Tuberculosis最新文献_第7页

Customized MHC Class I & II restricted peptides from clinical isolates of Mycobacterium tuberculosis tweak strong cellular immune response in Healthy individuals and Pulmonary Tuberculosis patients: A potential candidate in vaccine design 从结核分枝杆菌临床分离株中定制的MHC I类和II类限制性肽在健康个体和肺结核患者中改变了强烈的细胞免疫反应：疫苗设计的潜在候选物

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-04-15 DOI: 10.1016/j.tube.2025.102640

Niharika Sharma , Beenu Joshi , Bhawna Sharma , Santosh Kumar , Keshar Kunja Mohanty , Hridayesh Prakash

Tuberculosis (TB) remains a global health challenge as annual mortality rate due to drug resistant TB is increasing exponentially. This is mostly associated with the delayed diagnosis of Multidrug-resistant (MDR) or latent TB. Effective management of TB demands development of novel immunological strategies, such as peptide-based/subunit vaccines that can stimulate specific immune responses. In this context, we evaluated the immunogenic potential of two Major Histocompatibility Complex (MHC) Class I/II-restricted peptides from Mycobacterium tuberculosis (M. tuberculosis): Rv2588c and Rv0148. The peptides were tested on T and monocyte populations from healthy donors and pulmonary TB (PTB) patients. Flow cytometry analysis revealed significant T cell activation in peripheral blood mononuclear cells (PBMC) from both groups. Enzyme-linked immunosorbent assay (ELISA) demonstrated a strong IFN-γ response, confirming effective T cell activation. Additionally, these peptides induced increased nitric oxide (NO) production in macrophages, indicating their role in activating the innate immune system. Overall, Rv2588c and Rv0148 peptides exhibited robust immunogenicity, stimulating both adaptive and innate immune responses in PBMCs from healthy and PTB individuals. These findings highlight their potential as promising TB vaccine candidates, paving the way for improved TB treatment and prevention strategies.

由于耐药结核病每年造成的死亡率呈指数级增长，结核病仍然是全球卫生挑战。这主要与耐多药（MDR）或潜伏性结核病的诊断延迟有关。结核病的有效管理需要开发新的免疫策略，例如可以刺激特异性免疫反应的肽基/亚单位疫苗。在这种情况下，我们评估了结核分枝杆菌（M. tuberculosis）的两种主要组织相容性复合体（MHC） I/ ii类限制性肽的免疫原性潜力：Rv2588c和Rv0148。这些肽在健康供体和肺结核患者的T细胞和单核细胞群体中进行了测试。流式细胞术分析显示两组外周血单个核细胞（PBMC） T细胞活化显著。酶联免疫吸附试验（ELISA）显示了强烈的IFN-γ反应，证实了有效的T细胞激活。此外，这些肽诱导巨噬细胞中一氧化氮（NO）的产生增加，表明它们在激活先天免疫系统中的作用。总的来说，Rv2588c和Rv0148肽表现出强大的免疫原性，在健康和肺结核患者的pbmc中刺激适应性和先天免疫反应。这些发现突出了它们作为有希望的结核病候选疫苗的潜力，为改进结核病治疗和预防战略铺平了道路。

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引用次数: 0

Characterization of the global bovine microRNAome of peripheral blood mononuclear cells isolated from Mycobacterium bovis exposed cattle 暴露牛分枝杆菌分离的牛外周血单个核细胞的整体microRNAome特征

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-04-04 DOI: 10.1016/j.tube.2025.102639

Anna E. Karagianni , Lindert Benedictus , Sabine Steinbach , Femke Broere , Elisabeth M.D.L. van der Heijden

