutaneous biopsy may be a complementary method for the analysis of nerve involvement in peripheral neuropathies, systemic diseases, and several pathologies of the central nervous system. Thus, a biopsy of cutaneous sensory corpuscles can provide information for the diagnosis, evolution, and effectiveness of treatments of some pathologies in which they are involved. Here, we updated and summarized the current knowledge about the immunohistochemistry of human sensory corpuscles with the aim to provide information to dermatologists and skin pathologists.

Heparan sulfate in human cutaneous Meissner's and Pacinian corpuscles.

Heparan sulfate proteoglycans are pericellular/cell surface molecules involved in somatosensory axon guidance in the peripheral nervous system. However, the distribution of heparan sulfate proteoglycans in the extracellular matrix of human cutaneous sensory corpuscles is unknown. Immunohistochemistry and immunofluorescence assays were performed to define the localization of heparan sulfate proteoglycans in human cutaneous Meissner's and Pacinian corpuscles using two anti-heparan sulfate antibodies together with anti-S100 protein, anti-PGP9.5, anti-CD34 (to immunolabel basement membranes, Schwann cells, axon and the intermediate endoneurial layer of Pacinian corpuscles, respectively), anti-Type IV collagen, and anti-chondroitin sulfate antibodies. Heparan sulfate proteoglycans were colocalized with Type IV collagen in Meissner's corpuscles and were located in the outer core lamellae and capsule, but not in the inner core or the intermediate layer, in Pacinian corpuscles. Chondroitin sulfate was observed in the intermediate layer of Pacinian corpuscles but was never colocalized with heparan sulfate proteoglycans. The present results strongly suggest that heparan sulfate proteoglycans are associated with the basement membranes of the lamellar cells in Meissner's corpuscles and with the complex outer core capsule in Pacinian corpuscles. The functional significance of these results, if any, remains to be elucidated.

[Delayed diagnosis of HIV infection in the Spanish VACH cohort [1997-2002]]. / Diagnóstico tardío de la infección por el virus de la inmunodeficiencia humana en la Cohorte VACH (1997-2002).

OBJECTIVE: To study the prevalence of delayed diagnosis of HIV infection and associated factors. METHODS: A cross sectional study of patients included in the Spanish VACH cohort who had been diagnosed with HIV infection between 1997 and 2002 was performed. Delayed diagnosis was defined as patients diagnosed with HIV infection and AIDS simultaneously or within the first month after the first positive serologic test, or those with a first CD4+ cell count below 200/ml. The epidemiological characteristics of these patients were compared with those of the remaining patients RESULTS: Of 2,820 new cases of HIV infection, delayed diagnosis was found in 506 (18%). These patients differed from the remaining patients in their lower mean age and higher HIV viral load, as well as in their distribution by sex (higher proportion of males), occupational status, history of incarceration in prison, and HIV-risk transmission group. The median survival during follow-up was significantly lower among AIDS patients with a delayed diagnosis. CONCLUSIONS: Delayed diagnosis remains a cause for concern in our environment, due to its magnitude and its association with mortality. Some epidemiological characteristics provide clues to guide future programs directed at increasing information and improving prevention.

Aetiology of renal failure in patients with infective endocarditis. The role of antibiotics. / Etiología de la insuficiencia renal en pacientes con endocarditis infecciosa. Papel de los antibióticos.

BACKGROUND AND OBJECTIVES: The possible renal toxicity of certain antibiotics (AB) is well known. The objective of our work is to know the possible effect of AB treatments in the development of renal failure (RF) in patients with infective endocarditis (IE). MATERIAL AND METHOD: Collection from a national multi-centre registry of collection on renal function, both prior and its impairment, if any, during the treatment of IE and in relation to possible causative factors, including the use of AB. RESULTS: Between 2008 and 2012, 1,853 episodes of IE reported from 26 Spanish centres were analysed. Of these, 21.6% had prior RF. They developed new RF or impairment of renal function in 38.7% of the cases. In patients with prior RF, impairment was more frequent (64 vs. 31.7%, P<.001). Overall, patients with RF were older (70.6 vs. 67 years, P<.01), had more comorbidities (Charlson index 5 vs. 4, P<.01), and IE by Staphylococcus aureus (32.1 vs. 16.5%, P<.01). Potentially nephrotoxic AB use was only associated with RF in patients without prior RF (aminoglycosides: OR=1.47 [95% CI 1.096-1.988], P=.010; aminoglycosides with vancomycin: OR=1.49 [95% CI 1.069-2.09], P=.019). CONCLUSIONS: In patients without prior RF, the use of nephrotoxic AB is associated with impairment of renal function. In patients with RF prior to the IE episode, impairment of renal function was more frequent but appears to be more related to the severity of infection.

Acid-sensing ion channel 2 (asic 2) and trkb interrelationships within the intervertebral disc.

The cells of the intervertebral disc (IVD) have an unusual acidic and hyperosmotic microenvironment. They express acid-sensing ion channels (ASICs), gated by extracellular protons and mechanical forces, as well as neurotrophins and their signalling receptors. In the nervous tissues some neurotrophins regulate the expression of ASICs. The expression of ASIC2 and TrkB in human normal and degenerated IVD was assessed using quantitative-PCR, Western blot, and immunohistochemistry. Moreover, we investigated immunohistochemically the expression of ASIC2 in the IVD of TrkB-deficient mice. ASIC2 and TrkB mRNAs were found in normal human IVD and both increased significantly in degenerated IVD. ASIC2 and TrkB proteins were also found co-localized in a variable percentage of cells, being significantly higher in degenerated IVD than in controls. The murine IVD displayed ASIC2 immunoreactivity which was absent in the IVD of TrkB-deficient mice. Present results demonstrate the occurrence of ASIC2 and TrkB in the human IVD, and the increased expression of both in pathological IVD suggest their involvement in IVD degeneration. These data also suggest that TrkB-ligands might be involved in the regulation of ASIC2 expression, and therefore in mechanisms by which the IVD cells accommodate to low pH and hypertonicity.

[Retrospective epidemiological study on the durability of the treatment of HIV infection or AIDS in Spain]. / Estudio epidemiológico retrospectivo sobre la duración del tratamiento de la infección por el virus de la inmunodeficiencia humana en España.

BACKGROUND AND OBJECTIVE: To know the durability of consecutive regimens of antiretroviral treatment is important to design a long-term therapy, but there is not much information about this subject. PATIENTS AND METHOD: Retrospective epidemiological study of a sample of 401 patients who began antiretroviral treatment between January 1997 and April 2000 at ten Spanish hospitals. The duration of each consecutive antiretroviral regimen was calculated and the reasons for modification and discontinuation were described. RESULTS: In the 3 years and 3 months covered by the study, 48.6% of the patients received more than one regimen of therapy. Seventy five of the initial prescribed combinations included protease inhibitors. Median duration of consecutive lines of therapy was decreasing: 560, 360, 330 and 202 days for the first, second, third and fourth regimens, respectively. The main reason to modification was intolerance or toxicity (46.2, 49.1 and 47.1% for the first, second and third modification). A fifth of changes was originated by difficulties to follow the therapy. Virological failure was the reason for modification in 21.8, 24.5 and 26.5% of first, second and third changes. CONCLUSIONS: Duration of consecutive antiretroviral regimens progressively decreases. Intolerance or drug toxicity were the main reasons conditioning the change of treatment.