RESUMEN
Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inflamación/inmunología , Células Asesinas Naturales/inmunología , Leishmania donovani/fisiología , Leishmaniasis Visceral/inmunología , Malaria/inmunología , Proteínas de la Membrana/metabolismo , Plasmodium/fisiología , Animales , Células Cultivadas , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Exocitosis , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Vesículas Secretoras/metabolismoRESUMEN
In an area endemic with Indian visceral leishmaniasis (VL), we performed direct xenodiagnosis to evaluate the transmission of Leishmania donovani from patients with VL-human immunodeficiency virus (HIV) coinfection to the vector sandflies, Phlebotomus argentipes. Fourteen patients with confirmed VL-HIV coinfection, with a median parasitemia of 42 205 parasite genome/mL of blood, were exposed to 732 laboratory-reared pathogen-free female P argentipes sandflies on their lower arms and legs. Microscopy revealed that 16.66% (122/732) of blood-fed flies were xenodiagnosis positive. Notably, 93% (13/14) of the VL-HIV group infected the flies, as confirmed by quantitative polymerase chain reaction and/or microscopy, and were 3 times more infectious than those who had VL without HIV.
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Coinfección , Infecciones por VIH , Leishmania donovani , Leishmaniasis Visceral , Leishmaniasis Visceral/epidemiología , Leishmaniasis Visceral/complicaciones , Animales , Humanos , India/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Femenino , Adulto , Coinfección/virología , Coinfección/epidemiología , Coinfección/parasitología , Leishmania donovani/aislamiento & purificación , Masculino , Phlebotomus/parasitología , Phlebotomus/virología , Enfermedades Endémicas , Persona de Mediana Edad , Adulto Joven , Xenodiagnóstico , Insectos Vectores/parasitología , Insectos Vectores/virología , AdolescenteRESUMEN
Dengue virus (DENV) is an arbovirus that comprises four antigenically different serotypes. Aedes aegypti (Diptera: Culicidae) acts as the principal vector for DENV transmission, and vector control is crucial for dengue fever epidemic management. To design effective vector control strategies, a comprehensive understanding of the insect vector and virus interaction is required. Female Ae. aegypti ingests DENV during the acquisition of a blood meal from an infected human. DENV enters the insect midgut, replicates inside it and reaches the salivary gland for transmitting DENV to healthy humans during the subsequent feeding cycles. DENV must interact with the proteins present in the midgut and salivary glands to gain entry and accomplish successful replication and transmission. Ae. aegypti midgut cDNA library was prepared, and yeast two-hybrid screening was performed against the envelope protein domain III (EDIII) protein of DENV-2. The polyubiquitin protein was selected from the various candidate proteins for subsequent analysis. Polyubiquitin gene was amplified, and the protein was purified in a heterologous expression system for in vitro interaction studies. In vitro pull-down assay presented a clear interaction between polyubiquitin protein and EDIII. To further confirm this interaction, a dot blot assay was employed, and polyubiquitin protein was found to interact with DENV particles. Our results enable us to suggest that polyubiquitin plays an important role in DENV infection within mosquitoes.
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Aedes , Virus del Dengue , Dengue , Humanos , Femenino , Animales , Virus del Dengue/genética , Dengue/veterinaria , Proteínas del Envoltorio Viral , Poliubiquitina , Mosquitos VectoresRESUMEN
Chemically modified mandua starch was successfully synthesized and applied to coat mesalamine-loaded matrix tablets. The coating material was an aqueous dispersion of mandua starch modified by sodium trimetaphosphate and sodium tripolyphosphate. To investigate the colon-targeting release competence, chemically modified mandua starch film-coated mesalamine tablets were produced using the wet granulation method followed by dip coating. The effect of the coating on the colon-targeted release of the resultant delivery system was inspected in healthy human volunteers and rabbits using roentgenography. The results show that drug release was controlled when the coating level was 10% w/w. The release percentage in the upper gastric phase (pH 1.2, simulated gastric fluid) was less than 6% and reached up to 59.51% w/w after 14 h in simulated colonic fluid. In addition to in vivo roentgenographic studies in healthy rabbits, human volunteer studies proved the colon targeting efficiency of the formulation. These results clearly demonstrated that chemically modified mandua starch has high effectiveness as a novel aqueous coating material for controlled release or colon targeting.
