Morphological variations and demographic responses of the Mediterranean pond turtle Mauremys leprosa to heterogeneous aquatic habitats.

Human activities affect terrestrial and aquatic habitats leading to changes at both individual and population levels in wild animal species. In this study, we investigated the phenotype and demographics of the Mediterranean pond turtle Mauremys leprosa (Schweigger, 1812) in contrasted environments of Southern France: two peri-urban rivers receiving effluents from wastewater treatment plants (WWTP), and another one without sewage treatment plant. Our findings revealed the presence of pesticides and pharmaceuticals in the three rivers of investigation, the highest diversities and concentrations of pollutants being found in the river subsections impacted by WWTP effluents. Principal component analysis and hierarchical clustering identified three levels of habitat quality, with different pollutant concentrations, thermal conditions, nutrient, and organic matter levels. The highest turtle densities, growth rates, and body sizes were estimated in the most disturbed habitats, suggesting potential adult benefits derived from harsh environmental conditions induced by pollution and eutrophication. Conversely, juveniles were the most abundant in the least polluted habitats, suggesting adverse effects of pollution on juvenile survival or adult reproduction. This study suggests that turtles living in polluted habitats may benefit from enhanced growth and body size, at the expense of reproductive success.

Brevipalpus yothersi Baker (Tenuipalpidae) development in sweet orange plants is influenced by previous mite infestation and the presence of shelters.

Citrus leprosis is the most important viral disease affecting citrus. The disease is caused predominantly by CiLV-C and is transmitted by Brevipalpus yothersi Baker mites. This study brings some insight into the colonization of B. yothersi in citrus [(Citrus × sinensis (L.) Osbeck (Rutaceae)] previously infested by viruliferous or non-viruliferous B. yothersi. It also assesses the putative role of shelters on the behavior of B. yothersi. Expression of PR1 and PR4 genes, markers of plant defense mechanisms, were evaluated by RT-qPCR to correlate the role of the plant hormonal changes during the tri-trophic virus-mite-plant interplay. A previous infestation with either non-viruliferous and viruliferous mites positively influenced oviposition and the number of adult individuals in the resulting populations. Mite populations were higher on branches that had received a previous mite infestation than branches that did not. There was an increase in the expression of PR4, a marker gene in the jasmonic acid (JA) pathway, in the treatment with non-viruliferous mites, indicating a response from the plant to their feeding. Conversely, an induced expression of PR1, a marker gene in the salicylic acid (SA) pathway, was observed mainly in the treatment with viruliferous mites, which suggests the activation of a plant response against the pathogen. The earlier mite infestation, as well as the presence of leprosis lesions and a gypsum mixture as artificial shelters, all fostered the growth of the B. yothersi populations after the second infestation, regardless of the presence or absence of CiLV-C. Furthermore, it is suggested that B. yothersi feeding actually induces the JA pathway in plants. At the same time, the CiLV-C represses the JA pathway and induces the SA pathway, which benefits the mite vector.

Gut Mycobiota Dysbiosis Is Associated with Melanoma and Response to Anti-PD-1 Therapy.

Recent research indicates that gut microbiota may be vital in the advancement of melanoma. In this study, we found that melanoma patients exhibited a distinct gut mycobiota structure compared with healthy participants. Candida albicans, Candida dubliniensis, and Neurospora crassa were more abundant in samples from patients with melanoma, whereas Saccharomyces cerevisiae and Debaryomyces hansenii were less abundant. During anti-PD-1 treatment, the relative amount of Malassezia restricta and C. albicans increased. A higher level of Saccharomyces paradoxus was associated with a positive response to anti-PD-1 treatment, whereas a higher level of Tetrapisispora blattae was associated with a lack of clinical benefits. High levels of M. restricta and C. albicans, elevated serum lactate dehydrogenase, and being overweight were linked to increased risk of melanoma progression and poorer response to anti-PD-1 treatment. Thus, this study has revealed melanoma-associated mycobiome dysbiosis, characterized by altered fungal composition and fungi species associated with a higher risk of melanoma progression, identifying a role for the gut mycobiome in melanoma progression.

