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CNS Neuroscience & Therapeutics Apr 2024Although programmed cell death protein 1 (PD-1) typically serves as a target for immunotherapies, a few recent studies have found that PD-1 is expressed in the nervous...
AIMS
Although programmed cell death protein 1 (PD-1) typically serves as a target for immunotherapies, a few recent studies have found that PD-1 is expressed in the nervous system and that neuronal PD-1 might play a crucial role in regulating neuronal excitability. However, whether brain-localized PD-1 is involved in seizures and epileptogenesis is still unknown and worthy of in-depth exploration.
METHODS
The existence of PD-1 in human neurons was confirmed by immunohistochemistry, and PD-1 expression levels were measured by real-time quantitative PCR (RT-qPCR) and western blotting. Chemoconvulsants, pentylenetetrazol (PTZ) and cyclothiazide (CTZ), were applied for the establishment of in vivo (rodents) and in vitro (primary hippocampal neurons) models of seizure, respectively. SHR-1210 (a PD-1 monoclonal antibody) and sodium stibogluconate (SSG, a validated inhibitor of SH2-containing protein tyrosine phosphatase-1 [SHP-1]) were administrated to investigate the impact of PD-1 pathway blockade on epileptic behaviors of rodents and epileptiform discharges of neurons. A miRNA strategy was applied to determine the impact of PD-1 knockdown on neuronal excitability. The electrical activities and sodium channel function of neurons were determined by whole-cell patch-clamp recordings. The interaction between PD-1 and α-6 subunit of human voltage-gated sodium channel (Nav1.6) was validated by performing co-immunostaining and co-immunoprecipitation (co-IP) experiments.
RESULTS
Our results reveal that PD-1 protein and mRNA levels were upregulated in lesion cores compared with perifocal tissues of surgically resected specimens from patients with intractable epilepsy. Furthermore, we show that anti-PD-1 treatment has anti-seizure effects both in vivo and in vitro. Then, we reveal that PD-1 blockade can alter the electrophysiological properties of sodium channels. Moreover, we reveal that PD-1 acts together with downstream SHP-1 to regulate sodium channel function and hence neuronal excitability. Further investigation suggests that there is a direct interaction between neuronal PD-1 and Nav1.6.
CONCLUSION
Our study reveals that neuronal PD-1 plays an important role in epilepsy and that anti-PD-1 treatment protects against seizures by suppressing sodium channel function, identifying anti-PD-1 treatment as a novel therapeutic strategy for epilepsy.
Topics: Humans; Epilepsy; Hippocampus; Programmed Cell Death 1 Receptor; Seizures; Sodium Channels; Antibodies, Monoclonal, Humanized; NAV1.6 Voltage-Gated Sodium Channel
PubMed: 37904722
DOI: 10.1111/cns.14504 -
Frontiers in Immunology 2023Ascites and pleural effusion are recognized complications of pancreatic cancer. These diseases are accompanied by ascites and pleural effusion, and drug treatment is...
Ascites and pleural effusion are recognized complications of pancreatic cancer. These diseases are accompanied by ascites and pleural effusion, and drug treatment is limited by high costs, long hospital stays, and failure rates. Immunotherapy may offer new option, but in most patients with late stages of cancer, immune cells may lose the ability to recognize tumor cells, how to activate their immune cells is a major problem, sodium glucosidate (SSG) is injected into ascites as a protein tyrosine phosphatase inhibitor to wake up immune cells and prepare for immunotherapy. We used single-cell RNA sequencing (scRNA-seq) to investigate whether and how SSG injected into ascites of pancreatic cancer elicits an immune response. Our study showed that the process of SSG fusion treatment of ascites and pleural effusion, the interaction between TandNK cells, MPs cells, monocytes and neutrophils was induced, and large numbers of genes were expressed, resulting in upregulation of immune response, which also approved that SSG is not only used as a protein tyrosine phosphatase inhibitor, but also it works as a protein tyrosine phosphatase inhibitor. It can also be used to regulate immune cell function, recruiting immune cells to the right place with the help of PD-1 or PD-L1 to fight cancer cells in ascites and pleural effusions in cancer patients.