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Liberación de Fármacos , Mesalamina , Almidón , Comprimidos , Mesalamina/química , Mesalamina/farmacocinética , Conejos , Almidón/química , Animales , Humanos , Concentración de Iones de Hidrógeno , Fosforilación , Preparaciones de Acción Retardada/química , Colon/metabolismoRESUMEN
Visceral leishmaniasis (VL; Leishmania donovani) cases produce interferon-γ and tumor necrosis factor in response to soluble leishmanial antigen (SLA) in whole-blood assays. Using transcriptional profiling, we demonstrate the impact of interleukin-10 (IL-10), a cytokine implicated in VL, on this response. SLA stimulation identified 28 differentially expressed genes (DEGs), 17/28 in a single network with TNF as hub. SLA plus anti-IL-10 produced 454 DEGs, 292 in a single network with TNF, IFNG, NFKBIA, IL6, and IL1B as hubs in concert with a remarkable chemokine/cytokine storm. Our data demonstrate the singular effect of IL-10 as a potent immune modulator in VL.
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Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Interleucina-10/inmunología , Leishmaniasis Visceral/inmunología , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/genética , Antígenos de Protozoos/sangre , Citocinas/inmunología , Expresión Génica , Humanos , Interferón gamma/inmunología , Leishmania donovani/inmunología , Factor de Necrosis Tumoral alfaRESUMEN
The countries in the Indian subcontinent have reported a dramatic decline in visceral leishmaniasis (VL) cases. However, the presence of the parasite reservoir in the form of post-kala-azar dermal leishmaniasis (PKDL), a dermal sequel of VL, is a hurdle in attaining VL elimination. Presently employed clinical specimens for the diagnosis of PKDL include skin biopsy specimens and slit skin smears. In this study, the use of blood as a clinical specimen was investigated in different manifestations of PKDL in India. This is a bicentric study (National Institute of Pathology, Indian Council of Medical Research [ICMR], New Delhi, and Institute of Medical Sciences [IMS], Banaras Hindu University, Varanasi), with 215 participants (120 PKDL patients and 95 controls). Highly sensitive quantitative real-time PCR (Q-PCR) and field-deployable loop-mediated isothermal amplification (LAMP) were employed using blood samples for diagnosis. Promising sensitivities of 77.50% (95% confidence interval [CI], 69.24 to 84.05%) for Q-PCR and 70.83% (95% CI, 62.16 to 78.22%) for LAMP were obtained for the diagnosis of PKDL. Further, enhanced sensitivities of 83.33% (95% CI, 71.28 to 90.98%) and 77.78% (95% CI, 65.06 to 86.80%) for Q-PCR and LAMP, respectively, were recorded for the detection of macular cases. The study revealed an inverse correlation between the parasite load estimated in slit and blood samples, thereby favoring the use of blood for the diagnosis of the macular variant, which may be missed due to scant parasite loads in the slit. This study is the first to propose the promising potential of blood as a clinical specimen for accurate diagnosis of PKDL, which would aid in fast-tracking VL elimination.
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Leishmania donovani , Leishmaniasis Cutánea , Leishmaniasis Visceral , Humanos , India , Leishmania donovani/genética , Leishmaniasis Cutánea/diagnóstico , Leishmaniasis Visceral/diagnóstico , Técnicas de Diagnóstico Molecular , Técnicas de Amplificación de Ácido Nucleico , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Visceral leishmaniasis (VL) is a potentially fatal parasitic disease causing high morbidity and mortality in developing countries. Vaccination is considered the most effective and powerful tool for blocking transmission and control of diseases. However, no vaccine is available so far in the market for humans. In the present study, we characterized the hypothetical protein LDBPK_252400 of Leishmania donovani (LdHyP) and explored its prophylactic behavior as a potential vaccine candidate against VL. We found reduced hepato-splenomegaly along with more than 50% parasite reduction in spleen and liver after vaccination in mice. Protection in vaccinated mice after the antigen challenge correlated with the stimulation of antigen specific IFN-γ expressing CD4+T cell (~4.6 fold) and CD8+T cells (~2.1 fold) in vaccinated mice in compared to infected mice, even after 2-3 months of immunization. Importantly, antigen-mediated humoral immunity correlated with high antigen specific IgG2/IgG1 responses in vaccinated mice. In vitro re-stimulation of splenocytes with LdHyP enhances the expression of TNF-α, IFN-γ, IL-12 and IL-10 cytokines along with lower IL-4 cytokine and IL-10/IFN-γ ratio in vaccinated mice. Importantly, we observed ~3.5 fold high NO production through activated macrophages validates antigen mediated cellular immunity induction, which is critical in controlling infection progression. These findings suggest that immunization with LdHyP mount a very robust immunity (from IL-10 towards TFN-γ mediated responses) against L. donovani infection and could be explored further as a putative vaccine candidate against VL.