CYBB-Mediated Ferroptosis Associated with Immunosuppression in Mycobacterium leprae-Infected Monocyte-Derived Macrophages.

Mycobacterium leprae-infected macrophages preferentially exhibit the regulatory M2 phenotype in vitro, which helps the immune escape unabated growth of M leprae in host cells. The mechanism that triggers macrophage polarization is still unknown. In this study, we performed single-cell RNA sequencing to determine the initial responses of human monocyte-derived macrophages against M leprae infection of 4 healthy individuals and found an increase in a major alternative-activated macrophage type that overexpressed NEAT1, CCL2, and CD163. Importantly, further functional analysis showed that ferroptosis was positively correlated with M2 polarization of macrophages, and in vitro experiments have shown that inhibition of ferroptosis promotes the survival of M leprae within macrophages. In addition, further joint analysis of our results with mutisequencing data from patients with leprosy and in vitro validation identified that CYBB was the pivotal molecule for ferroptosis that could promote the M2 polarization of M leprae-infected macrophages, resulting in the immune escape and unabated growth of pathogenic bacteria. Overall, our results suggest that M leprae facilitated its survival by inducing CYBB-mediated macrophage ferroptosis leading to its alternative activation and might reveal the potential for a new therapeutic strategy of leprosy.

Mycobacterium leprae is able to infect adipocytes, inducing lipolysis and modulating the immune response.

Leprosy is a chronic infectious disease caused by the intracellular bacillus Mycobacterium leprae (M. leprae), which is known to infect skin macrophages and Schwann cells. Although adipose tissue is a recognized site of Mycobacterium tuberculosis infection, its role in the histopathology of leprosy was, until now, unknown. We analyzed the M. leprae capacity to infect and persist inside adipocytes, characterizing the induction of a lipolytic phenotype in adipocytes, as well as the effect of these infected cells on macrophage recruitment. We evaluated 3T3-L1-derived adipocytes, inguinal adipose tissue of SWR/J mice, and subcutaneous adipose tissue biopsies of leprosy patients. M. leprae was able to infect 3T3-L1-derived adipocytes in vitro, presenting a strong lipolytic profile after infection, followed by significant cholesterol efflux. This lipolytic phenotype was replicated in vivo by M. leprae injection into mice inguinal adipose tissue. Furthermore, M. leprae was detected inside crown-like structures in the subcutaneous adipose tissue of multibacillary patients. These data indicate that subcutaneous adipose tissue could be an important site of infection, and probably persistence, for M. leprae, being involved in the modulation of the innate immune control in leprosy via the release of cholesterol, MCP-1, and adiponectin.

F-waves persistence in peripheral sensory syndromes.

BACKGROUND: The distinction between sensory neuronopathies (SN), which is by definition purely sensory, and sensory polyneuropathies (SP) and sensory multineuropathies (SM) is important for etiologic investigation and prognosis estimation. However, this task is often challenging in clinical practice. We hypothesize that F-wave assessment might be helpful, since it is able to detect subtle signs of motor involvement, which are found in SP and SM, but not in SN. OBJECTIVE: The aim of the present study was to determine whether F-waves are useful to distinguish SN from SP and SM. METHODS: We selected 21 patients with SP (12 diabetes mellitus, 4 transthyretin familial amyloid polyneuropathy, 4 others), 22 with SM (22 leprosy), and 26 with SN (13 immune-mediated, 10 idiopathic, 3 others) according to clinical-electrophysiological-etiological criteria. For every subject, we collected data on height and performed 20 supramaximal distal stimuli in median, ulnar, peroneal, and tibial nerves, bilaterally, to record F-waves. Latencies (minimum and mean) and persistences were compared across groups using the Kruskal-Wallis and Bonferroni tests. P-values < 0.05 were considered significant. RESULTS: All groups were age, gender, and height-matched. Overall, there were no significant between-group differences regarding F-wave latencies. In contrast, F-wave persistence was able to stratify the groups. Peroneal F-wave persistence was higher, bilaterally, in the SN group compared to SM and SP (p < 0.05). In addition, F-waves persistence of the ulnar and tibial nerves was also helpful to separate SN from SP (p < 0.05). CONCLUSION: F-wave persistence of the peroneal nerves might be an additional and useful diagnostic tool to differentiate peripheral sensory syndromes.

