Sihler's Staining of the Thoracic Cutaneous Nerve and its Significance / Tinción de Sihler del Nervio Cutáneo Torácico y su Relevancia

SUMMARY: Our team has modified Sihler's intramuscular nerve staining method to allow for calculation of nerve density. Therefore, this study aimed to show the overall distribution pattern of the thoracic cutaneous nerves to provide a morphological basis for selecting and matching sensory reconstruction during skin flap transplantation. Twelve Chinese adult cadavers were dissected; the thoracic skin was removed, and the modified Sihler's staining method was performed. Centered around the nipple, the chest skin was divided into four regions: medial-superior, lateral-superior, lateral-inferior, and medial-inferior. The thoracic skin was not only innervated by the branches of the 1st to 7th intercostal and supraclavicular nerves, but also by a small number of nerves that directly reached the skin and passed through the pectoralis major muscle. There is a phenomenon of cross overlap between the branches of adjacent intercostal nerves. The branches of the 2nd to 7th intercostal nerves were distributed in the breast, and the branches of the lateral and anterior cutaneous branches were densely distributed around the nipple, forming a grid-like anastomosis. There was no cross-overlapping innervation between the anterior cutaneous branches on both sides. The density of nerve distribution in the four regions of the chest was in the order of the medial-superior, lateral-superior, lateral-inferior and medial-inferior region, respectively. These results may be used to map sensory regions when designing thoracic skin flaps for reconstruction surgery to obtain improved sensory recovery.

Nuestro equipo ha modificado el método de tinción nerviosa intramuscular de Sihler para permitir el cálculo de la densidad nerviosa. Por lo tanto, este estudio tuvo como objetivo mostrar el patrón de distribución general de los nervios cutáneos torácicos proporcionando una base morfológica para seleccionar y combinar la reconstrucción sensorial durante el trasplante de colgajo de piel. Se diseccionaron 12 cadáveres de individuos adultos chinos. Se eliminó la piel torácica y se realizó el método de tinción de Sihler modificado, centrada alrededor del pezón, la piel del pecho se dividió en cuatro regiones: medial- superior, lateral-superior, lateral-inferior y medial-inferior. La piel torácica no solo estaba inervada por los ramos de los nervios intercostal y supraclavicular 1º a 7º, sino también por un pequeño número de nervios que llegaban directamente a la piel y pasaban a través del músculo pectoral mayor. Existe un fenómeno de superposición cruzada entre los ramos de los nervios intercostales adyacentes. Los ramos de los nervios intercostales 2º a 7º se distribuyeron en la mama, y los ramos de los ramos cutáneos lateral y anterior se distribuyeron densamente alrededor del pezón, formando una anastomosis en forma de rejilla. No hubo inervación cruzada entre los ramos cutáneos anteriores en ambos lados. La densidad de la distribución nerviosa en las cuatro regiones del tórax estaba en el orden de región medial-superior, lateral-superior, lateral-inferior y medial-inferior, respectivamente. Estos resultados pueden ser útiles para mapear regiones sensoriales al diseñar colgajos de piel torácicos para utilizarlos en cirugía de reconstrucción y obtener así una mejor recuperación sensorial.

Immunohistochemical and histopathological analyses of cutaneous innervation to improve the diagnostic efficacy in hansen disease skin lesion.

BACKGROUND: The diagnosis of Hansen disease (HD) can be difficult when acid-fast bacilli are not detected in the patient's skin sample. OBJECTIVE: To demonstrate that detailed morphological analysis of nonspecific inflammatory and/or noninflammatory alterations in dermal nerves as well as skin adnexa in leprosy-suspected biopsy samples could improve the efficacy of histopathological diagnosis. METHODS: Patients with one to five skin lesions were enrolled in the study and classified into three groups by skin histopathology findings: Hansen disease (HD, n = 13), other diseases (OD, n = 11), and inconclusive cases (INC, n = 11). We quantified dermal nerve damage via the nerve lesion index (NLI) and PGP9.5-immunoreactive axon quantitative index in dermal nerves (AQI). We also measured inflammatory involvement of adnexa in cutaneous samples as indirect evidence of HD. RESULTS: We observed a higher median endoneurial inflammatory infiltrate NLI (HD = 0.5; INC = 0; OD = 0; p < 0.001) and more frequent inflammatory involvement of skin adnexa in samples of the HD group compared with those of the INC and OD groups (HD = 7; INC = 1; OD = 0). However, samples from the INC and OD groups also showed inflammatory and noninflammatory damage of dermal nerves, with 2 or more kinds of alterations in nerves in the same sample (respectively: INC = in 1 and 2 samples; OD = in 3 and 5 respectively). The quantification of PGP9.5-immunoreactive axons in dermal nerves revealed no difference between the groups. CONCLUSION: A detailed morphological analysis of cutaneous nerves in lesions with a suspicion of HD enabled us to select patients with nonspecific inflammatory or non-inflammatory lesions in the dermal nerves in the INC and OD groups, so they may be clinically monitored aiming at a possible future diagnosis of the disease. These INC and OD patients cannot have the HD diagnosis definitely excluded, and HD may coexist with another disease as a comorbidity.

