Histiocytosis - cutaneous manifestations of hematopoietic neoplasm and non-neoplastic histiocytic proliferations.

Histiocytoses are rare disorders characterized by the accumulation of cells derived from macrophages, dendritic cells or monocytes in various tissues. There is a broad spectrum of disease manifestations with some subtypes commonly showing skin lesions, while in others, the skin is rarely involved. Here, we describe cutaneous manifestations of histiocytoses belonging to the Langerhans group (L group), the group of cutaneous and mucocutaneous histiocytoses (C group) and the group of Rosai-Dorfman disease (RDD) and related histiocytoses (R group) according to the current classification. Characteristic clinical presentations noted were a rust-brown colour or xanthomatous aspect in many cases of histiocytoses. Histological criteria for differentiation are described. Immunohistochemistry shows positivity for S100 and CD1a in Langerhans-cell histiocytoses (LHCH) of the L group, while CD68 positivity with S100 and CD1a negativity are typical in histiocytoses of the C group of cutaneous and mucocutaneous histiocytoses. RDD in the R group shows positivity for S100 and CD68, while CD1a is negative. We further review the pathogenesis of LHCH based on insights on the central role of the mitogen-activated protein (MAPK) kinase pathway. Common mutations in various histiocytic populations of diverse ontogeny and at different stages of differentiation may be responsible for the diverse clinical picture of this neoplastic entity. For histiocytoses of the C group and R group, a reactive origin is discussed with the exception of the disseminated form of juvenile xanthogranuloma. We suggest exploring the role of an origin from skin residing histiocytes for the isolated cutaneous manifestation in some types. With regard to therapeutic options, skin-directed therapies are the first choice in limited disease, while systemic chemotherapy has traditionally been used in extensive disease. In Langerhans-cell histiocytoses and related entities, therapy by BRAF inhibition has led to a breakthrough especially in patients with an activation of the MAPK pathway.

A Compression Kit of a Stocking and Three Superimposed Leggings Is Easy to Don and Dose Adjustable.

BACKGROUND: Forty percent of patients with chronic venous insufficiency (CVI) do not wear their indicated and prescribed compression stockings. Difficulties in donning and a feeling of constraint are the most common reasons for non-adherence. OBJECTIVE: The aim was to develop a compression stocking system that is easy to don and dose adjustable. METHODS: A modular compression stocking kit composed of an understocking and three superimposable leggings (SLLLs) was developed. Substocking pressures (P) at the thinnest part above the ankle (cB level) were 17 mm (understocking) + 15 + 10 + 10 mmHg (3 superimposed leggings; Hatra method). Twenty healthy subjects and 20 patients over 65 years with CVI donned the SLLL compression kit. P was measured in vivo (Picopress method) at the transition of the Achilles tendon to the calf muscle (level cB1) during rest and ankle movements (DSI; dynamic stiffness index) and compared with a strong compression stocking of 40 mmHg (S40). RESULTS: Twenty (20/20) patients aged over 65 with CVI (C4-6) successfully donned the SLLL compression kit without aid, compared with 12 (12/20) who were able to don the S40 without aid (p = .02). In vivo resting P at level cB1 was 34.3 mmHg (SLLL) compared with 37.3 mmHg (S40) (p = .1). The DSI was 16.1 (SLLL) compared with 17.9 (p = .79; S40; CVI group). CONCLUSION: The physical properties of the SLLL compression stocking kit correspond to the characteristics of a strong stocking at rest and exercise (DSI). The donning success rate is excellent (100%). A further potential advantage is that the SLLL leg compression kit is dose adjustable, according to indication or patient tolerance. Wearing comfort over periods of several days and clinical effectiveness need to be investigated in future trials.

Three-dimensional evaluation of cyclic displacement in single-row and double-row rotator cuff reconstructions under static external rotation.