Topics: Humans; Antimony Sodium Gluconate; Ascites; Pancreatic Neoplasms; Protein Tyrosine Phosphatases; Pleural Effusion; Enzyme Inhibitors; Immunotherapy
PubMed: 38313432
DOI: 10.3389/fimmu.2023.1315468 -
Indian Journal of Dermatology 2023Cutaneous leishmaniasis (CL) is a vector-borne protozoal disease. Antimonial drugs remain the first-line treatment for CL despite the widespread drug resistance and high...
Effect of Intralesional Sodium Stibogluconate Alone versus Combinations with Topical Trichloroacetic Acid 50% or Fractional Carbon Dioxide Laser on Cutaneous Leishmaniasis.
BACKGROUND
Cutaneous leishmaniasis (CL) is a vector-borne protozoal disease. Antimonial drugs remain the first-line treatment for CL despite the widespread drug resistance and high incidence of side effects. The present study aimed to compare the efficacy and safety of traditional intralesional sodium stibogluconate (SSG) alone and its combinations with trichloroacetic acid (TCA) 50% and fractional carbon dioxide (CO) laser for the treatment of CL.
MATERIALS AND METHODS
An interventional study was carried out on 25 CL patients. In each patient, three lesions were assigned to treatment either by SSG alone (GI), SSG plus TCA 50% (GII), or SSG plus fractional CO laser (GIII). The overall clinical improvement and changes in the sizes of lesions and scars were assessed and compared among the three groups.
RESULTS
GIII patients had significantly lower treatment sessions as compared to GI patients (3.6 ± 1.29 versus 4.04 ± 2.11, = 0.042). Moreover, GII and GIII patients had significantly shorter healing times when compared with GI (3.63 ± 1.35 and 3.46 ± 1.25, respectively, versus 4.0 ± 2.15 weeks, = 0.019). Also, it was shown that GIII patients had significantly lower scar scores (1.40 ± 1.52) when compared with GI (3.00 ± 0.0) and GII (2.80 ± 1.10), = 0.017.
CONCLUSIONS
Intralesional SSG with TCA 50% is more effective than SSG alone and is comparable to SSG and fractional CO combination in the treatment of CL with better safety profile and patient satisfaction.
PubMed: 38099118
DOI: 10.4103/ijd.ijd_329_23 -
Tropical Medicine and Infectious Disease Aug 2023Cutaneous leishmaniasis (CL) is common in Ethiopia, but the national guideline does not offer specific treatment recommendations. Consequently, different treatment...
Treatment of Cutaneous Leishmaniasis with Sodium Stibogluconate and Allopurinol in a Routine Setting in Ethiopia: Clinical and Patient-Reported Outcomes and Operational Challenges.
Cutaneous leishmaniasis (CL) is common in Ethiopia, but the national guideline does not offer specific treatment recommendations. Consequently, different treatment regimens are used in the country, without quality evidence. In Boru Meda Hospital, sodium stibogluconate (SSG) is routinely used in combination with allopurinol for systemic CL treatment, although evidence on its effectiveness is limited. An observational cohort study was carried out to document clinical treatment outcomes in patients receiving SSG/allopurinol at the end of each 28-day treatment cycle and after 180 days. Patient-reported outcomes were assessed by asking patients to rate lesion severity, and by the dermatological life quality index. A total of 104 patients were included. After one treatment cycle, only four patients were clinically cured, although patient-reported outcomes significantly improved. The majority (88) of patients were appointed for a second treatment cycle, of whom only 37 (42%) attended. Among the 36 patients who came for final outcome assessment, 50% were cured. Follow-up and treatment were severely affected by conflict; drug stock-outs and insufficient ward capacity for treatment were additional challenges. The treatment outcomes of SSG/allopurinol were relatively poor, and most patients required more than one cycle of treatment. Shortages of drugs and beds indicate the existing gaps in providing CL treatment in Ethiopia.
PubMed: 37624352
DOI: 10.3390/tropicalmed8080414 -
Acta Dermato-venereologica Apr 2024Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's... (Comparative Study)
Comparative Study
Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.
Topics: Humans; Meglumine Antimoniate; Leishmaniasis, Cutaneous; Female; Male; Injections, Intralesional; Antimony Sodium Gluconate; Retrospective Studies; Adult; Antiprotozoal Agents; Middle Aged; Leishmania major; Aged; Young Adult; Adolescent; Treatment Outcome; Child; Time Factors; Israel; Meglumine; Organometallic Compounds
PubMed: 38682801
DOI: 10.2340/actadv.v104.35089 -
PLoS Neglected Tropical Diseases Apr 2024With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is...