ANTECEDENTES: A hanseníase pode ter o seu diagnóstico histopatológico dificultado quando bacilos álcool-ácido resistentes não são encontrados nas amostras de pele dos pacientes. OBJETIVO: Demonstrar que uma análise morfológica detalhada de alterações histopatológicas dos nervos dérmicos pode aumentar a eficácia diagnóstica. MéTODOS: Foram selecionadas amostras de pele de pacientes com uma a cinco lesões suspeitas de hanseníase. Os casos selecionados foram classificados conforme achados histopatológicos: hanseníase (HD, n = 13), casos inconclusivos (INC, n = 11), e outras doenças (OD, n = 11). Quantificamos as lesões dos nervos cutâneos por meio do índice de lesão de nervos (nerve lesion index, NLI, em inglês) e do índice quantitativo de axônios (axon quantitative index, AQI, em inglês) imunorreativos a PGP9.5 nos nervos cutâneos. Também medimos o envolvimento inflamatório dos anexos em amostras de pele como evidência indireta de hanseníase. RESULTADOS: Foram observadas no grupo HD medianas mais altas do NLI com relação a infiltrados inflamatórios endoneurais (HD = 0,5; INC = 0; OD = 0; p < 0,001) e mais alta frequência de acometimento inflamatório de anexos cutâneos (HD = 7; INC = 1; OD = 0). Entretanto, as amostras dos grupos INC e OD também mostraram comprometimento inflamatório e não inflamatório dos nervos cutâneos, com 2 ou mais tipos de alterações de nervos na mesma amostra (respectivamente: INC = 1 e 2; OD = 3 e 5). Não houve diferença significativa na quantidade de axônios endoneurais imunorreativos a PGP9.5 entre os grupos. CONCLUSãO: A análise morfológica detalhada dos nervos cutâneos em lesões suspeitas de hanseníase permitiu selecionar pacientes com lesões inespecíficas inflamatórias ou não inflamatórias nos nervos dérmicos nos grupos INC e OD, para que sejam monitorados clinicamente visando um possível diagnóstico futuro da doença. Esses pacientes INC e OD não podem ter o diagnóstico de HD definitivamente excluído, e a hanseníase pode coexistir com outra doença como uma comorbidade.

Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis.

BACKGROUND: ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. OBJECTIVES: To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. METHODS: Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. RESULTS: At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. CONCLUSIONS: Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.

Leishmania spp. amastigotes surrounding sensory nerve fibers in human painless skin ulcers: Evidence of pathogen-neuron proximity and absence of neuronal apoptosis.

In this present study, carried out between November 2020 and July 2023 at Londrina's University Hospital, patients with active lesions of cutaneous leishmaniasis (CL) were analyzed regarding pain perception and anatomopathological aspects of the ulcers. Pain was assessed using a numerical rating scale (NRS) to compare five patients diagnosed with CL with four control patients diagnosed with vascular skin ulcers. Histopathological evaluations were used to investigate the nociceptor neuron-Leishmania interface. Patients with CL ulcers reported less pain compared to patients with vascular ulcers (2.60 ± 2.30 and 7.25 ± 0.95, respectively, p = 0.0072). Histopathology evidenced Leishmania spp. amastigote forms nearby sensory nerve fibers in profound dermis. Schwann cells marker (S100 protein) was detected, and caspase-3 activation was not evidenced in the in the nerve fibers of CL patients' samples, suggesting absence of apoptotic activity in nerve endings. Additionally, samples taken from the active edge of the lesion were negative for bacilli acid-alcohol resistant (BAAR), which excludes concomitant leprosy, in which painless lesions are also observed. Thus, the present data unveil for the first time anatomopathological and microbiological details of painless ulcers in CL patients, which has important clinical implications for a better understanding on the intriguing painless clinical characteristic of CL.

Pain-Related Vertex Evoked Potentials. Comparison of Surface Electrical to Heat Stimulation.