BACKGROUND: The double-row suture bridge repair was recently introduced and has demonstrated superior biomechanical results and higher yield load compared with the traditional double-row technique. It therefore seemed reasonable to compare this second generation of double-row constructs to the modified single-row double mattress reconstruction. HYPOTHESIS: The repair technique, initial tear size, and tendon subregion will have a significant effect on 3-dimensional (3D) cyclic displacement under additional static external rotation of a modified single-row compared with a double-row rotator cuff repair. STUDY DESIGN: Controlled laboratory study. METHODS: Rotator cuff tears (small to medium: 25 mm; medium to large: 35 mm) were created in 24 human cadaveric shoulders. Rotator cuff repairs were performed as modified single-row or double-row repairs, and cyclic loading (10-60 N, 10-100 N) was applied under 20° of external rotation. Radiostereometric analysis was used to calculate cyclic displacement in the anteroposterior (x), craniocaudal (y), and mediolateral (z) planes with a focus on the repair constructs and the initial tear size. Moreover, differences in cyclic displacement of the anterior compared with the posterior tendon subregions were calculated. RESULTS: Significantly lower cyclic displacement was seen in small to medium tears for the single-row compared with double-row repair at 60 and 100 N in the x plane (P = .001) and y plane (P = .001). The results were similar in medium to large tears at 100 N in the x plane (P = .004). Comparison of 25-mm versus 35-mm tears did not show any statistically significant differences for the single-row repairs. In the double-row repairs, lower gap formation was found for the 35-mm tears (P ≤ .05). Comparison of the anterior versus posterior tendon subregions revealed a trend toward higher anterior gap formation, although this was statistically not significant. CONCLUSION: The tested single-row reconstruction achieved superior results in 3D cyclic displacement to the tested double-row repair. Extension of the initial rupture size did not have a negative effect on the biomechanical results of the tested constructs. CLINICAL RELEVANCE: Single-row repairs with modified suture configurations provide comparable biomechanical strength to double-row repairs. Furthermore, as increased gap formation in the early postoperative period might lead to failure of the construct, a strong anterior fixation and restricted external rotation protocol might be considered in rotator cuff repairs to avoid this problem.

Comparable biomechanical results for a modified single-row rotator cuff reconstruction using triple-loaded suture anchors versus a suture-bridging double-row repair.

PURPOSE: To compare the biomechanical properties and footprint coverage of a single-row (SR) repair using a modified suture configuration versus a double-row (DR) suture-bridge repair in small to medium and medium to large rotator cuff tears. METHODS: We created 25- and 35-mm artificial defects in the rotator cuff of 24 human cadaveric shoulders. The reconstructions were performed as either an SR repair with triple-loaded suture anchors (2 to 3 anchors) and a modified suture configuration or a modified suture-bridge DR repair (4 to 6 anchors). Reconstructions were cyclically loaded from 10 to 60 N. The load was increased stepwise up to 100, 180, and 250 N. Cyclic displacement and load to failure were determined. Furthermore, footprint widths were quantified. RESULTS: In the 25-mm rupture, ultimate load to failure was 533 ± 107 N for the SR repair and 681 ± 250 N for the DR technique (P ≥ .21). In the 35-mm tear, ultimate load to failure was 792 ± 122 N for the SR reconstruction and 891 ± 174 N for the DR reconstruction (P ≥ .28). There were no statistically significant differences for both tested rupture sizes. Cyclic displacement showed no significant differences between the tested configurations at 60 N (P = .563), 100 N (P = .171), 180 N (P = .211), and 250 N (P = .478) for the 25-mm tear. For the 35-mm tear, cyclic displacement showed significantly lower gap formation for the SR reconstruction at 180 N (P = .037) and 250 N (P = .020). No significant differences were found at 60 N (P = .296) and 100 N (P = .077). A significantly greater footprint width (P = .028) was seen for the DR repair (16.2 mm) compared with the SR repair (13.8 mm). However, both reconstructions were able to achieve complete footprint coverage compared with the initial footprint. CONCLUSIONS: The tested SR repair using a modified suture configuration was similar in load to failure and cyclic displacement to the DR suture-bridge technique independent of the tested initial sizes of the rupture. The tested DR repair consistently restored a larger footprint than the SR method. However, both constructs achieved complete footprint coverage. CLINICAL RELEVANCE: SR repairs with modified suture configurations might combine the biomechanical advantages and increased footprint coverage that are described for DR repairs without increasing the overall costs of the reconstruction.

Anatomy of the superior glenohumeral ligament.

BACKGROUND: The aim of the present study was to give a detailed, anatomical description of the superior glenohumeral ligament and its relationship with the neighbouring structures in the rotator interval. METHOD: Twenty-seven cadaveric shoulder specimens were dissected in fine detail to describe superior glenohumeral ligament and additional histologic examination was performed. RESULTS: The superior glenohumeral ligament is a constant, gross anatomic structure that was present in all of twenty-seven investigated specimens. The fibers of the superior glenohumeral ligament could be divided into two groups - the oblique and direct fibers. The direct fibers of the superior glenohumeral ligament arise from the glenoid labrum, run parallel with the tendon of the long head of the biceps brachii towards the lesser tubercle, which they also partly insert onto. The rest of the direct fibers course into the bottom of the bicipital groove and bridge over it, forming the superior part of the transverse humeral ligament. The oblique fibers arise from the supraglenoid tubercle, run over the intraarticular part of the tendon of the long head of the biceps brachii and insert below the coracohumeral ligament into the humeral semicircular ligament. CONCLUSION: Due to its anatomic composition and tight connection with the neighboring articular structures, the superior glenohumeral ligament is involved in the stabilizing mechanisms of the intraarticular part of the tendon of the long head of the biceps brachii and plays an important role in the variety of clinical disorders that occur within the rotator interval.

