"Tuberculosis on the spot" - Discussion of a probable sternal tuberculosis from a late medieval cemetery from Hungary.

Investigations of non-adult remains are particularly suitable for finding epidemic periods in past populations. This study presents a probable unique example of osseous manifestation of tuberculosis on a child's skeletal remains from medieval Hungary. Between 2009 and 2011 the Field Service for Cultural Heritage excavated the exceptional cemetery of Perkáta - Nyúli-dulo in Hungary, with around 5000+ graves. The analysed skeleton (SNR 948) was located in the medieval (10-16th century) part of the cemetery. Besides the standard macroscopic pathological observation, we also performed radiographic analysis. The remains of the child (13-14 year-old) showed numerous skeletal lesions: the ribs have proliferative lesions (dense nodules) on the visceral surface of the shaft, lytic lesions with rounded edges occurred on the thoracic and lumbar vertebral bodies, and on the facies auricularis of the left ilium we can see pitting and new bone formation. What makes this pathological case exceptional is the significant change in the manubrium. It shows extensive osteolytic lesions, probably due to tuberculous osteomyelitis, which is a unique phenomenon in an archaeological context. This rare type of extra-spinal tuberculous osteomyelitis appears in less than 1% of cases with skeletal TB, and even less in case of children, according to modern medical literature. Although some cases of slight lesions on the manubrium have been described from an archaeological context, no such cases showing advanced lesions have been published so far. In the future, biomolecular analyses should be conducted as well, in order to confirm the presence of TB in this individual.

More than one millennium (2nd-16th century CE) of the White Plague in the Carpathian Basin - New cases, expanding knowledge.

The causative agent of tuberculosis is still a widespread pathogen, which caused the death of ca. 1.6 million people globally in 2021. The paleopathological study of human remains revealed the antiquity of the disease and its continuous presence throughout the history of humankind. The Carpathian Basin has always been a biocultural melting pot, since it has seen several migrations over the centuries, and served as a location of admixture and interaction for numerous populations of different cultures. Thus, this geographical territory is ideal for the examination of the coevolutionary processes of hosts and their pathogens. We aimed to reveal the spatial and temporal distribution of tuberculosis cases excavated inside the borders of Hungary between the 2nd and 16th centuries CE. We established a comprehensive database by collecting 114 already published cases and introducing 39 new cases. The involved cases include those that have been confirmed by different molecular methods, as well as possible infections that were identified based on the presence of macromorphological and radiological alterations. The progress of future molecular and paleopathological studies can be facilitated by our dataset, as it presents spatial and temporal information concerning the spread of the disease in the Carpathian Basin, as well as the biological profile and detailed paleopathological description of lesions illustrated by photo- and radiographs.

A rare case of calvarial tuberculosis from the Avar Age (8th century CE) cemetery of Kaba-Bitózug (Hajdú-Bihar county, Hungary) - Pathogenesis and differential diagnostic aspects.

The aim of our paper is to present and discuss in detail the bony changes indicative of tuberculosis (TB) that were identified in a skeleton (KB67), unearthed from grave 67 of the 8th-century-CE cemetery of Kaba-Bitózug (Hungary). Furthermore, to provide the differential diagnoses of the observed alterations, with special attention to the cranial osteolytic lesions. During the macro- and micromorphological examinations of KB67, the skull revealed three small, well-circumscribed, punched-out osteolytic lesions accompanied by endocranial granular impressions, abnormal blood vessel impressions, periosteal appositions, and cortical erosion. The postcranial skeleton exhibited osteolytic lesions, cortical remodelling and erosion, and signs of hypervascularisation in the spine. Based on the differential diagnosis of the cranial osteolytic lesions and their co-occurrence with endocranial and vertebral bony changes indicative of TB, they most likely resulted from tuberculous involvement of the frontal and left parietal bones. The morphologically established diagnosis was confirmed by a PCR analysis that provided evidence for the presence of Mycobacterium tuberculosis DNA in KB67. KB67, the first reported archaeological case with calvarial TB from the present-day territory of Hungary, gives us a unique insight into the occurrence of a rare manifestation of TB in the Avar Age of the Great Plain.

The development of musculoskeletal radiology for 100 years as presented in the pages of Acta Radiologica.

During the last 100 years, musculoskeletal radiology has developed from bone-only radiography performed by everyone to a dedicated subspecialty, still secure in its origins in radiography but having expanded into all modalities of imaging. Like other subspecialties in radiology, it has become heavily dependent on cross-sectional and functional imaging, and musculoskeletal interventions play an important role in tumor diagnosis and treatment and in joint diseases. All these developments are reflected in the pages in Acta Radiologica, as shown in this review.