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Vacunas contra la Leishmaniasis/inmunología , Leishmaniasis Visceral/tratamiento farmacológico , Animales , Antígenos de Protozoos/inmunología , Citocinas/inmunología , Inmunidad Celular/inmunología , Inmunización/métodos , Leishmania donovani/inmunología , Leishmania donovani/patogenicidad , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/metabolismo , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Proteínas Protozoarias/inmunología , Proteínas Recombinantes/inmunología , Linfocitos T/inmunología , Vacunación/métodosRESUMEN
Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γ production by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses.
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Linfocitos T CD4-Positivos/inmunología , Interleucina-2/inmunología , Leishmaniasis Visceral/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Animales , Femenino , Humanos , Interferón gamma/inmunología , Leishmania donovani/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Células Th17/inmunología , Células Th2/inmunologíaRESUMEN
BACKGROUND: Visceral leishmaniasis (VL), caused by the Leishmania donovani complex, is a fatal, neglected tropical disease that is targeted for elimination in India, Nepal, and Bangladesh. Improved diagnostic tests are required for early case detection and for monitoring the outcomes of treatments. Previous investigations using Leishmania lysate antigen demonstrated that the immunoglobulin (Ig) G1 response is a potential indicator of a patient's clinical status after chemotherapy. METHODS: IgG1 or IgG enzyme-linked immunosorbent assays (ELISAs) with rK39 or lysate antigens and novel IgG1 rK39 rapid diagnostic tests (RDTs) were assessed with Indian VL serum samples from the following clinical groups: paired pre- and postchemotherapy (deemed cured); relapsed; other infectious diseases; and endemic, healthy controls. RESULTS: With paired pre- and post-treatment samples (n = 37 pairs), ELISAs with rK39- and IgG1-specific conjugates gave a far more discriminative decrease in post-treatment antibody responses when compared to IgG (P < .0001). Novel IgG1 rK39 RDTs provided strong evidence for decreased IgG1 responses in patients who had successful treatment (P < .0001). Furthermore, both IgG1 rK39 RDTs (n = 38) and ELISAs showed a highly significant difference in test outcomes between cured patients and those who relapsed (n = 23; P < .0001). RDTs were more sensitive than corresponding ELISAs. CONCLUSIONS: We present strong evidence for the use of IgG1 in monitoring treatment outcomes in VL, and the first use of an IgG1-based RDT using the rK39 antigen for the discrimination of post-treatment cure versus relapse in VL. Such an RDT may have a significant role in monitoring patients and in targeted control and elimination of this devastating disease.
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Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Inmunoglobulina G/inmunología , Leishmania/inmunología , Leishmaniasis Visceral/inmunología , Anticuerpos Antiprotozoarios/sangre , Antiprotozoarios/uso terapéutico , Pruebas Diagnósticas de Rutina , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/sangre , Leishmaniasis Visceral/sangre , Leishmaniasis Visceral/diagnóstico , Leishmaniasis Visceral/tratamiento farmacológico , Recurrencia , Resultado del TratamientoRESUMEN
CD8+ T-cell function is compromised in chronic diseases such as visceral leishmaniasis (VL). However, little is known about the changes in gene expression that cause CD8+ T-cell dysfunction during VL. We used targeted transcriptional profiling of peripheral blood CD8+ T cells from VL patients pre- and post-anti-parasitic drug treatment, and compared them with the same cell population from healthy endemic controls to assess their activation, differentiation and functional status during disease. We found a predominance of downregulated immune genes in CD8+ T cells from VL patients. However, genes encoding several notable immune checkpoint molecules, including LAG-3, TIM-3 and CTLA-4, cytolytic molecules, such as granzymes A, B and H and perforin, as well as SOCS3, STAT1, JAK2 and JAK3 cytokine signalling genes were found to be increasingly expressed by VL patient CD8+ T cells. Additional studies confirmed increased expression of the inhibitory receptors LAG3 and TIM3 on VL patient CD8+ T cells, thereby identifying these molecules as potential targets to improve antigen-specific CD8+ T-cell responses during disease.