INTRODUCTION: Demonstration of nociceptive fiber abnormality is important for diagnosing neuropathic pain and small fiber neuropathies. This is usually assessed by brief heat pulses using lasers, contact heat, or special electrodes. We hypothesized that pain-related evoked potentials to conventional surface electrical stimulation (PREPse) can index Aδ afferences despite tactile Aß fibers coactivation. PREPse may be more readily used clinically than contact heat evoked potentials (CHEPS). METHODS: Twenty-eight healthy subjects. Vertex (Cz-A1/A2) recordings. Electrical stimulation of middle finger and second toe with conventional ring, and forearm/leg skin with cup, electrodes. Contact heat stimulation to forearm and leg. Compression ischemic nerve blockade. RESULTS: PREPse peripheral velocities were within the midrange of Aδ fibers. N1-P1 amplitude increased with pain numerical rating scale graded (0-10) electrical stimulation (n = 25) and decreased with increasing stimulation frequency. Amplitudes were unchanged by different presentation orders of four stimulation intensities. PREPse N1 (∼130 milliseconds) and N2 (∼345 milliseconds) peaks were approximately 40 milliseconds earlier than that with CHEPS. PREPse and CHEPS N1-N2 interpeak latency (∼207 milliseconds) were similar. PREPse became unrecordable with nerve blockade of Aδ fibers. CONCLUSIONS: PREPse earlier N1 and N2 peaks, and similar interpeak N1-N2 latencies and central conduction velocities, or synaptic delays, to CHEPS are consistent with direct stimulation of Aδ fibers. The relation of vertex PREPse amplitude and pain, or the differential effects of frequency stimulation, is similar to pain-related evoked potential to laser, special electrodes, or contact heat stimulation. The relationship to Aδ was validated by conduction velocity and nerve block. Clinical utility of PREPse compared with CHEPS needs validation in somatosensory pathways lesions.

Mirror peripheral neuropathy and unilateral chronic neuropathic pain: insights from asymmetric neurological patterns in leprosy.

ABSTRACT: Leprosy-related multiple mononeuropathy offers a pattern of impairment where neuropathy with and without neuropathic pain (NeP) are present in the same individual, thus allowing to investigate peripheral sensory and innervation in both conditions. This cross-sectional study collected data on clinical and neurological examination, pain assessment questionnaires, quantitative sensory test, and intraepidermal nerve fiber density of patients with leprosy and divided the cohort into 2 groups: with NeP (P+) and without NeP (P-). Furthermore, we assessed mirror body areas in the same NeP individuals with bilateral neuropathy also presenting unilateral NeP. Pain-free patients having unilateral neuropathy were controls. A total of 37 P+ and 22 P- patients were evaluated. Limb areas with NeP had signs of C-fiber dysfunction and hyperesthesia on quantitative sensory testing compared with limb areas having neuropathy without NeP. Skin denervation was found in all patients with leprosy. Comparisons of limbs with and without neuropathy and with and without NeP revealed that higher heat pain thresholds (HPTs) were associated with neuropathic pain areas, whereas less altered HPT was correlated with higher fiber density. Furthermore, a relationship was found between time of leprosy treatment termination and more intense neuropathy, expressed by HPT increasing 0.03°C each month. As expected, interindividual comparisons failed to show differences in intraepidermal nerve fiber density and subepidermal plexus areas between P+ and P- patients ( P = 0.2980, P = 0.9044; respectively). Higher HPT and lower mechanical detection threshold were related to NeP. This study pointed out the relevance of intraindividual comparisons including mirror areas when assessing local changes in peripheral NeP.

Semmes-Weinstein monofilament: A tool to quantify skin sensation in macular lesions for leprosy diagnosis.