Effect of a biplanar osteotomy on primary stability following high tibial osteotomy: a biomechanical cadaver study.

Open-wedge high tibial osteotomy (HTO) is becoming increasingly popular for the treatment of varus gonarthrosis in the active patient. The various implants used in HTO differ with regard to its design, the fixation stability and osteotomy technique. It is assumed that the combination of a plate fixator with a biplanar, v-shaped osteotomy supports bone healing. So far, there are no biomechanical studies that quantify the stabilizing effect of a biplanar versus uniplanar osteotomy. We hypothesized that a significant increase in primary stability of bone-implant constructs is achieved when using a biplanar as opposed to a uniplanar osteotomy. Twenty-four fresh-frozen human tibiae were mounted in a metal cylinder, and open-wedge osteotomy (12 mm wedge size) was performed in a standardized fashion. Proximal and distal tibial segments were marked with tantalum markers of 0.8 mm diameter. Two different plates with locking screws were used for fixation: a short spacer plate (group 1, n = 12) and a plate fixator (group 2, n = 12). In six specimens of each group, a biplanar V-shaped osteotomy with a 110 degrees angulated anterior cut behind the tuberosity parallel to the ventral tibial shaft axis was performed. In the remaining six specimens of each group, a simple uniplanar osteotomy was performed in an oblique fashion. Axial compression of the tibiae was performed using a material testing machine under standardized alignment of the loading axis. Load-controlled cyclical staircase loading tests were performed. The specimens were radiographed simultaneously in two planes together with a biplanar calibration cage in front of a film plane with and without load after each subcycle. Radiostereometry allowed for serial quantification of plastic and elastic micromotion at the osteotomy site reflecting the stability provided by the combination of implant and osteotomy technique. No significant additional stabilizing effect of a biplanar osteotomy in craniocaudal and mediolateral plane was found. However, additional stability was achieved in anteroposterior (AP) and all rotational planes in those specimens fixated with a short spacer plate. In this biomechanical set-up with axial load, the additional stabilizing effect of a biplanar osteotomy did not come into effect in the presence of a long and rigid plate fixator. However, biplanar osteotomy increased the fixation stability significantly in AP and rotational planes when a short spacer plate was used. Clinically, the biplanar osteotomy promotes bone healing regardless of the implant used. Biomechanically, biplanar osteotomy is advantageous for shorter plate designs to increase primary stability of the bone-implant construct.

Atypical Toxoplasma gondii genotypes identified in oocysts shed by cats in Germany.

A total of 18,259 feline faecal samples from cats in Germany were collected and analysed for the presence of Toxoplasma gondii oocysts between June 2007 and December 2008. The proportion of T. gondii-positive samples collected between January and June was significantly lower than between July and December. The age of cats shedding T. gondii oocysts was not significantly different from the age of negative control cats. Forty-six T. gondii-positive samples were genetically characterised using nine PCR-restriction fragment length polymorphism (RFLP) markers which included newSAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1 and Apico. In addition, 22 isolates that had already been partially characterised in a previous study were further typed using PCR-RFLP markers c22-8, c29-2, L358, PK1 and Apico. Genotyping of the 68 isolates revealed that the majority of T. gondii isolates (n=54) had Type II patterns at all loci but displayed a Type I pattern at the Apico locus. Three isolates displayed Type II patterns at all loci, including the Apico locus. In addition, we detected one isolate with clonal Type III patterns at all loci and three isolates with atypical and mixed genotypes. Seven isolates could not be fully genotyped. One of those isolates displayed alleles of both Types I and II at the Apico locus. To our knowledge this is the first description of the presence of T. gondii genotypes different from the clonal Types I, II and III in the faeces of naturally infected cats.

The spiral glenohumeral ligament: an open and arthroscopic anatomy study.