Accurate diagnostics are urgently needed for bovine TB – an economically devastating disease posing a re-emerging threat to veterinary and public health worldwide. MicroRNAs, post-transcriptional gene regulators involved in a range of biological processes and immunological pathways, have emerged as promising diagnostic biomarkers for numerous diseases. In human TB, microRNAs have been widely studied, but not much is currently known about their role in bovine TB. This study aimed to investigate the diagnostic potential of microRNAs in bTB through comprehensive analysis of their expression profiles in disparate states of M. bovis exposure. We used RNA-sequencing to characterize the global microRNAome of peripheral blood mononuclear cells from cattle that were either unvaccinated, BCG-vaccinated, unprotected or protected. A total of 468 microRNAs were detected across all samples, none of which were uniquely expressed in any group. Significant differential expression was observed for bta-miR-6122–3p, bta-miR-3533 and bta-miR29b in various comparisons. Subsequent target analysis of bta-miR-29b, a candidate biomarker in human tuberculosis, revealed that several genes (ACVR2A, PIK3R1, TBX21, TGFBR1 and TGFBR2) involved in a number of relevant T-cell and immune signaling pathways, were amongst the predicted targets. Overall, this study provides evidence that microRNAs could be promising novel biomarkers for bovine TB diagnostics.

牛结核病是一种经济上具有破坏性的疾病，对全世界的兽医和公共卫生构成了重新出现的威胁，迫切需要准确的诊断。microrna是参与一系列生物过程和免疫途径的转录后基因调控因子，已成为许多疾病的有希望的诊断生物标志物。在人类结核病中，microrna已经得到了广泛的研究，但是目前对它们在牛结核病中的作用知之甚少。本研究旨在通过综合分析microrna在牛分枝杆菌暴露不同状态下的表达谱，探讨microrna在bTB中的诊断潜力。我们使用rna测序来表征未接种、接种bcg、未接种或保护的牛外周血单个核细胞的全局microRNAome。在所有样本中共检测到468个microrna，其中没有一个在任何组中唯一表达。在各种比较中，bta-miR-6122-3p、bta-miR-3533和bta-miR29b的表达存在显著差异。随后对人类结核病候选生物标志物bta-miR-29b的靶标分析显示，参与许多相关t细胞和免疫信号通路的几个基因（ACVR2A, PIK3R1, TBX21， TGFBR1和TGFBR2）是预测的靶标之一。总的来说，这项研究提供了证据，证明microrna可能是牛结核病诊断中有希望的新型生物标志物。

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引用次数: 0

Response to “Prevalence of non-tuberculous mycobacteria by Line-Probe Assay” 对“线探针法检测非结核分枝杆菌患病率”的回应

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-04-02 DOI: 10.1016/j.tube.2025.102637

Elizna Maasdorp , Monique J. Williams

引用次数: 0

The anti-mycobacterial potential of ibuprofen 布洛芬的抗分枝杆菌潜能

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-04-01 DOI: 10.1016/j.tube.2025.102638

Pir Tariq Shah , Li Xing

Background

Ibuprofen (IBU) is a non-prescription analgesic drug from the non-steroidal anti-inflammatory drug class. It is widely used for treating pain, fever, and inflammation. Both the in silico and in vitro experiments were performed to determine the antibacterial potentials of the IBU against Mycobacterium tuberculosis (Mtb).

Methods

The STITCH v.5 pipeline was used to analyze the interaction of IBU with the proteome of the Mtb H37Ra and H37Rv strains. The GFP-tagged Bacillus Calmette Guerin (BCG) and td-tomato-tagged Mtb H37Ra were used to determine the bacteriostatic and bactericidal activities of IBU. The IBU-treated THP-1-derived macrophages were infected by td-tomato-tagged Mtb H37Ra and wild-type BCG to analyze the effects of IBU on bacterial phagocytosis and apoptosis, respectively.

Results

The in-silico study revealed that the IBU interacts with Mtb proteins primarily involved in cellular process, metabolism, and virulence, and targets four virulent proteins of Mtb, e.g., Cyp-123, Cyp-126, Cyp-130, and Cyp-139 in the cytochrome p450 system. The increasing concentrations of IBU showed significant bacteriostatic activity against Mtb H37Ra in vitro, where the 100 μg/ml and 200 μg/ml concentrations especially led to almost complete bacterial growth arrest. The IBU treatment does not affect BCG-induced apoptosis of THP-1-derived macrophages, but significantly enhances bacterial uptake, especially at 100 μg/ml and 200 μg/ml concentrations.