INTRODUCTION: Hypochromatic macules with altered sensitivity are the first manifestations of skin leprosy. Validation of this sensory loss assists in the confirmation of the clinical diagnosis. AIMS: The aim of the study was to quantify the loss of sensation in leprosy lesions using the Semmes-Weinstein monofilament to strengthen the clinical diagnosis mainly of macular forms. METHODS: Seventy-four hypochromatic macules in the macular leprosy subgroup, 27 typical borderline leprosy subgroup lesions and 49 macules of other macular dermatoses (non-leprosy group) were evaluated using the 0.05 g force Semmes-Weinstein monofilament to quantify the alteration of sensitivity within and outside of the lesions. The esthesiometric change index was established as the total number of points with altered sensation divided by the total number of tested points within the lesions to calculate the internal esthesiometric change index and outside the lesions to calculate the peripheral esthesiometric change index; these indexes were calculated for all groups. The difference (Δ) between the esthesiometric change indices of the lesional area and the adjacent skin was calculated for the leprosy and nonleprosy groups. RESULTS: The percentage of points with touch sensitivity alterations within the macular and typical borderline leprosy lesions was higher in leprosy than in the non-leprosy group. The borderline and macular leprosy presented higher esthesiometric change index within injured areas than outside injured areas or in the nonleprosy group (P < 0.005). When internal esthesiometric change index values in the macular and borderline leprosy groups were higher than 0.53 and 0.5, respectively, the receiver operating characteristic curve showed 98% sensitivity and approximately 99% specificity for both groups (P < 0.0001). Regarding the difference between indices, borderline and macular leprosy had values that were higher and closer to one than in the nonleprosy group (P < 0.0001), with 100% sensitivity and 96.5% specificity for leprosy diagnosis when ΔLG was higher than 0.34. A limitation was the inability to perform a double-blind study. CONCLUSION: Semmes-Weinstein esthesiometry is a simple, useful and low-cost tool to quantify the focal alteration of cutaneous sensitivity to improve clinical leprosy diagnosis, especially for macular lesions.

The overall distribution pattern of the hand's cutaneous nerves and its clinical implications in sensory reconstruction / Patrón de distribución general de los nervios cutáneos de la mano y sus implicancias clínicas en la reconstrucción sensorial

SUMMARY: The objective of this study was to reveal the overall distribution pattern of the hand's cutaneous nerves to provide a morphological basis for the selection and matching of the hand skin for sensory reconstruction during flap transplantation. The hands of 12 adult cadavers were used for the study. Palmar region and dorsum of the hand were divided into regions I-VI. The skin of the hand containing subcutaneous fat was removed close to the muscle surface. The modified Sihler's staining method was used to visualize the overall distribution pattern of the cutaneous nerves and the areas they innervate. The median nerve, superficial branch of the ulnar nerve, and the superficial branch of the radial nerve innervated 59.27 % (containing 4.65 % of the palmar cutaneous branch of the median nerve), 36.91 %, and 3.82 % of the palm area, respectively. The superficial branch of the radial nerve, the dorsal branch of the ulnar nerve, and the median nerve innervated 45.16 %, 47.25 %, and 7.59 % of the hand's dorsal skin area, respectively. Communication was found between the arborized branches of these cutaneous nerves. Region III of the palm and region VI of the dorsum of the hand had relatively more dense nerve distribution. Except for region V, the density of the total nerve branches in each palm region was higher than that of the dorsum of the hand. The total number of nerve branches in the distal phalanx and dorsum decreased from the thumb to the digitus minimus. Our results provide morphological guidance when designing a reasonable matching flap to improve the hand's sensory function reconstruction.

RESUMEN: El objetivo de este estudio fue revelar el patrón de distribución general de los nervios cutáneos de la mano y proporcionar una base morfológica para la selección y adaptación de la piel de la mano, para la reconstrucción sensorial durante el trasplante de colgajo. Para el estudio se utilizaron 12 manos de cadáveres adultos. Las regiones palmar y dorsal se dividieron en regiones I-VI. La piel de la mano que contiene grasa subcutánea se eliminó cerca de la superficie del músculo. Para visualizar el patrón de distribución general de los nervios cutáneos y las áreas que inervan se utilizó el método de tinción de Sihler modificado. El nervio mediano, la rama superficial del nervio ulnar y la rama superficial del nervio radial inervaban el 59,27 % (que contenía el 4,65 % de la rama cutánea palmar del nervio mediano), el 36,91 % y el 3,82 % del área de la palma, respectivamente. La rama super-ficial del nervio radial, la rama dorsal del nervio ulnar y el nervio mediano inervaban el 45,16 %, el 47,25 % y el 7,59 % del área dorsal de la mano, respectivamente. Se observó comunicación entre las ramas arborizadas de estos nervios cutáneos. La región III de la palma y la región VI del dorso de la mano tenían una distribución nerviosa relativamente más densa. A excepción de la región V, la densidad de las ramas nerviosas totales en cada región de la palma fue mayor que el dorso de la mano. El número total de ramas nerviosas en la falange distal y el dorso disminuyó desde el pulgar hasta el dedo mínimo. Nuestros resultados proporcionan una guía morfológica al diseñar un colgajo compatible razonable para mejorar la reconstrucción de la función sensorial de la mano.