ANTECEDENTES: A distinção entre neuronopatias sensitivas (SN) e polineuropatias sensitivas (SP) e multineuropatias sensitivas (SM) é importante para a investigação etiológica e para o prognóstico. Contudo, esta tarefa é desafiadora na prática clínica. Hipotetizou-se que a avaliação das ondas-F pode ser útil, por ser capaz de detectar envolvimento motor nas SP e SM, mas não nas SN. OBJETIVO: Determinar se as ondas-F podem ajudar a distinguir entre SN, SP e SM. MéTODOS: Selecionou-se 21 pacientes com SP (12 diabetes mellitus, 4 ATTR-FAP e 4 com outras neuropatias), 22 com SM (22 hanseníases) e 26 com SN (13 imunomediadas, 10 idiopáticas e 3 com outras neuronopatias), de acordo com critérios clínicos, etiológicos e eletrofisiológicos. Para cada indivíduo, foi aferida a altura e foram aplicados 20 estímulos distais supramáximos nos nervos mediano, ulnar, fibular e tibial, bilateralmente, para registrar as ondas-F. Uma comparação foi feita, por grupo, das latências (mínimas e médias) e persistências pelos testes Kruskal-Wallis e Bonferroni. Valores de p < 0.05 foram considerados estatisticamente significativos. RESULTADOS: Todos os grupos foram pareados por idade, sexo e altura. Não houve diferença estatística significativa entre os grupos quanto às latências das ondas-F. A persistência da onda-F foi capaz de estratificar os grupos, sendo as dos nervos fibulares bilateralmente maiores no grupo SN que nos grupos SM e SP (p < 0.05). Adicionalmente, a persistência das ondas-F dos nervos ulnares e tibiais também foi útil para distinguir SN de SP (p < 0.05). CONCLUSãO: A persistência das ondas-F dos nervos fibulares pode ser uma ferramenta adicional e útil para diferenciar síndromes sensitivas periféricas.

Exploration of Neurofilament Light Chain and Nerve Ultrasound in Leprotic Neuropathy.

OBJECTIVES: To explore neurofilament light chain (NfL) levels in leprotic neuropathy compared to controls, and to determine if the changes correlate with ultrasonographic nerve findings. METHODS: Individuals with leprosy with signs or symptoms suggestive of peripheral nerve involvement were recruited. They were evaluated by clinical examination, functional scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was conducted in bilateral median, ulnar, tibial, fibular, sural, and vagus nerves as well as cervical roots 5 and 6. Results were compared to age, sex, and body mass index matched healthy controls. RESULTS: A total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with leprosy with a mean and standard deviation of 7.50 + 2.83 compared with 3.42 + 1.18 in controls (P < .001). Ultrasound showed focal enlargement of the nerves, particularly at entrapment sites. Additionally, there were noticeable changes in neural Doppler signal, echogenicity, and epineural thickness among the measured nerve sites. NfL levels in those with leprosy correlated closely with nerve cross-sectional area at all sites (P < .05). Functional and clinical assessment scores correlated with NfL and sonographic cross-sectional area as well (P ≤ .05). CONCLUSIONS: NfL is elevated in leprotic neuropathy. Ultrasound showed specific morphological changes in individuals with leprosy, and nerve enlargement correlated with NfL levels. Thus, both modalities may be useful for the diagnosis, prognosis, and disease monitoring in those with leprotic neuropathy, and further investigations are warranted.

Single-cell sequencing analysis reveals development and differentiation trajectory of Schwann cells manipulated by M. leprae.