BACKGROUND
With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease.
METHODS
Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling.
RESULTS
Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease.
CONCLUSION
This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.
Topics: Leishmaniasis, Visceral; Humans; Antiprotozoal Agents; Adult; Female; Male; Young Adult; Adolescent; Africa, Eastern; Amphotericin B; Recurrence; DNA, Kinetoplast; Parasite Load; Middle Aged; Child; Antimony Sodium Gluconate; Child, Preschool; DNA, Protozoan; Nitroimidazoles; Phosphorylcholine
PubMed: 38640118
DOI: 10.1371/journal.pntd.0012078 -
Infection and Drug Resistance 2023Visceral leishmaniasis (VL) is fatal neglected parasitic illness caused by . The diagnosis remains a challenge due to the non-specific clinical symptoms, especially in...
BACKGROUND
Visceral leishmaniasis (VL) is fatal neglected parasitic illness caused by . The diagnosis remains a challenge due to the non-specific clinical symptoms, especially in areas where infections like malaria and limited access to diagnostic tools coexist. Here, we describe a case of late diagnosis of visceral leishmaniasis using tru-cut biopsy of the spleen and malaria co-infection.
CASE PRESENTATION
Here case report, a 24-year-old patient from an endemic region of Somalia presented with fever, headache, abdominal pain, nausea, vomiting, and weight loss for two months. Initially, the patient received symptomatic treatment and a blood transfusion but showed no improvement. Physical examination revealed fever, pallor, and hepatosplenomegaly. Laboratory tests showed pancytopenia and positive rapid diagnostic test for parasite antigen. Despite three days of anti-malarial treatment, the symptoms persisted, and hepatosplenomegaly worsened. Further investigations, including infectious disease tests, were conducted, ruling out HIV, viral hepatitis, , and antibodies. Peripheral blood smear showed pancytopenia and bone marrow aspiration revealed no evidence of infection or malignancy. A tru-cut biopsy of the spleen was performed, confirming the diagnosis of visceral leishmaniasis. The patient received a combination therapy of sodium stibogluconate and paromomycin, leading to significant improvement. After completing treatment, the patient was discharged with normal spleen biopsy results.
CONCLUSION
Visceral leishmaniasis (VL) is a challenging disease to diagnose, especially in areas where it coexists with other infectious diseases, such as malaria. Co-infection with malaria should also be considered in patients with fever and hepatosplenomegaly. A high index of suspicion is necessary for the timely diagnosis of VL, and a tru-cut biopsy of the spleen can be conducted in cases where other investigations are inconclusive in endemic areas. Early diagnosis and prompt treatment of visceral leishmaniasis are crucial to prevent complications and reduce mortality.
PubMed: 37809037
DOI: 10.2147/IDR.S420832 -
Case Report: Visceral Leishmaniasis Falsely Diagnosed as Viral Hepatitis C Without Febrile Symptoms.Infection and Drug Resistance 2024Visceral leishmaniasis (VL), also known as kala-azar, is caused by an intracellular parasite transmitted to humans by the bite of a sand fly, and with the source of the...
BACKGROUND
Visceral leishmaniasis (VL), also known as kala-azar, is caused by an intracellular parasite transmitted to humans by the bite of a sand fly, and with the source of the infection mainly being dogs. The main features of the disease are irregular fever, weight loss, hepatosplenomegaly and anaemia. Diagnosis relies mainly on bone marrow aspiration tests to find Leishman-Donovan(LD) bodies. And we report the case without febrile symptoms and hepatitis C virus antibody was probably false positive.
CASE PRESENTATION
The case was a 74-year-old male residing in Yangquan City, Shanxi Province, a VL endemic area. He presented with generalised malaise, hepatosplenomegaly and scarring pigmentation on the skin as a result of scratching. Laboratory tests showed pancytopenia, positive hepatitis C virus antibody (HCV-Ab), positive direct anti-human globulin test (DAT), positive anti-cardiolipin antibody IgG, IgM (+), and increased immunoglobulin IgG. Symptomatic treatments such as hepatoprotection and blood transfusion were given, but the patient's symptoms still persisted and his spleen and liver further enlarged. Further repeat tests were performed and found to be negative for hepatitis C virus antibodies and antigens. The patient was eventually found to be infected with by rk39 rapid diagnostic test and metagenomic next-generation sequencing(mNGS). And the patient quickly relieved after one course of treatment with sodium stibogluconate.