Conclusions

The IBU enhances Mtb uptake by macrophages and exhibits direct bacteriostatic activity in vitro.

背景布洛芬（IBU）是一种非处方镇痛药，属于非甾体抗炎药类。它被广泛用于治疗疼痛、发烧和炎症。为了确定 IBU 对结核分枝杆菌（Mtb）的抗菌潜力，我们进行了硅学和体外实验。方法使用 STITCH v.5 管道分析 IBU 与 Mtb H37Ra 和 H37Rv 菌株蛋白质组的相互作用。用GFP标记的卡介苗（Bacillus Calmette Guerin，BCG）和td-tomato标记的Mtb H37Ra来测定IBU的抑菌和杀菌活性。IBU处理的THP-1衍生巨噬细胞分别被td-番茄标记的Mtb H37Ra和野生型卡介苗感染，以分析IBU对细菌吞噬和细胞凋亡的影响、细胞色素 p450 系统中的 Cyp-123、Cyp-126、Cyp-130 和 Cyp-139 。在体外，浓度不断增加的 IBU 对 Mtb H37Ra 有明显的抑菌作用，尤其是 100 μg/ml 和 200 μg/ml 浓度的 IBU 几乎完全抑制了细菌的生长。IBU 处理不会影响卡介苗诱导的 THP-1 巨噬细胞的凋亡，但会显著增强细菌的吸收，尤其是在 100 μg/ml 和 200 μg/ml 的浓度下。

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引用次数: 0

Construction and expression of multi-stage antigen fusion protein RPC4 vaccine for Mycobacterium tuberculosis and its immunogenicity analysis in combination with adjuvant DIMQ 多阶段抗原融合蛋白RPC4结核分枝杆菌疫苗的构建、表达及与佐剂DIMQ联合免疫原性分析

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-26 DOI: 10.1016/j.tube.2025.102635

Xiaochun Wang , Yun Xu , Qiangsen Zhong , Zian Zhang , LingYun Kong , Mingming Zhou , Runlin Wang , Xinxin Pi , Suwen Qiao

Mycobacterium tuberculosis (M. tb) serves as the main pathogen responsible for Tuberculosis (TB). It predominantly targets the lungs and leads to a persistent infectious disease. The spread of drug-resistant tuberculosis and the exacerbation of economic burdens due to co-infections with Human Immunodeficiency Virus (HIV)/M. tb pose significant challenges in prevention and treatment. The BCG vaccine is currently the only approved (TB) vaccine, but its protective effect is limited for adults. In this research, we engineered the fusion protein gene RPC4, incorporating four crucial antigens from M. tb. The study revealed that the IFN-γ levels in the peripheral blood of infected patients significantly surpassed those in healthy individuals. To assess the immune response of RPC4 as a BCG-enhanced vaccine following initial immunity, researchers administered it alongside the novel adjuvant DIMQ to immunize mice. Experiments revealed that the BCG + RPC4/DIMQ vaccine induces a substantial immunogenic response in the mice.

结核分枝杆菌（M. tb）是导致结核病的主要病原体。它主要以肺部为目标，并导致一种持续的传染病。耐药结核病的蔓延和人类免疫缺陷病毒(HIV)/M合并感染造成的经济负担加剧。结核病在预防和治疗方面构成重大挑战。卡介苗是目前唯一被批准的（结核病）疫苗，但它对成人的保护作用有限。在这项研究中，我们设计了融合蛋白基因RPC4，结合了结核分枝杆菌的四种关键抗原。研究表明，感染患者外周血中的IFN-γ水平明显超过健康个体。为了评估RPC4作为bcg增强疫苗在初始免疫后的免疫反应，研究人员将其与新型佐剂DIMQ一起给予小鼠免疫。实验表明，卡介苗+ RPC4/DIMQ疫苗在小鼠体内诱导了大量的免疫原性应答。

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引用次数: 0

Prevalence of non-tuberculous mycobacteria estimated by line-probe assay 用线探针法估计非结核分枝杆菌的患病率