BACKGROUND: M. leprae preferentially infects Schwann cells (SCs) in the peripheral nerves leading to nerve damage and irreversible disability. Knowledge of how M. leprae infects and interacts with host SCs is essential for understanding mechanisms of nerve damage and revealing potential new therapeutic strategies. METHODOLOGY/PRINCIPAL FINDINGS: We performed a time-course single-cell sequencing analysis of SCs infected with M. leprae at different time points, further analyzed the heterogeneity of SCs, subpopulations associated with M. leprae infection, developmental trajectory of SCs and validated by Western blot or flow cytometry. Different subpopulations of SCs exhibiting distinct genetic features and functional enrichments were present. We observed two subpopulations associated with M. leprae infection, a stem cell-like cell subpopulation increased significantly at 24 h but declined by 72 h after M. leprae infection, and an adipocyte-like cell subpopulation, emerged at 72 h post-infection. The results were validated and confirmed that a stem cell-like cell subpopulation was in the early stage of differentiation and could differentiate into an adipocyte-like cell subpopulation. CONCLUSIONS/SIGNIFICANCE: Our results present a systematic time-course analysis of SC heterogeneity after infection by M. leprae at single-cell resolution, provide valuable information to understand the critical biological processes underlying reprogramming and lipid metabolism during M. leprae infection of SCs, and increase understanding of the disease-causing mechanisms at play in leprosy patients as well as revealing potential new therapeutic strategies.

Role of Nerve Conduction Studies in Hansen's Disease.

Background and Objective: To report the role of nerve conduction study (NCS) in diagnosis, monitoring, and prognosis of Hansen's disease (HD). Materials and Methods: In a hospital-based prospecive observational study, the patients with HD as per World Health Organization (WHO) criteria were included; muscle wasting power, reflexes, and sensations were recorded. Motor NCS of median, ulnar, and peroneal nerves and sensory NCS of ulnar, median, and sural nerves were recorded. Disability was graded using WHO grading scale. The outcome was assessed after 6 months using modified Rankin scale. Results: In the present study, 38 patients with a median age of 40 (15-80) years and five females were included. The diagnosis was tuberculoid in seven, borderline tuberculoid in 23, borderline lepromatous in two, and borderline in six patients. The disability was grade 1 and 2 in 19 patients each. Out of 480 nerves studied, NCS was normal in 139 sensory (57.4%) and 160 (67.2%) motor nerves. NCSs were axonal in seven sensory and eight motor nerves, demyelinating in three nerves, and mixed in one in seven patients who had lepra reaction. NCS findings did not correlate with disability (p = 1.0) or outcome (0.304) and provided additional information in 11 nerves (seven patients). Peripheral nerves were enlarged in 79. NCSs were normal in 32 (29.90%) in thickened nerves. Conclusion: In HD, NCS abnormalities correlated with respective sensory or motor abnormality but related with neither disability nor the outcome.

Gait analysis of leprosy patients with foot drop using principal component analysis.

BACKGROUND: Peripheral nerve injury caused by leprosy can lead to foot drop, resulting in an altered gait pattern that has not been previously described using 3D gait analysis. METHODS: Gait kinematics and dynamics were analyzed in 12 patients with unilateral foot drop caused by leprosy and in 15 healthy controls. Biomechanical data from patients' affected and unaffected limbs were compared with controls using inferential statistics and a standard distance, based on principal components analysis (PCA). FINDINGS: Patients walked slower than controls (0.8 ± 0.2 vs. 1.1 ± 0.2 m/s, p = 0.003), with a reduced stance and increased swing percentage. The affected limb increased (p < 0.05) plantar flexion at the initial contact (-16.8o ± 8.3), terminal stance (-29.1o ± 11.5), and swing (-12.4o ± 6.2) in the affected limb compared to unaffected (-6.6o ± 10.3; -14.6o ± 11.6; 2.4o ± 7.6) and controls (-5.4o ± 2.5; -18.8o ± 5.8; -1.4o ± 3.9). Increased pelvic tilt and knee adduction/abduction range, with lower hip adduction, were observed. The second peak of ground reaction force (98.6 ± 5.2 %BW), ankle torque (0.99 ± 0.33 Nm/kg), and net ankle work in stance (-0.03 ± 5.4 J/Kg) decreased in the affected limb compared to controls (104.1 ± 5.5 %BW; 1.24 ± 0.4 Nm/kg; -4.58 ± 5.19 J/kg; p < 0.05). There were decreasing multivariate standard distances in the affected limb compared with the unaffected and controls. PCA loading factors highlighted the major differences between groups. INTERPRETATION: Leprosy patients with foot drop presented altered gait patterns in affected and unaffected limbs. There were remarkable differences in ankle kinematics and dynamics. Rehabilitation devices, such as ankle foot orthosis or tendon transfer surgeries to increase ankle dorsiflexion, could benefit these patients and reduce deviations from normal gait.