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Linfocitos T CD8-positivos/inmunología , Regulación de la Expresión Génica/inmunología , Inmunidad Celular/genética , Inmunidad Celular/inmunología , Leishmaniasis Visceral/inmunología , Adulto , Antígenos CD/genética , Antígeno CTLA-4/genética , Femenino , Perfilación de la Expresión Génica , Granzimas/biosíntesis , Granzimas/genética , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Janus Quinasa 2/genética , Janus Quinasa 3/genética , Leishmaniasis Visceral/parasitología , Masculino , Perforina/biosíntesis , Perforina/genética , Factor de Transcripción STAT1/genética , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
BACKGROUND: Recent reports of emergence and spread of artemisinin resistance in the Southeast Asia region, including Myanmar, pose a greater threat to malaria control and elimination in India. Whole genome sequencing studies have associated mutations in the K13 propeller gene (k13), PF3D7_1343700 with artemisinin resistance both in vitro and in vivo. The aim of the present study was to find the k13 gene polymorphisms in Plasmodium falciparum parasites from the three sites in the Northeast region of India, bordering Bangladesh and Myanmar. METHODS: A total of 254 samples collected during 2014-2015 from Tripura, Mizoram and Arunachal Pradesh states in the Northeast region of India were used to obtain the full-length k13 gene sequences. RESULTS: Three non-synonymous (NS) mutations: two in the propeller region, namely at codon 446 and 578, were observed besides one at codon 189 in the non-propeller region. The treatment outcome was not affected by these mutations at any of the sites. In addition, microsatellite variation in the N-terminus of the k13 protein was observed at all the study sites. CONCLUSION: This is the first study to document the presence of F446I NS mutation in the k13 propeller region from Changlang district, Arunachal Pradesh, a site adjoining the Indo-Myanmar border region, where this mutation is highly prevalent. In addition, NS mutation A578S has been observed only at Lunglei district, Mizoram, a site bordering Bangladesh and K189T mutation with relatively higher frequency in Mizoram and Tripura states. The presence of F446I mutation in a region close to the Myanmar border is notable. Considering the spread of anti-malarial drug resistance from Southeast Asia to the Northeast region of India in the past, there is an urgent need to undertake systematic mapping studies to ascertain the role and extent of this mutation in artemisinin resistance in this region of country.
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Malaria Falciparum/parasitología , Mutación Missense , Plasmodium falciparum/clasificación , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas Protozoarias/genética , Resistencia a Medicamentos , Humanos , India/epidemiología , Epidemiología Molecular , Plasmodium falciparum/aislamiento & purificación , Proteínas Protozoarias/química , Análisis de Secuencia de ADNRESUMEN
Visceral leishmaniasis (VL) is a serious parasitic disease, causing high morbidity and mortality in the developing world. The pathogenesis of VL is complex, and the clinical presentation ranges from asymptomatic infection to severe and fatal disease. Despite a wealth of research on the full-blown "clinical VL" syndrome, asymptomatic leishmania infections remain poorly understood. Asymptomatic infection could present a major challenge for control programs if its infectiousness is confirmed. In this viewpoint, we highlight the crucial knowledge gaps as well as the obstacles in research on asymptomatic leishmanial infection. Research in this area is essential for the development of more-effective VL control strategies.
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Infecciones Asintomáticas , Leishmaniasis Visceral , Leishmaniasis , Infecciones Asintomáticas/epidemiología , Portador Sano , Humanos , Leishmania donovani/inmunología , Leishmaniasis/epidemiología , Leishmaniasis/inmunología , Leishmaniasis/prevención & control , Leishmaniasis Visceral/epidemiología , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/parasitología , Leishmaniasis Visceral/prevención & control , Factores de RiesgoRESUMEN
The immune evasion gene family of malaria parasites encodes variant surface proteins that are expressed at the surface of infected erythrocytes and help the parasite in evading the host immune response by means of antigenic variation. The identification of Plasmodium vivax vir orthologous immune evasion gene family from primate malaria parasites would provide new insight into the evolution of virulence and pathogenesis. Three vir subfamilies viz. vir-B, vir-D and vir-G were successfully PCR amplified from primate malaria parasites, cloned and sequenced. DNA sequence analysis confirmed orthologues of vir-D subfamily in Plasmodium cynomolgi, Plasmodium simium, Plasmodium simiovale and Plasmodium fieldi. The identified vir-D orthologues are 1-9 distinct members of the immune evasion gene family which have 68-83% sequence identity with vir-D and 71.2-98.5% sequence identity within the members identified from primate malaria parasites. The absence of other vir subfamilies among primate malaria parasites reflects the limitations in the experimental approach. This study clearly identified the presence of vir-D like sequences in four species of Plasmodium infecting primates that would be useful in understanding the evolution of virulence in malaria parasites.
