Abnormal development of pacinian corpuscles in double trkB;trkC knockout mice.

Pacinian corpuscles depend on either Aalpha or Abeta nerve fibers of the large- and intermediate-sized sensory neurons for the development and maintenance of the structural integrity. These neurons express TrkB and TrkC, two members of the family of signal transducing neurotrophin receptors, and mice lacking TrkB and TrkC lost specific neurons and the sensory corpuscles connected to them. The impact of single or double targeted mutations in trkB and trkC genes in the development of Pacinian corpuscles was investigated in 25-day-old mice using immunohistochemistry and ultrastructural techniques. Single mutations on trkB or trkC genes were without effect on the structure and S100 protein expression, and caused a slight reduction in the number of corpuscles. In mice carrying a double mutation on trkB;trkC genes most of the corpuscles were normal with a reduction of 17% in trkB-/-;trkC+/- mice, and 8% in trkB +/-;trkC -/- mice. Furthermore, a subset of the remaining Pacinian corpuscles (23% in trkB-/-;trkC+/- mice; 3% in trkB+/-;trkC-/- mice) were hypoplasic or atrophic. Present results strongly suggest that the development of a subset of murine Pacinian corpuscles is regulated by the Trk-neurotrophin system, especially TrkB, acting both at neuronal and/or peripheral level. The precise function of each member of this complex in the corpuscular morphogenesis remains to be elucidated, though.

[Medication errors and non-compliance in polymedicated elderly patients]. / Errores de medicación e incumplimiento terapéutico en ancianos polimedicados.

OBJECTIVE: To detect and describe medication errors and adherence to therapy in polymedicated (> 5 drugs) elderly patients (> 65 years). METHOD: A descriptive, observational study using a phone survey to polymedicated elderly outpatients. Sociodemographic, clinical, and pharmacotherapeutic data were collected, as well as information on their functional and mental capability. The number, type and severity of medication errors were measured, as was non-adherence. RESULTS: Errors were detected in 42.5% of 73 responders, with a total of 55 errors, and a mean 1.77 errors per patient. Most commonly found errors included inappropriate administration frequency and therapeutic duplicity. Regarding adherence, 43.8% were non-compliants, being sporadic in 68.8% and sequential in 31.2% of the cases. A positive relationship between error number and drug number or adherence was found. CONCLUSIONS: Actions are required from a multidisciplinary standpoint to reduce this high percentage of errors.

Immunohistochemistry of human cutaneous Meissner and pacinian corpuscles.

This paper reviews the immunohistochemical characteristics of two kinds of human cutaneous sensory nerve formations (SNFs), the Meissner and Pacinian corpuscles. In both kinds of SNF the central axon might be easily identifiable because it displays immunoreactivity (IR) for the neuroendocrine markers neuron-specific enolase and protein gene product 9.5, as well as for neuron-specific intermediate filament proteins, i.e., neurofilaments. Other intermediate filament proteins such as vimentin are localized in the lamellar cells of Meissner corpuscles, and in the inner core, outer core and capsule of Pacinian corpuscles. However, they lack cytokeratins or glial fibrillary acidic protein IR. On the other hand, and in agreement with ultrastructural data, IR for basement membrane constituents laminin and type IV collagen is found underlying all SNF constituents, with the exception of the axon. One of the mechanisms involved in the maintenance of intracellular calcium ions (Ca2+) homeostasis is the calcium binding proteins. Ca2+ play a key role in the mechanoelectric transduction and have been localized in SNFs. In this way IR for the Ca(2+)-binding proteins calbindin D28K, parvalbumin and calretinin, is present and colocalized in both Meissner and Pacinian corpuscles; furthermore, S-100 protein is exclusively localized in the lamellar cells and the inner core. On the other hand, the skin is a main source of neurotrophins for a subset of neural crest sensory neurons, some of which end forming SNF. These factors are conveyed via retrograde axonal transport from the skin to the cell body of the responsive neurons. Interestingly, Meissner and Pacinian corpuscles also display IR for the pan-neurotrophin low-affinity receptor (p75), and for the trkA receptor protein, a basic constituent of the high-affinity receptor for some neurotrophins. Moreover, they express IR for the epidermal growth factor receptor. Finally, other antigens not proper to the cells forming human cutaneous SNF, such as the epithelial membrane antigen and the leucocytary antigen-7, have also been detected.

Beta-amyloid precursor protein in human digital skin.

The occurrence and distribution of beta-amyloid precursor protein (beta APP) and of beta-amyloid peptide (beta/A4) was investigated using immunoblotting and immunohistochemical techniques in the digital skin of healthy adult subjects. beta APP-like proteic bands with apparent molecular masses between 55-60 kDa, 100-125 kDa (corresponding to the full-length beta APP isoforms), 145-150 kDa, and 200 kDa were found in pellets and supernatants of whole skin and dermis. The same proteins, except that of approximately 200 kDa, were also found in pellets from the epidermis, whereas epidermic supernatants were unreactive. beta/A4 was not found by immunoblotting. Light microscope immunohistochemistry showed beta APP immunoreactivity (IR) in: (a) dermal nerves; (b) lamellar cells of Meissner, as well as inner-core, outer-core and capsule of Pacinian corpuscles; and (c) dermal blood vessels, sweat glands and, occasionally, epidermis. The distribution of beta/A4 IR matched that of beta APP, and no evidence of extracellular beta/A4 IR was encountered. Present results demonstrate that beta APP, but not beta/A4, is normally present in human glabrous (digital) skin. The potential clinical relevance of these findings is discussed.

Immunohistochemical study of sensory nerve formations in human glabrous skin.