PURPOSE: The purpose of this study was to visualize arthroscopically and to describe the micro- and macroscopic anatomy of the poorly known ligament of the anterior capsule of the glenohumeral joint: the so-called ligamentum glenohumerale spirale (spiral GHL). METHODS: Twenty-two fresh shoulder joints were dissected, and the anatomy of the anterior capsular structures (the spiral GHL, the middle glenohumeral ligament [MGHL], and the anterior band as well as the axillary part of the inferior glenohumeral ligament [AIGHL and AxIGHL, respectively]) was investigated. For arthroscopic visualization, 30 prospective arthroscopic clinical cases and 19 retrospective video clips of the patients who had an arthroscopic shoulder procedure with a normal subscapularis tendon, labrum, and anterior joint capsule were evaluated. RESULTS: The spiral GHL and the AxIGHL were present in all 22 shoulder specimens. The AIGHL was not recognizable on the extra-articular side of the joint capsule. The MGHL was absent in 3 shoulder specimens (13.6%). Arthroscopically, the spiral GHL was found in 22 (44.9%), the MGHL in 43 (87.8%), and the AIGHL in 46 (93.9%) of the cases. The spiral GHL arose from the infraglenoid tubercle and the triceps tendon and inserted together with subscapularis tendon onto the lesser tubercle of the humerus. CONCLUSIONS: Our results suggest that extra-articular structure of the spiral GHL is consistently recognizable, the upper part of which can be arthroscopically identified. CLINICAL RELEVANCE: Advanced anatomic knowledge of the spiral GHL helps the clinician better understand the normal anatomy of the shoulder joint and also helps to differentiate it from pathologic findings of the patient. The biomechanical importance of the spiral GHL and its connection with shoulder pathology remains to be determined in further studies.

Magnetic resonance imaging and correlative gross anatomy of the ligamentum semicirculare humeri (rotator cable).

The purpose of this study has been to demonstrate macroscopic and MRI anatomy of the so-called rotator cable, otherwise known as the ligamentum semicirculare humeri (LSCH) of the superior shoulder joint capsule. Twelve shoulder joints from eight cadavers were dissected; seven of which, from four of the cadavers, were studied using MR arthrography (1.5-Tesla device Somatom Symphony, Siemens, Erlangen, Germany) prior to dissection. The MRI protocol included T1WI, PDWI, and DESS 3D WI standard sequences. The results of MRI were compared with gross anatomic dissection findings. The macroscopically recognizable capsular bundle of LSCH fibers was identified by anatomic dissection in all specimens. On MRI, the entire ligament or parts of it could be identified in six of seven cases. It was best visualized on axial images. In the evaluation of magnetic resonance images of superior shoulder joint structures, additional knowledge on the anatomy of the LSCH can be used by the radiologist to facilitate detailed interpretation of the shoulder MRI.

Pro- and anti-apoptotic activities of protozoan parasites.

During infection, programmed cell death, i.e. apoptosis, is an important effector mechanism of innate and adaptive host responses to parasites. In addition, it fulfils essential functions in regulating host immunity and tissue homeostasis. Not surprisingly, however, adaptation of parasitic protozoa to their hosts also involves modulation or even exploitation of cell death in order to facilitate parasite survival in a hostile environment. During recent years, considerable progress has been made in our understanding of apoptosis during parasitic infections and there is now convincing evidence that apoptosis and its modulation by protozoan parasites has a major impact on the parasite-host interaction and on the pathogenesis of disease. This review updates our current knowledge on the diverse functions apoptosis may fulfil during infections with diverse protozoan parasites including apicomplexans, kinetoplastids and amoebae. Furthermore, we also summarize common mechanistic themes of the pro- and anti-apoptotic activities of protozoan parasites. The diverse and complex effects which parasitic protozoa exert on apoptotic cell death within the host highlight fascinating interactions of parasites and their hosts. Importantly, they also stress the importance of further investigations before the modulation of host cell apoptosis can be exploited to combat parasitic infections.

Apoptosis and its modulation during infection with Toxoplasma gondii: molecular mechanisms and role in pathogenesis.

Infection with the obligate intracellular protozoan Toxoplasma gondii leads to lifelong persistence of the parasite in its mammalian hosts including humans. Apoptosis plays crucial roles in the interaction between the host and the parasite. This includes innate and adaptive defense mechanisms to restrict intracellular parasite replication as well as regulatory functions to modulate the host's immune response. Not surprisingly, however, T. gondii also extensively modifies apoptosis of its own host cell or of uninfected bystander cells. After infection, apoptosis is triggered in T lymphocytes and other leukocytes, thereby leading to suppressed immune responses to the parasite. T cell apoptosis may be largely mediated by Fas engagement but also occurs independently of Fas under certain conditions. Depending on the magnitude of T cell apoptosis, it is either associated with unrestricted parasite replication and severe pathology or facilitates a stable parasite-host-interaction. However, T. gondii has also evolved strategies to inhibit host cell apoptosis. Apoptosis is blocked by indirect mechanisms in uninfected bystander cells, thereby modulating the inflammatory response to the parasite. In contrast, inhibition of apoptosis in infected host cells by direct interference with apoptosis-signaling cascades is thought to facilitate the intracellular development of T. gondii. Blockade of apoptosis by intracellular parasites may be achieved by different means including interference with the caspase cascade, increased expression of antiapoptotic molecules by infected host cells, and a decreased activity of the poly(ADP-ribose) polymerase. The intriguing dual activity of T. gondii to both promote and inhibit apoptosis requires a tight regulation to promote a stable parasite host-interaction and establishment of persistent toxoplasmosis.