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Antígenos de Protozoos/genética , Evasión Inmune/genética , Malaria/veterinaria , Plasmodium/inmunología , Enfermedades de los Primates/inmunología , Proteínas Protozoarias/genética , Animales , Variación Antigénica , Antígenos de Protozoos/inmunología , ADN Protozoario/química , ADN Protozoario/genética , Interacciones Huésped-Parásitos , Malaria/inmunología , Malaria/parasitología , Familia de Multigenes , Filogenia , Plasmodium/genética , Plasmodium/patogenicidad , Enfermedades de los Primates/parasitología , Primates , Proteínas Protozoarias/inmunología , Alineación de Secuencia/veterinaria , Análisis de Secuencia de ADN/veterinaria , Virulencia/genéticaRESUMEN
OBJECTIVE: To evaluate the utility of color Doppler ultrasonography in assessing infantile hemangioma response to treatment with oral propranolol. METHODS: A prospective study was conducted between January, 2016 and December, 2022, wherein children with symptomatic (ulceration, bleeding, pain and scarring) infantile hemangioma were given oral propranol (2 mg/kg per day in three divided doses) as outpatient therapy. The clinical response was assessed three months post-initiation of treatment (intermediate clinical response) and three months post-completion of treatment (final clinical response, FCR). The primary outcome measurement was a clinical and radiological response (resistivity index (RI), pulsatility index (PI) and peak systolic velocity) to treatment. The secondary outcomes assessed were the complications related to treatment. RESULTS: Out of 601 patients who were started on propranolol, 99 developed severe adverse effects and were excluded from analysis. At FCR assessment, out of 502 participants, 64.3% (n = 323) showed excellent response, 17.7% (n = 89) showed partial, and 17.9% (n = 90) were non-responders. A significant increase in RI and PI values was noted in all children following propranolol treatment for six months. An increase > 7.5% in RI could identify responders with 92% sensitivity, 91% specificity and area under the curve (AUC) of 0.963. An increase of > 11.5% in PI could identify responders with 86% sensitivity, 91% specificity and AUC of 0.896. Patients initially showing no response but later becoming excellent responders had significantly higher RI and PI values. CONCLUSIONS: Color Doppler ultrasonography is a valuable tool in predicting the treatment outcome of infantile hemangioma using propranolol.
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Hemangioma Capilar , Neoplasias Cutáneas , Niño , Humanos , Lactante , Propranolol/efectos adversos , Antagonistas Adrenérgicos beta/efectos adversos , Estudios Prospectivos , Hemangioma Capilar/inducido químicamente , Hemangioma Capilar/tratamiento farmacológico , Resultado del Tratamiento , Ultrasonografía Doppler en Color , Administración Oral , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
Objectives: To investigate the efficacy and safety of individualized homeopathic medicines (IHMs) in treating hemorrhoids compared with placebo. Design: This is a double-blind, randomized (1:1), two parallel arms, placebo-controlled trial. Setting: The trial was conducted at the surgery outpatient department of the State National Homoeopathic Medical College and Hospital, Lucknow, Uttar Pradesh, India. Subjects: Patients were 140 women and men, aged between 18 and 65 years, with a diagnosis of primary hemorrhoids grades I-III for at least 3 months. Excluded were the patients with grade IV hemorrhoids, anal fissure, and fistula, hypertrophic anal papillae, inflammatory bowel disease, coagulation disorders, rectal malignancies, obstructed portal circulation, patients requiring immediate surgical intervention, and vulnerable samples. Interventions: Patients were randomized to Group 1 (n = 70; IHMs plus concomitant care; verum) and Group 2 (n = 70; placebos plus concomitant care; control). Outcome measures: Primary-the anorectal symptom severity and quality-of-life (ARSSQoL) questionnaire, and secondary-the EuroQol 5-dimensions 5-levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS); all of them were measured at baseline, and every month, up to 3 months. Results: Out of the 140 randomized patients, 122 were protocol compliant. Intention-to-treat sample (n = 140) was analyzed. The level of significance was set at p < 0.05 two tailed. Statistically significant between-group differences were elicited in the ARSSQoL total (Mann-Whitney U [MWU]: 1227.0, p < 0.001) and EQ-5D-5L VAS (MWU: 1228.0, p = 0.001) favoring homeopathy against placebos. Sulfur was the most frequently prescribed medicine. No harm or serious adverse events were reported from either of the groups. Conclusions: IHMs demonstrated superior results over placebo in the short-term treatment of hemorrhoids of grades I-III. The findings are promising, but need to be substantiated by further phase 3 trials. Clinical Trial Registration Number: CTRI/2020/03/024342.