An unusual case of childhood osteoarticular tuberculosis from the Árpádian Age cemetery of Gyorszentiván-Révhegyi tag (Gyor-Moson-Sopron county, Hungary).

Ancient human remains exhibiting bony changes consistent with osteoarticular tuberculosis (OATB) indicate that the disease has afflicted mankind for millennia. Nonetheless, not many pediatric OATB cases have been published in the paleopathological literature-from Hungary, only three cases have been described up to now. In our paper, we demonstrate a child (S0603) from the Árpádian Age cemetery of Gyorszentiván-Révhegyi tag (northwestern Hungary), who represents a unique case of OATB regarding both the pattern and severity of the observed bony changes. During the macromorphological and radiological investigations, the most serious alterations were discovered in the upper thoracic spine-the development of osteolytic lesions led to severe bone loss and consequent collapse and fusion of several adjacent vertebrae. The pathological process terminated in a sharp, rigid angular kyphosis. Disruption of the normal spine curvature resulted in consequent deformation of the whole thoracic wall-it became "rugby-ball-shaped". The overall nature and pattern of the detected alterations, as well as their resemblance to those of described in previously published archaeological and modern cases from the pre-antibiotic era indicate that they are most consistent with OATB. Based on the severity and extent of the lesions, as well as on the evidence of secondary healing, S0603 suffered from TB for a long time prior to death. Besides body deformation, OATB resulted in consequent disability in daily activities, which would have required regular and significant care from others to survive. It implies that in the Árpádian Age community of Gyorszentiván-Révhegyi tag, there was a willingness to care for people in need. Detailed archaeological case studies can give us a unique insight into the natural history and different presentations of OATB. Furthermore, they can provide paleopathologists with a stronger basis for diagnosing TB and consequently, with a more sensitive means of assessing TB frequency in past populations.

Oldest evidence of tuberculosis in Argentina: A multidisciplinary investigation in an adult male skeleton from Saujil, Tinogasta, Catamarca (905-1030 CE).

The Mycobacterium tuberculosis complex (MTC) has affected South American populations since ca. 200 years BCE. In Argentina, possible cases date from ca. 1000-1400 Common Era (CE). This paper describes the oldest (905-1030 CE) confirmed case of tuberculosis (TB) in a young adult male from Lomitas de Saujil (Tinogasta, Catamarca, Argentina). Osteolytic lesions on the bodies of the lower spine were macroscopically and radiographically identified. Bilateral new bone formation was seen on the visceral vertebral third of several ribs and in long bones, compatible with hypertrophic osteoarthropathy. Representative rib and hand bones gave profiles for MTC-specific C27-C32 mycocerosic acid lipid biomarkers; these were strongest in one heavily-lesioned lower rib, which also had MTC-diagnostic C76-C89 mycolic acids and positive amplification of MTC-typical IS6110 aDNA fragments. During the first millennium CE, the intense social interaction, the spatial circumscription of villages among the pre-Hispanic societies in the mesothermal valleys of Catamarca and the fluid contacts with the Eastern lowlands, valleys and puna, were factors likely to favor disease transmission. It is proposed that TB arrived from northern Chile and dispersed towards the northeast into the Yocavil valley, where several cases of TB infection were macroscopically identified for a later chronology.

A brief history of tuberculosis in the Czech Lands.

Tuberculosis currently remains a serious medical problem, therefore increased attention is being paid to this disease. Paleopathological studies focused on the monitoring of morbid changes in skeletal remains of historical populations facilitate a detailed study of the development of this disease. They provide direct evidence of the existence of tuberculosis and its past forms. In addition to literary and iconographic sources, the present study is focused on recording the findings of bone tuberculosis in historical osteological sets from the Czech Lands and is the starting point for their detailed review. Approximately 76 cases of bone tuberculosis from the Czech Lands have been published and more or less reliably documented from 20 archeological sites dated back from the Eneolithic to the modern period.

A 6500-year-old Middle Neolithic child from Pollera Cave (Liguria, Italy) with probable multifocal osteoarticular tuberculosis.