The sensory nerve formations (or corpuscles) of normal human glabrous skin from hand and fingers, obtained by punch biopsies, were studied by the streptavidin-biotin method using monoclonal antibodies directed against neurofilament protein (NFP), S-100 protein, glial fibrillary acidic protein (GFAP), cytokeratins, and vimentin. NFP immunoreactivity (IR) was observed in the central axons of most sensory formations, while S-100 protein IR was restricted to non-neuronal cells forming the so-called inner cells core or lamellar cells. Furthermore, vimentin IR was found in the same cells of Meissner's and glomerular corpuscles. None of the sensory nerve formations were stained for GFAP or keratin. The present results suggest that the main nature of the intermediate filaments of the non-neuronal cells of sensory nerve formations from human glabrous skin is represented by vimentin and not by GFAP. Thus, our findings suggest that lamellar and inner core cells of SNF are modified and specialized Schwann cells and not epithelial or perineurial derived cells.

The inner-core, outer-core and capsule cells of the human Pacinian corpuscles: an immunohistochemical study.

The distribution of several markers for Schwann cells and perineurial cells, including S-100 protein, Leu-7 antigen, vimentin and epithelial membrane antigen was studied immunohistochemically in Pacinian corpuscles from human digital skin. Formaldehyde fixed paraffin embedded tissues, and monoclonal antibodies were used. A positive immunostaining for S-100 protein, Leu-7 antigen and vimentin was found in the inner-core cells, whereas the outer-core and capsule lamellae were labelled for both epithelial membrane antigen and vimentin. The pattern of vimentin immunoreactivity was not homogeneous but focally distributed, and occasionally, positive immunoreactivity for vimentin was observed in blood vessels supplying the capsule. Present results provide evidence that some antibodies against Schwann cells and perineurial fibroblastic cells, selectively stain the Pacinian corpuscles derivatives while others are commonly expressed for non-neuronal cells of sensory nerve corpuscles.

Human glabrous skin autografts partially reinnervated without sensory corpuscles. An immunohistochemical study.

The reinnervation of human glabrous skin autografts was investigated in biopsy specimens obtained four weeks to 15 months after transplantation. The grafted skin was taken from the volar aspect of the wrist and transplanted to the fingers. Immunohistochemical methods were used to detect the presence of nerve fibres and sensory corpuscles, using monoclonal antibodies against neurofilament proteins and S-100 protein. In normal skin, immunoreactivity of neurofilament proteins was localised in the axons of nerves and sensory corpuscles, while S-100 protein immunoreactivity was found in Schwann cells, lamelar cells and inner core cells of sensory corpuscles. In the transplanted skin, there was no positive immunoreactivity in the youngest grafts (four weeks), but in eight week old grafts immunoreactivity to both proteins, identified as axons or Schwann cells, respectively, were seen in the deep nerve plexus, and these reached subepithelial dermis in the 15 month old grafts. In no case, however, were immunoreactive structures found that resembled reinnervated or regenerated sensory nerve corpuscles. Clinical assessment of sensibility was consistent with morphological findings. These results suggest that reinnervation of human skin autografts is far from normal, and that sensory corpuscles are not able to regenerate in grafted human glabrous skin, at least during the times studied.

Nerve growth factor receptor immunoreactivity in Meissner and Pacinian corpuscles of the human digital skin.

The presence of nerve growth factor receptors (NGFr) in sensory nerve corpuscles of human digital skin, primarily Meissner and Pacinian corpuscles, was investigated immunohistochemically using two monoclonal antibodies directed against human-NGFr. To ensure the localization of NGFr immunoreactivity (IR) alternative sections to that processed for NGFr detection were assayed for neurofilament protein (NFP) and S-100 protein which selectively label the axon and the periaxonic specialized cells (lamellar cells of Meissner's corpuscles; inner-core cells of Pacinian corpuscles), respectively. Occurrence of NGFr IR was observed in both types of sensory corpuscles. In Meissner's corpuscles NGFr-IR was found in the lamellar cells, whereas in the Pacinian corpuscles the lamellae of the inner core, outer core, and capsule displayed NGFr IR. Moreover, a positive IR was observed in the central axon of some Pacinian corpuscles. However, remarkable differences were encountered among Pacinian corpuscles in the pattern of NGFr IR distribution. Present results demonstrate the presence of NGFr IR in sensory nerve corpuscles of the human digital skin, suggesting that NGFr could be involved in the concentration of NGF and in the conveying of this molecule from the cutaneous sources to the cell body of NGF-dependent primary sensory neurons. However, the mechanisms involved in this process remain to be clarified.

Effect of denervation on lamellar cells of Meissner-like sensory corpuscles of the rat. An immunohistochemical study.

The denervation-induced changes on S-100 protein, glial fibrillary acidic protein (GFAP) and vimentin immunoreactivity (IR) of the lamellar cells from cutaneous Meissner-like sensory nerve formations (SNF), or corpuscles, of the adult rat hind limb foot-pads were studied, using combined immunohistochemical and image analysis (optic microdensitometry) techniques. Animals were allowed to survive for 1, 3 and 7 days following sciatic and saphenous nerves transection. Lamellar cells of Meissner-like corpuscles displayed S-100 protein- and vimentin-IR, but not GFAP-IR. Denervation caused a marked time-dependent decrease of S-100 protein IR whereas vimentin-IR did not change or weakly increased. No positive GFAP-IR was observed in denervated SNF. These findings suggest that continuity of SNF with nerve fibers supplying them is necessary to maintain some of the immunohistochemical characteristics of the non-neuronal cells of SNF.