Response to Hansen Wheat et al.: Additional analysis further supports the early emergence of cooperative communication in dogs compared to wolves raised with more human exposure.

Here, we address Hansen Wheat et al.'s commentary in this journal in response to Salomons et al. Current Biology, 31(14), 3137-3144.E11, (2021). We conduct additional analyses in response to Hansen Wheat et al.'s two main questions. First, we examine the claim that it was the move to a human home environment which enabled the dog puppies to outperform the wolf puppies in gesture comprehension tasks. We show that the youngest dog puppies who had not yet been individually placed in raisers' homes were still highly skilled, and outperformed similar-aged wolf puppies who had higher levels of human interaction. Second, we address the claim that willingness to approach a stranger can explain the difference between dog and wolf pups' ability to succeed in gesture comprehension tasks. We explain the various controls in the original study that render this explanation insufficient, and demonstrate via model comparison that the covariance of species and temperament also make this parsing impossible. Overall, our additional analyses and considerations support the domestication hypothesis as laid out by Salomons et al. Current Biology, 31(14), 3137-3144.E11, (2021).

A-waves are associated with neuropathic pain in leprosy.

INTRODUCTION/AIMS: The A-wave is a late response related either to demyelination or early axonal regeneration. It may be helpful in the evaluation of some peripheral neuropathies. In leprosy, previous studies suggested that A-waves could be a neurophysiological marker of pain in patients during reactions. Herein we have attempted to further assess the profile and clinical correlates of A-waves by exploring a large leprosy cohort. METHODS: Between 2015 and 2018, 63 patients with leprosy (47 men and 16 women) had A-waves in nerve conduction studies and were included in this study. We included patients regardless of whether they were experiencing leprosy reactions or not. We then compared clinical features in nerves with and without A-waves. RESULTS: The mean age of study participants was 46.5 ± 12.3 years and most had borderline leprosy. From this cohort, we assessed separately 83 motor nerves that demonstrated A-waves (group A+ ) and 29 motor nerves that did not demonstrate A-waves (group A- ). Neuropathic pain (NP) was found in 66 of 83 nerves in group A+ , but only 5 of 29 in group A- (79.5 vs 17.2%, P < .001). In contrast, no significant between-group difference emerged regarding presence of reactions, sensory function (based on Semmes-Weinstein evaluations), or muscle strength. A-waves were found in nerves with neuropathic pain experiencing (39 of 66 = 59%) or not experiencing (27 of 66 = 41%) leprosy reactions. DISCUSSION: These results show that A-waves are associated with neuropathic pain in leprosy patients, regardless of the nerves affected and the immune status (in reaction or not).

Development of Anxiolytic and Depression-like Behavior in Mice Infected with Mycobacterium lepraemurium.

Murine leprosy is a systemic infectious disease of mice caused by Mycobacterium lepraemurium (MLM) in which the central nervous system (CNS) is not infected; nevertheless, diseased animals show measurable cognitive alterations. For this reason, in this study, we explored the neurobehavioral changes in mice chronically infected with MLM. BALB/c mice were infected with MLM, and 120 days later, the alterations in mice were evaluated based on immunologic, histologic, endocrine, neurochemical, and behavioral traits. We found increases in the levels of IL-4 and IL-10 associated with high bacillary loads. We also found increase in the serum levels of corticosterone, epinephrine, and norepinephrine in the adrenal gland, suggesting neuroendocrine deregulation. Mice exhibited depression-like behavior in the tail suspension and forced swimming tests and anxiolytic behavior in the open field and elevated plus maze tests. The neurobehavioral alterations of mice were correlated with the histologic damage in the prefrontal cortex, ventral hippocampus, and amygdala, as well as with a blood-brain barrier disruption in the hippocampus. These results reveal an interrelated response of the neuroimmune--endocrinological axis in unresolved chronic infections that result in neurocognitive deterioration.