Clear skeletal evidence of prehistoric tuberculosis (TB) is rare, especially in children. We describe and differentially diagnose the pathological changes displayed by a five-year-old child, Pollera 21 (PO21) dated to the Middle Neolithic of Liguria (Italy), or 5740±30 BP (Beta-409341; 6635-6453cal BP, 2σ, OxCal 4.2). PO21 shows a number of osteoarticular lesions, mainly of a lytic nature with very little bone proliferation: the vertebral column, the shoulder and pelvic girdles, and the ribcage are involved. Given the nature and pattern of the lesions, we propose a diagnosis of multifocal (or multiple) bone TB. Attempts to detect TB aDNA through molecular analysis gave negative results, but this alone is not sufficient to prove that PO21 was not infected with TB. The lesions observed in PO21 share similarities with other published evidence, such as spinal and joint involvement, and disseminated cyst-like lesions. Conversely, PO21 does not show diffuse bone deposition, such as hypertrophic osteoarthropathy (HOA) or endocranial modifications such as serpens endocrania symmetrica (SES). PO21 adds to our knowledge of patterns of TB manifestation in archaeological skeletal remains, which is especially important considering the variability in types and patterns of osteoarticular lesions seen today in people with TB.

Dr. Józef Aleksiewicz Activity in Support of the Development of Orthopedics and Rehabilitation in Iwonicz-Zdrój (1921-1957).

Based on source materials in the possession of Józef Aleksiewicz family (typescripts, manuscripts, photographs, other documents) and articles published in professional medical journals and newspapers, the authors present the contribution of Dr. J. Aleksiewicz to the development of orthopedics and rehabilitation in Iwonicz-Zdrój. In May 1921, he was appointed Surgeon General of the Spa Commission in Iwonicz-Zdrój. After holding several scholarly trips abroad in 1925 to sanatoriums treating cases of osteo-articular tuberculosis, he commenced the construction of "Sanato", a modern sanatorium. Opened in 1930, it was the only center in Poland treating osteo-articular tuberculosis in a spa setting. It was the first orthopedic rehabilitation center in what is now Podkarpackie Voivodship offering diagnostic work-up, surgery and conservative treatment of osteo-articular tuberculosis in children. Modelled on the best Western centers, Dr. Aleksiewicz widely employed physical methods, such as Swedish therapeutic gymnastics, mechanotherapy, massage, physical therapy and hydrotherapy.

Activity of Dr Józef Aleksiewicz, PhD, Towards the Development of Orthopedics and Rehabilitation in Lviv in the Years 1912-1930.

The article describes the work of Dr Aleksiewicz towards the development of orthopedics and rehabilitation in Lviv in the years 1912-1930 based on source materials belonging to his family and articles published in medical journals and daily press. In 1919, Dr Aleksiewicz established a Surgical and Orthopedic Department and a factory of prostheses at the Disabled House in Lviv. He also formed a 200-bed division for the visually impaired with basket- and comb-making workshops as well as massage and typing courses. It was an innovative undertaking aiming to provide surgical treatment, orthopaedic aids and rehabilitation for victims of World War I. From 1919, Dr Aleksiewicz ran his Private Orthopedic Clinic with Factory of orthopaedic aids and pro-stheses" at 2 Friedrichów St. in Lviv. He specialised in therapy of surgical tuberculosis, fractures, dislocations and abnormal spinal curvatures. His work in Lviv in the period 1912-1930 undeniably contributed to the development of orthopaedics and rehabilitation, which were new medical specialties at the time.

The Early Mediaeval manorial estate of Gars/Thunau, Lower Austria: An enclave of endemic tuberculosis?

In recent decades, an increasing number of studies have aimed to shed light on the origin and spread of tuberculosis in past human populations. Here we present the results of a systematic palaeodemographic and palaeopathological survey of the Early Mediaeval population of Gars/Thunau (Lower Austria), which - at this stage - includes 373 individuals recovered at two archaeological sub-sites: a fortified settlement (including a necropolis) at the top of a hill - probably reserved for social and military elites; and a large riverine settlement at the foot of the hill, a so-called 'suburbium', where burials and an area of 'industrial' character were discovered. We recorded a great number of pathological alterations and a variety of 'classical' features of tuberculosis, such as vertebral destructions (Pott's disease) and joint destructions, and other pathological (unspecific) features probably linked with Mycobacterium tuberculosis infection (e.g. new bone formation at the inner surface of the ribs, endocranial alterations in the form of 'pits', and new bone formation at the cranial base). We hypothesize that the two contemporaneous (∼900-1000 AD) populations of Gars/Thunau differed not only in their social affiliation/condition, but also in the type and frequencies of their population-density-related infectious diseases (in particular tuberculosis). Moreover, we investigated the molecular genetic evidence of the causative organism in a few selected immatures exhibiting pathological changes at the inner wall of the cranium and discuss these findings in regard to the macroscopic features observed. Finally, we analysed carbon and nitrogen stable isotopes of both populations and strontium isotope ratios of the hill-top inhabitants in order to reconstruct certain aspects of diet and mobility to test our hypothesis concerning the specific social and/or military character of the site.