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-26 DOI: 10.1016/j.tube.2025.102636

Sarman Singh

引用次数: 0

IgG antibody response to Mycobacterium tuberculosis curli pili (MTP) in people from different geographical regions in Sub-Saharan Africa 撒哈拉以南非洲不同地理区域人群对毛卷曲结核分枝杆菌（MTP）的IgG抗体反应

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-20 DOI: 10.1016/j.tube.2025.102634

Koobashnee Pillay , Theresa Coetzer , Catherine Connolly , Balakrishna Pillay , Thamsanqa Chiliza , Kogieleum Naidoo , Jayne Sutherland , Thumbi Ndung'u , Harriet Mayanja-Kizza , Manormoney Pillay

Previously, a slot blot or an indirect enzyme-linked immunosorbent assay (ELISA) using a synthetic or purified MTP antigen, conceptually demonstrated IgG antibody induction in pulmonary TB patients, albeit with small sample sizes and differing sensitivity. Therefore, we evaluated an IgG MTP ELISA in larger populations from The Gambia (n = 549), Uganda (n = 161), and South Africa (n = 193), comprising human immunodeficiency virus (HIV) positive and negative, with microbiologically confirmed active TB. The association between the IgG level and demographic characteristics was determined by multivariate logistic regression. The sensitivity (44.8–61.2 %) and specificity (33.4–78.5 %) varied in the three cohorts. Anti-MTP antibody titres differed between the TB positive and negative groups within the South African and The Gambian cohorts (p < 0.001), but not in Uganda (p = 0.35). Antibodies were detected in HIV positive and negative patients and were reduced at 6-month follow-up after treatment (p > 0.067). The study verified previous findings that anti-MTP antibodies, and therefore MTP antigen, are produced during active TB. However, the accuracy of the MTP-IgG ELISA was low, and is therefore not suitable as a target product profile in the high burden TB areas investigated. Further studies are needed to clarify the variable reactivities in different geographical areas.

以前，使用合成或纯化的MTP抗原的槽印迹或间接酶联免疫吸附试验（ELISA）在概念上证明了IgG抗体对肺结核患者的诱导作用，尽管样本量小且敏感性不同。因此，我们在冈比亚（n = 549）、乌干达（n = 161）和南非（n = 193）的更大人群中评估了IgG MTP ELISA，包括人类免疫缺陷病毒（HIV）阳性和阴性，微生物学证实为活动性结核病。IgG水平与人口统计学特征之间的关系通过多变量logistic回归确定。三个队列的敏感性（44.8 - 61.2%）和特异性（33.4 - 78.5%）各不相同。抗mtp抗体滴度在南非和冈比亚队列中结核阳性和阴性组之间存在差异(p <；0.001)，但乌干达没有（p = 0.35）。在HIV阳性和阴性患者中检测到抗体，并在治疗后6个月随访时降低(p >；0.067)。该研究证实了以前的发现，即在活动性结核病期间产生抗MTP抗体，从而产生MTP抗原。然而，MTP-IgG ELISA的准确性较低，因此不适合作为所调查的高负担结核病地区的目标产品。需要进一步的研究来阐明不同地理区域的不同反应性。

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引用次数: 0

High centrifugation speed improves recovery of M. tuberculosis and yield of culture 高离心速度可提高结核分枝杆菌的回收率和培养产量

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-15 DOI: 10.1016/j.tube.2025.102633

Godlove T. Chaula , Lucy Namkinga , Ally Mahadhy , Wilber Sabiiti , Nyanda Elias Ntinginya , Bariki Mtafya

Background

We assessed the impact of centrifugation on recovery of Mycobacterium tuberculosis (M.tb).

Methods

We used 0.5 McFarland from the 2 weeks M. tb, H37Rv culture and homogenized sputum for our experiments. Samples were decontaminated by 2 % NaOH for 20 min and with PBS for controls. Decontaminated aliquots were centrifuged at 2000×g, 3000×g and 6000×g for 40 min and inoculated on MGIT and LJ media. MGITs were incubated into the BACTEC MGIT 960 Systems following BD manuals and data analyzed on GraphPad Software.