Follow-up assessment of patients with Pure Neural Leprosy in a reference center in Rio de Janeiro-Brazil.

INTRODUCTION: Pure Neural Leprosy (PNL) is a rare clinical form of leprosy in which patients do not present with the classical skin lesions but have a high burden of the disability associated with the disease. Clinical characteristics and follow up of patients in PNL are still poorly described in the literature. OBJECTIVE: This paper aims to describe the clinical, electrophysiological and histopathological characteristics of PNL patients, as well as their evolution after multidrug therapy (MDT). METHODS: Fifty-two PNL patients were selected. Clinical, nerve conduction studies (NCS), histopathological and anti-PGL-1serology were evaluated. Patients were also assessed monthly during the MDT. At the end of the MDT, all of the patients had a new neurological examination and 44 were submitted to another NCS. RESULTS: Paresthesia was the complaint most frequently reported by patients, and in the neurological examination the most common pattern observed was impairment in sensory and motor examination and a mononeuropathy multiplex. Painful nerve enlargement, a classical symptom of leprosy neuropathy, was observed in a minority of patients and in the motor NCS axonal injuries, alone or in combination with demyelinating features, were the most commonly observed. 88% of the patients did not present any leprosy reaction during MDT. There was no statistically significant difference between the neurological examinations, nor the NCS pattern, performed before and after the MDT. DISCUSSION: The classical hallmarks of leprosy neuropathy are not always present in PNL making the diagnosis even more challenging. Nerve biopsy is an important tool for PNL diagnosis as it may guide therapeutic decisions. This paper highlights unique characteristics of PNL in the spectrum of leprosy in an attempt to facilitate the diagnosis and management of these patients.

Recent developments in the biology and biotechnological applications of halotolerant yeasts.

Natural hypersaline environments are inhabited by an abundance of prokaryotic and eukaryotic microorganisms capable of thriving under extreme saline conditions. Yeasts represent a substantial fraction of halotolerant eukaryotic microbiomes and are frequently isolated as food contaminants and from solar salterns. During the last years, a handful of new species has been discovered in moderate saline environments, including estuarine and deep-sea waters. Although Saccharomyces cerevisiae is considered the primary osmoadaptation model system for studies of hyperosmotic stress conditions, our increasing understanding of the physiology and molecular biology of halotolerant yeasts provides new insights into their distinct metabolic traits and provides novel and innovative opportunities for genome mining of biotechnologically relevant genes. Yeast species such as Debaryomyces hansenii, Zygosaccharomyces rouxii, Hortaea werneckii and Wallemia ichthyophaga show unique properties, which make them attractive for biotechnological applications. Select halotolerant yeasts are used in food processing and contribute to aromas and taste, while certain gene clusters are used in second generation biofuel production. Finally, both pharmaceutical and chemical industries benefit from applications of halotolerant yeasts as biocatalysts. This comprehensive review summarizes the most recent findings related to the biology of industrially-important halotolerant yeasts and provides a detailed and up-to-date description of modern halotolerant yeast-based biotechnological applications.

Influence of Second Generation Oral Contraceptive Use on Adaptations to Resistance Training in Young Untrained Women.