Tuberculosis in Late Neolithic-Early Copper Age human skeletal remains from Hungary.

Alsónyék-Bátaszék in Southern Hungary is one of the largest late Neolithic settlements and cemeteries excavated in Central Europe. In total, 2359 burials from the Late Neolithic - Early Copper Age Lengyel culture were found between 2006 and 2009 [1]. Anthropological investigations previously carried out on individuals from this site revealed an interesting paleopathological case of tuberculosis in the form of Pott's disease dated to the early 5(th) millennium BC. In this study, selected specimens from this osteoarcheological series were subjected to paleomicrobiological analysis to establish the presence of MTBC bacteria. As all individuals showing clear osteological signs of TB infection belonged to a single grave group, 38 individuals from this grave group were analysed. The sample included the case of Pott's disease as well as individuals both with and without osseous TB manifestations. The detection of TB DNA in the individual with Pott's disease provided further evidence for the occurrence of TB in Neolithic populations of Europe. Moreover, our molecular analysis indicated that several other individuals of the same grave group were also infected with TB, opening the possibility for further analyses of this unique Neolithic skeletal series.

AG 85, a major secretion protein of Mycobacterium tuberculosis, can be identified in ancient bone.

For the confirmation of Ag 85 in ancient and recent ECM of native macerated human bone, five cases were investigated. In three individuals, highly positive results for Ag 85 were identified in Western blot: 1) a male from Arzhan, South Siberia, dating from the 7th century BC, 2) a male from Kirchberg in Hesse, Germany, dating from the 10th - 12th century AD and 3) a recent female with a proven diagnosis of TB. As a negative control, a recent male is presented who did not suffer from TB. In another recent male, Ag 85 could be identified only very weakly. From cases in the literature it is well-known that highly positive results for Ag 85 indicate active TB, however, weakly positive results indicate a silent initial infection with Mtb. Thus, apparently, also in ancient individuals, it might well be possible to differentiate between diseased persons and disease carriers using paleoproteomic techniques.

Human tuberculosis predates domestication in ancient Syria.

The question of pre-neolithic tuberculosis is still open in paleopathological perspective. One of the major interests is to explore what type of infection could have existed around the early stage of animal domestication. Paleopathological lesions evoking skeletal TB were observed on five human skeletons coming from two PPNB sites in Syria, which belongs to the geographical cradle of agriculture. These sites represent respectively pre-domestication phase (Dja'de el Mughara, Northern Syria, 8800-8300 BCE cal.) and early domestication phase (Tell Aswad, Southern Syria, 8200-7600 BCE cal.). MicroCT scan analyses were performed on two specimens (one per site) and revealed microscopic changes in favor of TB infection. Detection of lipid biomarkers is positive for two specimens (one per site). Initial molecular analysis further indicates the presence of TB in one individual from Dja'de. Interestingly, no morphological evidence of TB was observed on animal remains of wild and newly domesticated species, discovered in these sites. These observations strongly suggest the presence of human tuberculosis before domestication and at its early stages.

Two positive tuberculosis cases in the late Nigrovits family, 18th century, Vác, Hungary.

Two mummies of the Hungarian mummy collection from Vác were the subjects of anthropological, paleopathological, radiological, paleomicrobiological, paleohistological and paleoproteomic studies. Both individuals belonged to the same family. The father, József Nigrovits (No 29), died at the age of 55 on the 11th of November 1793; his son, Antal Nigrovits (No 54), died on the 16th of July 1803, at the age of 22. They lived in the 18th century in Vác, a small town in northern Hungary. The macroscopic examination of the son showed a severely deformed neck and back region; the father has no visible mark of any illnesses. As earlier researches showed that tuberculosis was widespread in the community, the etiology of these deformities was examined. The paleomicrobiological results found that both individuals were infected with tuberculosis. Although they suffered from TB, the CT scan data of the bodies and their 3D reconstructions showed no skeletal evidence of tuberculosis. The deformity of the son turned to be a developmental abnormality of unknown origin, but no Pott's gibbus was present.

Tuberculosis and survival in past populations: A paleo-epidemiological appraisal.