Results

The positivity (days) for M. tb, H37Rv in MGIT and LJ decreased from 20.4 to 17.7 and from 47.6 to 26.6 at 2000×g and 6000×g, respectively; P > 0.05. For controls, MGIT and LJ positivity (days) decreased from 19 to 10 and from 39.2 to 11.2 at 2000×g and 6000×g, respectively; P > 0.05. MGIT positivity was 6(60 %) at 2000×g and 8(80 %) at 6000×g, corresponding to mean (±SD) of 13.7 ± 6.7 and 9.06 ± 4.6 days, respectively for sputum. LJ positivity was 1(10 %) at 2000×g and 7(70 %) at 6000×g. MGIT contamination for controls (sputum) was over 50 % and 80 % for LJ.

Conclusion

Higher centrifugation speed improves yield and sensitivity of TB culture.

我们评估了离心对结核分枝杆菌（M.tb）回收的影响。方法采用2周结核分枝杆菌、H37Rv培养液和匀浆痰液0.5 McFarland进行实验。样品用2% NaOH净化20分钟，用PBS作为对照。净化后的等分液在2000×g、3000×g和6000×g离心40分钟，接种于MGIT和LJ培养基。根据BD手册和GraphPad软件分析的数据，将MGIT培养到BACTEC MGIT 960系统中。结果MGIT和LJ中结核分枝杆菌、H37Rv在2000×g和6000×g的阳性(d)分别由20.4和47.6降至17.7和26.6；P比;0.05. 对照中，在2000×g和6000×g， MGIT和LJ阳性（天）分别从19降至10天和从39.2降至11.2天；P比;0.05. 在2000×g和6000×g， MGIT阳性分别为6（60%）和8(80%)，对应于痰液的平均（±SD）分别为13.7±6.7和9.06±4.6天。LJ阳性在2000×g为1例（10%），在6000×g为7例（70%）。对照组（痰）MGIT污染超过50%，LJ超过80%。结论较高的离心速度可提高结核杆菌培养的产率和灵敏度。

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引用次数: 0

Functional analysis of genetic mutations in ddn and fbiA linked to delamanid resistance in rifampicin-resistant Mycobacterium tuberculosis 耐利福平结核分枝杆菌中与德拉曼耐药相关的ddn和fbiA基因突变的功能分析

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-14 DOI: 10.1016/j.tube.2025.102630

Seungmo Kim , Seung Heon Lee , Gisu Kang , Gyeong In Lee , Hyeon-Su Kim , Jeong Seong Yang , Youngsuk Park , Byoung Oh Hwang , Hyejin Kim

The connection between genetic mutations linked to delamanid resistance and phenotypic resistance remains unclear. We assessed the phenotypic effects of delamanid-resistant mutations in the Mycobacterium tuberculosis H37Rv strain through gene disruption using homologous recombination and complementation tests. Delamanid resistance was assessed by determining the minimum inhibitory concentration (MIC) via the 7H9 microdilution method. Sanger sequencing identified mutations, and conservation of the mutated residues was predicted through multiple sequence alignments of orthologs. A total of 116 isolates with MIC ≥0.025 μg/mL were analyzed, among which mutations were identified in the ddn and fbiA genes. Isogenic strains were generated based on these mutations. The ddn or fbiA isogenic strains with Ala77Val, Gly81Ser, Asn25fs, and Leu104Phe in fbiA had MICs ≥0.8 μg/mL, indicating resistance. In contrast, the ddn isogenic strain with Pro12Ala had an MIC of 0.012 μg/mL, showing susceptibility, while Gly96Asp in fbiA had an MIC of 0.1 μg/mL, indicating resistance. All mutations, except for Pro12Ala, were conserved in the protein sequences of both FbiA and Ddn and their mycobacterial orthologs. The characterization of these mutations provides insights into the mechanisms of delamanid resistance, which may inform the development of optimized treatment strategies.