Phase-Specific Motor Efference during a Rhythmic Motor Pattern.

Neuronal circuits that control motor behaviors orchestrate multiple tasks, including the inhibition of self-generated sensory signals. In the hermaphroditic leech, T and P mechanosensory neurons respond to light touch and pressure on the skin, respectively. We show that the low threshold T cells were also sensitive to topological changes of the animal surface, caused by contraction of the muscles that erect the skin annuli. P cells were unresponsive to this movement. Annuli erection is part of the contraction phase of crawling, a leech locomotive behavior. In isolated ganglia, T cells showed phase-dependent IPSPs during dopamine-induced fictive crawling, whereas P cells were unaffected. The timing and magnitude of the T-IPSPs were highly correlated with the activity of the motoneurons excited during the contraction phase. Together, the results suggest that the central network responsible for crawling sends a reafferent signal onto the T cells, concomitant with the signal to the motoneurons. This reafference is specifically targeted at the sensory neurons that are affected by the movements; and it is behaviorally relevant as excitation of T cells affected the rhythmic motor pattern, probably acting upon the rhythmogenic circuit. Corollary discharge is a highly conserved function of motor systems throughout evolution, and we provide clear evidence of the specificity of its targets and timing and of the benefit of counteracting self-generated sensory input.SIGNIFICANCE STATEMENT Neuronal circuits that control motor behaviors orchestrate multiple tasks, including inhibition of sensory signals originated by the animal movement, a phenomenon known as corollary discharge. Leeches crawl on solid surfaces through a sequence of elongation and contraction movements. During the contraction, the skin topology changes, affecting a subpopulation of mechanosensory receptors, T (touch) neurons, but not P (pressure) sensory neurons. In the isolated nervous system, T neurons were inhibited during the contraction but not during the elongation phase, whereas P cells were unaffected throughout crawling. Excitation of T cells during the contraction phase temporarily disrupted the rhythmic pattern. Thus, corollary discharge was target (T vs P) and phase (contraction vs elongation) specific, and prevented self-generated signals to perturb motor behaviors.

Cutaneous inflammation differentially regulates the expression and function of Angiotensin-II types 1 and 2 receptors in rat primary sensory neurons.

Neuropathic and inflammatory pain results from cellular and molecular changes in dorsal root ganglion (DRG) neurons. The type-2 receptor for Angiotensin-II (AT2R) has been involved in this type of pain. However, the underlying mechanisms are poorly understood, including the role of the type-1 receptor for Angiotensin-II (AT1R). Here, we used a combination of immunohistochemistry and immunocytochemistry, RT-PCR and in vitro and in vivo pharmacological manipulation to examine how cutaneous inflammation affected the expression of AT1R and AT2R in subpopulations of rat DRG neurons and studied their impact on inflammation-induced neuritogenesis. We demonstrated that AT2R-neurons express C- or A-neuron markers, primarily IB4, trkA, and substance-P. AT1R expression was highest in small neurons and co-localized significantly with AT2R. In vitro, an inflammatory soup caused significant elevation of AT2R mRNA, whereas AT1R mRNA levels remained unchanged. In vivo, we found a unique pattern of change in the expression of AT1R and AT2R after cutaneous inflammation. AT2R increased in small neurons at 1 day and in medium size neurons at 4 days. Interestingly, cutaneous inflammation increased AT1R levels only in large neurons at 4 days. We found that in vitro and in vivo AT1R and AT2R acted co-operatively to regulate DRG neurite outgrowth. In vivo, AT2R inhibition impacted more on non-peptidergic C-neurons neuritogenesis, whereas AT1R blockade affected primarily peptidergic nerve terminals. Thus, cutaneous-induced inflammation regulated AT1R and AT2R expression and function in different DRG neuronal subpopulations at different times. These findings must be considered when targeting AT1R and AT2R to treat chronic inflammatory pain. Cover Image for this issue: doi: 10.1111/jnc.14737.

Possible involvement of peripheral TRP channels in the hydrogen sulfide-induced hyperalgesia in diabetic rats.