RESUMEN
OBJECTIVES: Monitoring of Leishmania transmission is considered a strategic priority for sustaining elimination of visceral leishmaniasis as a public health problem in the Indian subcontinent. The objective of this study was to evaluate whether serological surveys can distinguish between communities with and without Leishmania transmission, and to assess which serological marker performs best. METHODS: Seven villages were selected from Bihar and Uttar Pradesh state, India, and categorized as either currently endemic, previously endemic or non-endemic. Blood samples were analyzed with the rK39 RDT, DAT, and rK39 ELISA. RESULTS: Contrary to the rK39 RDT and DAT, the rK39 ELISA showed a significant difference between all three categories of endemicity, with a seroprevalence of 5.21% in currently endemic villages, 1.55% in previously endemic villages, and 0.13% in non-endemic villages. Even when only looking at the seroprevalence among children aged <10 years, the rK39 ELISA was still able to differentiate between villages with and without ongoing transmission. CONCLUSIONS: Our findings suggest the rK39 ELISA to be the most promising marker for monitoring of Leishmania transmission. Further validation is required, and practical, context-adapted recommendations need to be formulated in order to guide policy makers towards meaningful and sustainable surveillance strategies in the post-elimination phase.
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IL-10 is believed to underlie many of the immunologic defects in human visceral leishmaniasis (VL). We have identified CD4(+)CD25(-)Foxp3(-) T cells as the major source of IL-10 in the VL spleen. IL-27, a member of the IL-6/IL-12 cytokine family, has been shown to promote development of IL-10-producing T cells, in part by upregulating their production of autocrine IL-21. We investigated whether IL-27 and IL-21 are associated with human VL. IL-27 was elevated in VL plasma, and at pretreatment, spleen cells showed significantly elevated mRNA levels of both IL-27 subunits, IL-27p28 and EBI-3, as well as IL-21, compared with posttreatment biopsies. CD14(+) spleen cells were the main source of IL-27 mRNA, whereas CD3(+) T cells were the main source of IL-21. IL-27 mRNA could be strongly upregulated in normal donor macrophages with IFN-γ and IL-1ß, conditions consistent with those in the VL spleen. Last, a whole-blood assay revealed that most VL patients could produce Ag-specific IFN-γ and IL-10 and that the IL-10 could be augmented with recombinant human IL-21. Thus, proinflammatory cytokines acting on macrophages in the VL spleen have the potential to upregulate IL-27, which in turn can induce IL-21 to expand IL-10-producing T cells as a mechanism of feedback control.
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Interleucinas/fisiología , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto , Retroalimentación Fisiológica/fisiología , Femenino , Humanos , Interleucina-10/biosíntesis , Interleucina-10/sangre , Interleucina-10/fisiología , Interleucina-17/biosíntesis , Interleucina-17/sangre , Interleucinas/biosíntesis , Interleucinas/sangre , Leishmaniasis Visceral/sangre , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , ARN Mensajero/biosíntesis , Bazo/inmunología , Bazo/metabolismo , Linfocitos T/patología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patología , Regulación hacia Arriba/inmunología , Adulto JovenRESUMEN
Prevalence of alcohol use in India is reported to be 21.4% and there is increasing alcohol intake among the young people. The present study was undertaken to study the socio-demographic characteristics of patients having alcohol-related disorders attending the de-addiction center at Burdwan Medical College in West Bengal and to find out some factors responsible for that. A clinic-based descriptive cross-sectional study was conducted among 187 patients with the help of pre-tested pre-designed schedule after obtaining informed consent. Data analysis was carried out with the help of Epi info software version 6. Majority of the patients were male, in productive age group and married. Age of initiation and amount of alcohol intake were significantly associated with positive family history of alcoholism. Children having family history of alcoholism should be counseled to prevent development of alcoholism.