与delamanid抗性相关的基因突变与表型抗性之间的联系尚不清楚。我们利用同源重组和互补试验对结核分枝杆菌H37Rv菌株进行基因破坏，评估了delamanid耐药突变的表型效应。通过7H9微量稀释法测定最小抑菌浓度（MIC）来评估Delamanid耐药性。Sanger测序鉴定突变，并通过多个同源物序列比对预测突变残基的保守性。共检测到MIC≥0.025 μg/mL的分离株116株，其中ddn和fbiA基因突变。基于这些突变产生了等基因菌株。fbiA中含有Ala77Val、Gly81Ser、Asn25fs和Leu104Phe的ddn或fbiA等基因菌株mic≥0.8 μg/mL，提示耐药。与此相反，含有Pro12Ala的ddn等基因菌株的MIC为0.012 μg/mL，表现为敏感性，而含有fbiA的Gly96Asp的MIC为0.1 μg/mL，表现为抗性。除Pro12Ala外，所有突变在FbiA和Ddn及其分枝杆菌同源物的蛋白序列中都是保守的。这些突变的特征提供了对delamanid耐药机制的深入了解，这可能为优化治疗策略的发展提供信息。

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引用次数: 0

Chasing the “White Plague” in the Barbaricum of the Carpathian Basin – A case with tuberculous meningitis discovered in a Sarmatian-period (2nd–3rd-century-CE) storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary) 在喀尔巴阡盆地的野蛮地区追逐“白色瘟疫”——在匈牙利Kiskundorozsma-Daruhalom-dűlő II考古遗址的一个萨尔马提亚时期（公元2 - 3世纪）的储存坑中发现的一例结核性脑膜炎病例

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-12 DOI: 10.1016/j.tube.2025.102632

Ágota Madai , Marcos De Andrés Montero , Luca Kis , Csaba Szalontai , Anna Szigeti , István Major , Attila Kiss P. , Olga Spekker

The aim of our paper is to demonstrate a case (KD429) with tuberculous meningitis (TBM) from the 2nd–3rd‒century‒CE Carpathian Basin. The skeleton of KD429 was subject to a detailed macromorphological evaluation, focusing on the detection of pathological lesions likely related to tuberculosis (TB). It was the presence of endocranial alterations, especially the TB-specific granular impressions, based on which the diagnosis of TBM was established in KD429. Besides KD429, only eight cases with TB have been published from the Sarmatian-period (1st–5th centuries CE) Carpathian Basin. Reports of archaeological cases with TB, like KD429, can provide invaluable information about the spatio-temporal distribution of the disease in the past. Nonetheless, to get a more accurate picture about the burden that TB may have put on the Sarmatians, the systematic macromorphological (re-)evaluation of their osteoarchaeological series would be advantageous. Interestingly, the skeleton of KD429 was unearthed from not a grave-pit but a storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary). At the current state of research, the motive behind the exclusion of KD429 from the “normal” burial custom cannot be determined; therefore, it remains an open question whether their disease (TBM) played a role in it or not.

我们的论文的目的是证明一个病例（KD429）结核性脑膜炎（TBM）来自公元2 - 3世纪的喀尔巴阡盆地。对KD429的骨骼进行了详细的宏观形态学评估，重点是检测可能与结核病（TB）相关的病理病变。正是颅内改变的存在，特别是结核病特异性颗粒印象，在KD429中建立了TBM的诊断。除KD429外，萨尔马时期（公元1 - 5世纪）喀尔巴阡盆地仅报告了8例结核病例。关于结核病考古病例的报告，如KD429，可以提供有关该疾病过去时空分布的宝贵信息。尽管如此，为了更准确地了解结核病可能给萨尔马特人带来的负担，对他们的骨考古系列进行系统的宏观形态学（重新）评估将是有利的。有趣的是，KD429的骨架不是从坟墓中出土的，而是从Kiskundorozsma-Daruhalom-dűlő II（匈牙利）考古遗址的一个储存坑中出土的。在目前的研究状态下，无法确定将KD429排除在“正常”丧葬习俗之外的动机；因此，他们的疾病（TBM）是否在其中起作用仍然是一个悬而未决的问题。

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引用次数: 0