BACKGROUND: Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (H2S) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which H2S induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in H2S-induced hyperalgesia in diabetic rats. RESULTS: Streptozotocin (STZ) injection produced hyperglycemia in rats. Intraplantar injection of NaHS (an exogenous donor of H2S, 3-100 µg/paw) induced hyperalgesia, in a time-dependent manner, in formalin-treated diabetic rats. NaHS-induced hyperalgesia was partially prevented by local intraplantar injection of capsazepine (0.3-3 µg/paw), HC-030031 (100-316 µg/paw) and SKF-96365 (10-30 µg/paw) blockers, at 21 days post-STZ injection. At the doses used, these blockers did not modify formalin-induced nociception. Moreover, capsazepine (0.3-30 µg/paw), HC-030031 (100-1000 µg/paw) and SKF-96365 (10-100 µg/paw) reduced formalin-induced nociception in diabetic rats. Contralateral injection of the highest doses used did not modify formalin-induced flinching behavior. Hyperglycemia, at 21 days, also increased protein expression of cystathionine-ß-synthase enzyme (CBS) and TRPC6, but not TRPA1 nor TRPV1, channels in dorsal root ganglia (DRG). Repeated injection of NaHS enhanced CBS and TRPC6 expression, but hydroxylamine (HA) prevented the STZ-induced increase of CBS protein. In addition, daily administration of SKF-96365 diminished TRPC6 protein expression, whereas NaHS partially prevented the decrease of SKF-96365-induced TRPC6 expression. Concordantly, daily intraplantar injection of NaHS enhanced, and HA prevented STZ-induced intraepidermal fiber loss, respectively. CBS was expressed in small- and medium-sized cells of DRG and co-localized with TRPV1, TRPA1 and TRPC6 in IB4-positive neurons. CONCLUSIONS: Our data suggest that H2S leads to hyperalgesia in diabetic rats through activation of TRPV1, TRPA1 and TRPC channels and, subsequent intraepidermal fibers loss. CBS enzyme inhibitors or TRP-channel blockers could be useful for treatment of painful diabetic neuropathy.

Palmar cutaneous branch of median nerve: an anatomical study / Rama cutánea palmar del nervio mediano: un estudio anatómico

The purpose of this study was to determine the origin, frequency and anatomical variations of the palmar cutaneous branch of the median nerve (PCBMN) and its clinical implications in surgical procedures such as decompression of the carpal tunnel and volar approach to the wrist. Dissection of 30 forearms from 18 adult male specimens (9 bilateral, 7 right limbs and 5 left limbs) were performed using 2.5X magnification loupe in order to better understand the PCBMN. Origin, number, length, positioning, anatomical relations and variations were recorded and analyzed. The PCBMN was identified in all dissected forearms, being the most distal branch of the median nerve in all forearms. The average origin was 4.8 cm (ranging 3.8 to 6.5 cm) proximal to the wrist flexion crease. Anatomical variations of the PCBMN are not rare and could endanger the nerve during surgical approach for the volar wrist and proximal palm. We did not find the PCBMN positioned ulnar to the fourth metacarpal axis as well as radial to the flexor carpi radialis tendon.

El objetivo de este estudio fue determinar el origen, la frecuencia y las variaciones anatómicas de la rama cutánea palmar del nervio mediano (RCPNM) y sus implicaciones clínicas en procedimientos quirúrgicos como la descompresión del túnel carpiano y el abordaje palmar de la muñeca. Se realizó la disección de 30 antebrazos de 18 especímenes adultos de sexo masculino (9 bilaterales, 7 miembros derechos y 5 miembros izquierdos) utilizando una lupa de aumento de 2,5X para comprender mejor la RCPNM. Origen, número, longitud, posicionamiento, relaciones anatómicas y variaciones fueron registradas y analizadas. El RCPNM fue identificado en todos los antebrazos disecados, siendo la rama más distal del nervio mediano en todos los antebrazos. El origen promedio fue de 4,8 cm (rango de 3,8 a 6,5 cm) proximal al pliegue de flexión de la muñeca. Las variaciones anatómicas de la RCPNM no son raras y podrían poner en peligro el nervio durante el abordaje quirúrgico de la cara volar y palmar proximal de la muñeca. No encontramos el RCPNM posicionado a nivel ulnar del cuarto metacarpiano, así como radial al tendón del músculo flexor radial del carpo.

The venous patterns of the cubital fossa in subjects from Brazil.

Venous punctures are among the most common procedures performed by healthcare professionals. In particular, the cubital fossa is the site where the venous accesses are frequently made due to the number of superficial veins and the numerous anastomoses in this region. The arrangement of these venous connections is of particular interest for clinical application in several areas, thus, the healthcare professional must possess knowledge about these vessels and their anatomical relationships. The present study aims to analyze the venous pattern of the cubital fossa among individuals from Brazil. This study was approved by a Research Ethics Committee. The sample had 100 healthy individuals (50 men and 50 women). The superficial veins of the cubital fossa were analyzed with the aid of a sphygmomanometer. When inflated, the pressure in the forearm increased and the veins became prominent. It was observed that in the selected sample the types with the highest prevalence were the Type I and Type VII, both with 22% in 200 limbs studied. The chi2 test showed a significant statistical difference between the anastomosis pattern and the sex of the studied sample. The anastomotic pattern of the superficial veins of the studies sample is similar to African, European and Asian populations. The study of these variations is necessary to provide scientific basis for the healthcare professional during a venipuncture in order to avoid iatrogenic errors and damages in cutaneous nerves or neighboring arteries.