CONCLUSION
Patients with VL may cause abnormalities in the immune system, leading to false positives for various antibodies without clear febrile symptoms, resulting in misdiagnosis or delayed diagnosis. It is important to consider VL in cases where there is a significant hepatosplenomegaly with a relevant epidemiological history. If the diagnosis cannot be confirmed through bone marrow aspiration and the patient is not suitable for splenic aspiration, the rk39 test can be used for initial exclusion and further verified through mNGS.
PubMed: 38800583
DOI: 10.2147/IDR.S456984 -
Tropical Medicine and Infectious Disease Sep 2023Cutaneous leishmaniasis incidence has been rising in the past couple of decades. Standard therapy often includes antileishmanial drugs; however, due to their low safety...
Cutaneous leishmaniasis incidence has been rising in the past couple of decades. Standard therapy often includes antileishmanial drugs; however, due to their low safety and toxicity threshold, alternative treatments are being investigated. The association between COVID-19 and cutaneous leishmaniasis remains unclear and exploring this connection may offer crucial insights into the pathophysiology of and treatment strategies for infected patients. In this article, we describe a case of a male patient with a history of cardiac and other comorbidities who presented with cutaneous leishmaniasis in the form of impetigo-like skin lesions after being infected with COVID-19. Due to the patient's poor cardiac profile, sodium stibogluconate was not used and an alternative therapeutic approach was employed. The patient was treated with oral terbinafine, cryotherapy on specific lesions, and a course of cephalexin. Following the course of treatment and subsequent follow-up, the patient exhibited complete resolution and healing of the lesions with scarring, and no active lesions or recurrence were observed. This case highlights the potential for alternative treatment strategies for cutaneous leishmaniasis in patients with comorbidities and emphasizes the importance of further research to better understand the link between COVID-19 and cutaneous leishmaniasis.
PubMed: 37755904
DOI: 10.3390/tropicalmed8090443 -
Sensors (Basel, Switzerland) Apr 2024Aerobic capacity plays a crucial role in football performance, making it a focal point in training processes. Small-sided games (SSGs) are widely used in football...
Aerobic capacity plays a crucial role in football performance, making it a focal point in training processes. Small-sided games (SSGs) are widely used in football training, but the relationship between aerobic capacity and running performance during SSGs remains unclear. The aim of this study was to investigate possible correlations between maximum oxygen uptake (VOmax) and running performance in youth football players in SSGs (4:4, 3:3, 2:2, 1:1) with three different pitch sizes per player (150, 100, 75 m/player). Sixteen male U15 football players participated in the study. Players underwent the Yo-Yo intermittent recovery test level 1, and their VOmax was estimated based on their performance. Subsequently, players participated in SSGs wearing GPS devices to measure internal and external load. Pearson or Spearman correlation was applied for statistical analysis depending on the normal distribution of the data. The results reveal that, for 4:4 and 3:3 relationships, larger pitches led to a greater impact of aerobic capacity (total distance (TD): 4:4, 150 m/pl, r = 0.715, = 0.002; 100 m/pl, r = 0.656, = 0.006; 75 m/pl, r = 0.586, = 0.017). In the 2:2 relationship, the opposite was observed, with more correlations appearing on smaller pitches (TD: 2:2, 100 m/pl, r = 0.581, = 0.018; 75 m/pl, r = 0.747, < 0.001). In the 1:1 relationship, correlations with VOmax, total distance, and speed were observed only on the larger pitch. In conclusion, the aerobic capacity of young football players can influence running performance indicators in SSGs. Therefore, aerobic capacity could serve as a criterion for team composition, making SSGs more competitive. Additionally, the variation in correlations in the 2:2 relationship and their limited presence in the 1:1 relationship may be attributed to technical-tactical factors, such as increased ball contacts and one-on-one situations typically occurring in smaller setups.
Topics: Adolescent; Humans; Male; Antimony Sodium Gluconate; Oxygen; Oxygen Consumption; Soccer
PubMed: 38610469
DOI: 10.3390/s24072258