ABSTRACT: Dalgaard, LB, Jørgensen, EB, Oxfeldt, M, Dalgaard, EB, Johansen, FT, Karlsson, M, Ringgaard, S, and Hansen, M. Influence of second generation oral contraceptive use on adaptations to resistance training in young untrained women. J Strength Cond Res 36(7): 1801-1809, 2022-The study purpose was to determine effects of using second generation oral contraceptives (OC) on muscle adaptations to resistance training in young untrained women. Twenty users and 18 nonusers of OC completed a 10-week supervised progressive resistance training program. Before and after the intervention, muscle cross-sectional area (mCSA) of the quadriceps was measured using magnetic resonance imaging and muscle fiber CSA (fCSA) was determined by immunohistochemistry. In addition, body composition (DXA, fat mass/fat-free mass), maximal isometric muscle strength (dynamometry), 5 repetition maximum (5RM) leg press strength, counter movement jump (CMJ) height, and average power using a modified Wingate test were determined. Serum hormone analysis ensured OC compliance and 4-day food records documented dietary intake. After the training period, quadriceps mCSA (OC: 11.0 ± 6.0% vs. non-OC: 9.2 ± 5.0%, p = 0.001), type II fCSA (OC: 19.9 ± 7.9% vs. non-OC: 16.6 ± 7.2%, p = 0.05), muscle strength (knee extension, knee flexion and 5RM, p < 0.001), and functional power (CMJ, AP, p < 0.001) were significantly increased with no significant difference between the groups. However, a tendency toward a greater increase in fat-free mass (FFM) in the OC group was observed (OC: 3.7 ± 3.8% vs. non-OC: 2.7 ± 3.5%, p = 0.08). Collectively, use of second generation OCs in young untrained women did not significantly improve adaptations to 10 weeks of resistance training compared with nonusers. The trend toward greater gains in FFM in the OC group warrant future studies.

Immunology of leprosy.

Leprosy is a disease caused by Mycobacterium leprae (ML) with diverse clinical manifestations, which are strongly correlated with the host's immune response. Skin lesions may be accompanied by peripheral neural damage, leading to sensory and motor losses, as well as deformities of the hands and feet. Both innate and acquired immune responses are involved, but the disease has been classically described along a Th1/Th2 spectrum, where the Th1 pole corresponds to the most limited presentations and the Th2 to the most disseminated ones. We discuss this dichotomy in the light of current knowledge of cytokines, Th subpopulations and regulatory T cells taking part in each leprosy presentation. Leprosy reactions are associated with an increase in inflammatory activity both in limited and disseminated presentations, leading to a worsening of previous symptoms or the development of new symptoms. Despite the efforts of many research groups around the world, there is still no adequate serological test for diagnosis in endemic areas, hindering the eradication of leprosy in these regions.

LRRK2 is required for CD38-mediated NAADP-Ca2+ signaling and the downstream activation of TFEB (transcription factor EB) in immune cells.

CD38 is a cell surface receptor capable of generating calcium-mobilizing second messengers. It has been implicated in host defense and cancer biology, but signaling mechanisms downstream of CD38 remain unclear. Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common genetic cause of Parkinson disease; it is also a risk factor for Crohn disease, leprosy, and certain types of cancers. The pathogenesis of these diseases involves inflammation and macroautophagy/autophagy, processes both CD38 and LRRK2 are implicated in. Here, we mechanistically and functionally link CD38 and LRRK2 as upstream activators of TFEB (transcription factor EB), a host defense transcription factor and the master transcriptional regulator of the autophagy/lysosome machinery. In B-lymphocytes and macrophages, we show that CD38 and LRRK2 exist in a complex on the plasma membrane. Ligation of CD38 with the monoclonal antibody clone 90 results in internalization of the CD38-LRRK2 complex and its targeting to the endolysosomal system. This generates an NAADP-dependent calcium signal, which requires LRRK2 kinase activity, and results in the downstream activation of TFEB. lrrk2 KO macrophages accordingly have TFEB activation defects following CD38 or LPS stimulation and fail to switch to glycolytic metabolism after LPS treatment. In overexpression models, the pathogenic LRRK2G2019S mutant promotes hyperactivation of TFEB even in the absence of CD38, both by stabilizing TFEB and promoting its nuclear translocation via aberrant calcium signaling. In sum, we have identified a physiological CD38-LRRK2-TFEB signaling axis in immune cells. The common pathogenic mutant, LRRK2G2019S, appears to hijack this pathway.Abbreviations:ADPR: ADP-ribose; AMPK: AMP-activated protein kinase; BMDM: bone marrow-derived macrophage; cADPR: cyclic-ADP-ribose; COR: C-terminal of ROC; CTSD: cathepsin D; ECAR: extracellular acidification rate; EDTA: ethylenediaminetetraacetic acid; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GPN: Gly-Phe ß-naphthylamide; GSK3B/GSK3ß: glycogen synthase kinase 3 beta; GTP: guanosine triphosphate; KD: knockdown; LAMP1: lysosomal-associated membrane protein 1; LRR: leucine rich repeat; LRRK2: leucine rich repeat kinase 2; mAb: monoclonal antibody; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MCOLN1: mucolipin 1; MFI: mean fluorescence intensity; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NAADP: nicotinic acid adenine dinucleotide phosphate; NAD: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; PD: Parkinson disease; PPP3CB: protein phosphatase 3, catalytic subunit, beta isoform; q-RT-PCR: quantitative reverse transcription polymerase chain reaction; ROC: Ras of complex; siRNA: small interfering RNA; SQSTM1/p62: sequestome 1; TFEB: transcription factor EB; TPCN: two pore channel; TRPM2: transient receptor potential cation channel, subfamily M, member 2; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.