Asociación de hipomelanosis de Ito y paquioniquia congénita / Association of hypomelanosis of Ito and pachyonychia congenita

La hipomelanosis de Ito constituye un síndrome genético neurocutáneo caracterizado por lesiones hipopigmentadas en piel y manifestaciones extracutáneas que involucran especialmente el sistema nervioso central, de presentación esporádica. La paquioniquia congénita, es un trastorno de origen genético con onicodistrofia como signo característico y herencia autosómica dominante.Objetivo: Contribuir al asesoramiento genético integral de un paciente con asociación de hipomelanosis de Ito y paquioniquia congénita.Presentación del caso: Se presenta un paciente adulto con hipopigmentación de pelo y piel, además de onicodistrofia, presente también, en varios miembros de su familia, por lo cual presenta dos condiciones genéticas asociadas.Conclusión: Resulta de interés médico demostrar la presencia de estas alteraciones genéticas asociadas en un mismo paciente, para su adecuado asesoramiento genético en la comunidad, por no encontrarse en los reportes publicados…(AU)

The importance of cutaneous feedback on neural activation during maximal voluntary contraction.

PURPOSE: The purpose of this study was to investigate the importance of cutaneous feedback on neural activation during maximal voluntary contraction (MVC) of the ankle plantar flexors. METHODS: The effects of cutaneous plantar anaesthesia were assessed in 15 subjects and compared to 15 controls, using a one-day pre/post-repeated measures design. Cutaneous plantar anaesthesia was induced by lidocaine injection at the centre of forefoot, lateral midfoot, and heel. Each subject performed isometric MVCs of the ankle plantar flexors. During each isometric ramp contraction, the following variables were assessed: maximal isometric torque; surface electromyography (EMG) activity of the medial gastrocnemius (MG) and tibialis anterior (TA) muscles; and co-contraction index (CCI) between the MG and TA. RESULTS: For ankle torque, two-way ANOVA showed no significant interaction between the pre/post-measurements × group (p = 0.166). However, MG activity presented significant interactions between the pre/post-measurements × group (p = 0.014). Post hoc comparisons indicated a decrease of MG activity in the experimental group, from 85.9 ± 11.9 to 62.7 ± 30.8% (p = 0.016). Additionally, the post-anaesthesia MG activity of the experimental group differed statistically with pre- and post-MG activity of the control group (p = 0.027 and p = 0.008, respectively). For TA activity and CCI, two-way ANOVA detected no significant interactions between the pre/post-measurements × group (p = 0.605 and p = 0.332, respectively). CONCLUSION: Our results indicate that during MVC, cutaneous feedback modulates neural activity to MG muscle, without changing the extent of MG-TA co-contraction.

Serotonin-gated inward currents are three times more frequent in rat hairy skin sensory afferents than in those innervating the skeletal muscle.

Tight whole-cell patch clamp was performed in 191 DiI (1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate) retrogradely labeled rat sensory afferents from skin shoulders ( n = 93) and biceps femoris muscles ( n = 98). 5-HT-gated inward currents were evoked with 50-µM serotonin (5-HT; 5-hydroxytryptamine), and their frequency and current densities were compared between skin and skeletal muscle sensory afferents. To evaluate if 5-HT-gated inward currents coexist with other ligand-gated currents, the skin and skeletal muscle sensory afferents were also sequentially exposed to external solution at pH 6.8, ATP (50 µM), and capsaicin (1 µM). 5-HT evoked inward currents in 72% (67 of 93) of hairy skin sensory afferents and in only 24% (24 of 98) of skeletal muscle sensory afferents, and this difference was statistically significant ( p < 0.0000, chi-square test). The current densities obtained in hairy skin and skeletal muscle sensory afferents were not significantly different. They were -45.8 ± 7.7 and -32.4 ± 10.5 pA/pF, respectively (mean ± SEM, p < 0.30734). These results indicate that 5-HT-gated inward currents are three times more frequently evoked in small- to medium-sized sensory afferents (25-40 µm) innervating the hairy skin than on those innervating the skeletal muscle. When cells were gathered in two clusters, the difference was four times larger in the small-sized cluster (25-32 µm) and two times larger in the medium-sized cluster (33-40 µm). The results can be explained if the superficial somatic (cutaneous) nociceptive system is more exposed than the deep somatic nociceptive system (musculoskeletal) to physical and chemical stimuli inducing 5-HT-mediated inflammatory pain.