Historical assessments of the last two centuries consistently placed tuberculosis as the leading cause of mortality. However, for earlier periods, we can only calculate the frequencies of archaeological bone lesions, which tell us little about the real impact of the disease on mortality. These lesions are usually observed in individuals who have developed immune resistance, which is visible as healed osteo-articular lesions. This study aimed to test the differential impacts of tuberculosis, cribra orbitalia and cribra femoris on adult survival and sex-based survival. We analyzed 28 French adult samples from the Antiquity and the Early Middle Ages. The age-at-death of 1480 individuals was estimated using cementochronology. Survival curves and median age-at-death were calculated to test new hypotheses that challenge the parasitic and deficiency theories of bone stress markers. Comparisons between carriers and non-carriers provided new information concerning the plausible causes of bone stress markers related to infections and TB. The most likely hypothesis is skeletal demineralization and osteoclastic resorption, which are usually observed close to tubercular granuloma or distant from active lesions. The bone marrow niche of Mycobacterium tuberculosis within CD271(+) BM-MSCs stem cells is the proposed explanation for the localized cortical resorption that is observed in bone stress markers.

Lipid biomarkers provide evolutionary signposts for the oldest known cases of tuberculosis.

Studies on the evolution of tuberculosis, and the influence of this disease on human and animal development and interaction, require the accumulation of indisputable biomarker evidence. Ideally, the determination of full genomes would provide all the necessary information, but for very old specimens DNA preservation may be compromised and only limited DNA amplification may be a possibility. Mycobacterium tuberculosis is characterised by the presence of unusual cell envelope lipids, with specific biomarker potential. Lipid biomarker recognition has been decisive in pinpointing the oldest known cases of human and animal tuberculosis; the former are a woman and child from a pre-pottery settlement at Atlit-Yam, Israel (∼9,000 ka) and the latter is an extinct Bison antiquus from Natural Trap Cave, Wyoming (∼17,000 ka). Including some new data, it is demonstrated how analysis of a combination of mycolic, mycocerosic and mycolipenic acid and phthiocerol biomarkers provide incontrovertible evidence for tuberculosis in these landmark specimens.

Tuberculosis infection in a late-medieval Hungarian population.

The AD 16-17(th) century skeletal series from Bácsalmás-Óalmás (southern Hungary) has already been the subject of previous paleopathological studies concerning TB-related bone lesions. Due to recent development of macroscopic and molecular diagnostic methods in paleopathology and paleomicrobiology, a five-year international research program was recently started in order to re-evaluate the TB-related lesions in the complete series, comprising 481 skeletons. The skeletal material of these individuals was examined using macromorphological methods focusing on both classical/advanced stage skeletal TB alterations and atypical/early-stage TB lesions. Paleomicrobial analysis was used to study the presence of Mycobacterium tuberculosis complex (MTBC) DNA both in morphologically positive and negative cases. Samples were tested for the repetitive element IS6110 and further characterized by spoligotyping. In the whole series, 283 possible cases of TB infections were identified based on morphological alterations. Skeletal samples of eighteen individuals, morphologically positive as well as negative cases, were selected for further biomolecular examinations. Among them, seven individuals were PCR positive for the repetitive IS6110 sequence of the MTBC genome. Compared to the few cases of TB from the Bácsalmás-Óalmás series previously described, a much higher prevalence of MTBC infected skeletons was revealed in this study. The atypical/early stage skeletal lesions occurred significantly more frequently than the so-called classical alterations. Paleomicrobial analysis confirmed a prevalence of MTBC infection nearing 40% among the selected sample. Preliminary results also indicated better preservation of bacterial DNA in the compact layer of long bones and teeth, while spoligotyping suggested infection by different MTBC pathogens.

Tuberculosis origin: The Neolithic scenario.

This paper follows the dramatic changes in scientific research during the last 20 years regarding the relationship between the Mycobacterium tuberculosis complex and its hosts - bovids and/or humans. Once the M. tuberculosis and Mycobacterium bovis genomes were sequenced, it became obvious that the old story of M. bovis evolving into the human pathogen should be reversed, as M. tuberculosis is more ancestral than M. bovis. Nevertheless, the timescale and geographical origin remained an enigma. In the current study human and cattle bone samples were examined for evidence of tuberculosis from the site of Atlit-Yam in the Eastern Mediterranean, dating from 9250 to 8160 (calibrated) years ago. Strict precautions were used to prevent contamination in the DNA analysis, and independent centers used to confirm authenticity of findings. DNA from five M. tuberculosis genetic loci was detected and had characteristics consistent with extant genetic lineages. High performance liquid chromatography was used as an independent method of verification and it directly detected mycolic acid lipid biomarkers, specific for the M. tuberculosis complex. These, together with pathological changes detected in some of the bones, confirm the presence of the disease in the Levantine populations during the Pre-pottery Neolithic C period, more than 8000 years ago.