Clinical and electrophysiological characteristics of neuropathic pain in leprosy patients: A prospective cross-sectional study.

Introduction Neuropathic pain is a common and disabling late complication of leprosy. We investigated the clinical and electrophysiological characteristics of neuropathic pain in leprosy patients by evaluating nerve conduction, sympathetic skin response (SSR) and A-waves. Methods Twenty one leprosy patients with neuropathic pain validated by the Douleur Neuropathique en 4 (DN4)Questionnaire were selected for study. Pain intensity was measured by the visual analog scale. Demographic and clinical data were collected for all patients. Clinical data included appraisal of the median, ulnar, radial, tibial and common peroneal nerves, assessment of the sympathetic skin response and conventional electrophysiological recordings. Results Among all electroneuromyographic presentations, multifocal mononeuropathy was still the most prevalent. Sensory loss was observed more frequently than motor deficits. As most patients presented advanced clinical forms of leprosy and were under treatment, this high mean was found and the ulnar nerve was most frequently affected. The sympathetic skin response was absent in 16 patients. Higher DN4 Questionnaire scores were observed in women and in those receiving corticosteroid therapy. These inferences are possible to be made, but our study's limitations don't allow us to be certain about it. The statistical significance found only permits us to evidence what we related on the textual part of the study. Limitations The small number of patients studied, the lack of sophisticated diagnostic methods for leprosy, as well as the difficulties in assessing nerve conduction were the main limitations of this study. Conclusion The neurophysiological and clinical findings in leprous neuropathy were modest despite the conspicuous neuropathic pain. Although electrophysiological studies are a vital tool to verify nerve damage, variations in the clinical presentation of leprosy neuropathic pain render the diagnosis challenging. Further studies are needed to describe the neurophysiological evolution of this disease.

A-waves associated are with neuropathic pain in leprosy

Introduction/Aims:The A-wave is a late response related either to demyelination or early axonal regeneration. It may be helpful in the evaluation of some peripheral neuropathies. In leprosy, previous studies suggested that A-waves could be a neurophysiological marker of pain in patients during reactions. Herein we have attempted to further assess the profile and clinical correlates of A-waves by exploring a large leprosy cohort. Methods: Between 2015 and 2018, 63 patients with leprosy (47 men and 16 women) had A-waves in nerve conduction studies and were included in this study. We included patients regardless of whether they were experiencing leprosy reactions ornot. We then compared clinical features in nerves with and without A-waves. Results:The mean age of study participants was 46.5 ± 12.3 years and most had borderline leprosy. From this cohort, we assessed separately 83 motor nerves that demonstrated A-waves (group A+) and 29 motor nerves that did not demonstrate A-waves (group A-). Neuropathic pain (NP) was found in 66 of 83 nerves in group A+,but only 5 of 29 in group A-(79.5 vs 17.2%,P< .001). In contrast, no significant between-group difference emerged regarding presence of reactions, sensory function (based on Semmes-Weinstein evaluations), or muscle strength. A-waves were found in nerves with neuropathic pain experiencing (39 of 66=59%) or not experiencing (27 of 66=41%) leprosy reactions. Discussion: These results show that A-waves are associated with neuropathic pain in leprosy patients, regardless of the nerves affected and the immune status (in reaction or not).