Cutaneous Sensibility Changes in Bell's Palsy Patients.

Objective Bell's palsy is a cranial nerve VII dysfunction that renders the patient unable to control facial muscles from the affected side. Nevertheless, some patients have reported cutaneous changes in the paretic area. Therefore, cutaneous sensibility changes might be possible additional symptoms within the clinical presentation of this disorder. Accordingly, the aim of this research was to investigate the relationship between cutaneous sensibility and facial paralysis severity in these patients. Study Design Prospective longitudinal cohort study. Settings Tertiary care medical center. Subjects and Methods Twelve acute-onset Bell's palsy patients were enrolled from March to September 2009. In addition, 12 sex- and age-matched healthy volunteers were tested. Cutaneous sensibility was evaluated with pressure threshold and 2-point discrimination at 6 areas of the face. Facial paralysis severity was evaluated with the House-Brackmann scale. Results Statistically significant correlations based on the Spearman's test were found between facial paralysis severity and cutaneous sensitivity on forehead, eyelid, cheek, nose, and lip ( P < .05). Additionally, significant differences based on the Student's t test were observed between both sides of the face in 2-point discrimination on eyelid, cheek, and lip ( P < .05) in Bell's palsy patients but not in healthy subjects. Conclusion Such results suggest a possible relationship between the loss of motor control of the face and changes in facial sensory information processing. Such findings are worth further research about the neurophysiologic changes associated with the cutaneous sensibility disturbances of these patients.

Neuroimmune interactions: dendritic cell modulation by the sympathetic nervous system.

Dendritic cells are of paramount importance bridging innate and adaptive immune responses. Depending on the context, after sensing environmental antigens, commensal microorganisms, pathogenic agents, or antigens from the diet, dendritic cells may drive either different effector adaptive immune responses or tolerance, avoiding tissue damage. Although the plasticity of the immune response and the capacity to regulate itself are considered essential to orchestrate appropriate physiological responses, it is known that the nervous system plays a relevant role controlling immune cell function. Dendritic cells present in the skin, the intestine, and lymphoid organs, besides expressing adrenergic receptors, can be reached by neurotransmitters released by sympathetic fibers innervating these tissues. These review focus on how neurotransmitters from the sympathetic nervous system can modulate dendritic cell function and how this may impact the immune response and immune-mediated disorders.

Pruritus in cholestasis / Prurido na colestase

Pruritus represents one of the main clinical complaints in medical practice, and leads to significant impairment of life quality and some discomfort. Although the knowledge of its main primary and secondary etiologies is well-established in Internal Medicine, especially in Hepatology, its pathophysiological basis and specific therapeutic-directed approaches are still very complex and need a proper systematization for comprehension. This review aims to present the main current themes regarding the main clinical, pathophysiological, therapeutical and management aspects of cholestasis-associated pruritus. METHODS: The authors performed a wide review of practical clinical guidelines, review articles and original articles from manuscripts published and indexed in PubMed. CONCLUSIONS: Pruritus in cholestasis represents a complex symptom in clinical practice and can be secondary to different pathophysiological mechanisms; its early recognition allows a proper therapeutic approach in most cases.

O prurido representa uma das principais queixas clínicas na prática médica e origina importante comprometimento da qualidade de vida, além de desconforto. Apesar de suas principais etiologias primárias e secundárias serem de conhecimento bem estabelecido na Clínica Médica, em especial na Hepatologia, suas bases fisiopatológicas e os princípios da terapêutica específica direcionada são bastante complexos e necessitam uma sistematização adequada para sua compreensão apropriada. Esta revisão objetiva abordar os principais temas atuais referentes às bases clínicas, fisiopatológicas, terapêuticas e de manejo do prurido relacionados à colestase. Os autores realizaram ampla revisão em diretrizes clínicas práticas, artigos de revisão e publicações originais de artigos publicados e indexados na base PubMed. O prurido na colestase representa um sintoma complexo na prática clínica e pode decorrer de diferentes mecanismos fisiopatológicos secundários. Seu reconhecimento precoce possibilita a abordagem terapêutica apropriada na maioria dos casos.