Novel management strategy for patients with suspected pulmonary embolism.

AIMS: A simple management strategy is required for patients with acute pulmonary embolism which allows a rapid and reliable diagnosis in order to start timely and appropriate treatment. METHODS AND RESULTS: Two hundred and four consecutive patients with suspected pulmonary embolism were managed according to a standardized protocol based on the clinical pretest probability and the initial haemodynamic presentation (shock index=heart rate divided by systolic blood pressure). Patients with a high pretest probability and a positive shock index (> or =1) (n=21) underwent urgent transthoracic echocardiography. Based on the presence or absence of right ventricular dysfunction, reperfusion treatment was initiated immediately. Patients with a negative shock index (<1) (n=183) underwent diagnostic evaluation including pretest probability, D-dimer, and spiral computed tomography (CT) as first-line tests. Echocardiography was performed only when a central pulmonary embolism was found in the spiral CT(n=33). According to our strategy, 98 patients met the diagnostic criteria of pulmonary embolism: 75 patients (all shock index <1) were treated with heparin alone, 16 (seven had a shock index > or =1) with thrombolysis, four (all shock index > or =1) with catheter fragmentation, and three (all shock index > or =1) with surgical embolectomy. The all-cause mortality rate at 30 days was 5%, and at 6 months 11%. Right ventricular dysfunction on baseline echocardiography was not associated with a higher mortality rate at 6 months (logrank 2.4, P=0.12). CONCLUSIONS: The novel management strategy for patients with suspected pulmonary embolism resulted in a rapid diagnosis and treatment with a low 30-day mortality. In patients with pulmonary embolism and a positive shock index, time-consuming imaging tests can be avoided to reduce the risk of sudden death and not to delay reperfusion therapy.

Macroscopical anatomy of the so-called "rotator interval". A cadaver study on 19 shoulder joints.

The triangular capsular space between the insertion tendons of the Mm. supraspinatus and subscapularis--the "rotator interval", can be divided into lateral, medio-superior and medio-inferior parts. The lateral part of the capsule is strengthened by the "Lig. semicirculare humeri" and the anterior fibres of the M. supraspinatus tendon. The Ligg. coracohumerale and "coracoglenoidale" are the macroscopical elements of the medio-superior part. The medio-inferior part of the "rotator interval" is reinforced by the Ligg. glenohumeralia superius et medium. The key ligament of the "rotator interval" is the "Lig. semicirculare humeri". Laterally it ensures the insertion of the anterior fibres of the M. supraspinatus tendon above the Lig. transversum humeri and on the Tubercula majus et minus. Medially it is the place of attachment of the Lig. coracohumerale and oblique fibres of the Lig. glenohumerale superius. The "rotator interval" is not a weak capsular region but a complex network of macroscopically recognizable tendinous and ligamentous structures.

Toxoplasmosis: a persisting challenge.

The sixth biennial International Congress on Toxoplasmosis, organized by Uwe Gross (University of Göttingen, Germany), was held on 21-25 May 2001 in Freising, Germany. The first meeting of this kind in 1990 was attended by only 26 investigators and this year there were 115 participants covering various research topics including the immunology, epidemiology, cellular and molecular biology of Toxoplasma gondii.

Intracellular protozoan parasites and apoptosis: diverse strategies to modulate parasite-host interactions.

Programmed cell death (apoptosis) is an important regulator of the host's response during infection with a variety of intracellular protozoan parasites. Parasitic pathogens have evolved diverse strategies to induce or inhibit host-cell apoptosis, thereby modulating the host's immune response, aiding dissemination within the host or facilitating intracellular survival. Here, we review the molecular and cell-biological mechanisms of the pathogen-induced modulation of host-cell apoptosis and its effects on the parasite-host interaction and the pathogenesis of parasitic diseases. We also discuss the previously unrecognized phenomenon of apoptotic cell death in (unicellular) protozoan parasites and its potential implications.

Inhibition of host cell apoptosis by Toxoplasma gondii is accompanied by reduced activation of the caspase cascade and alterations of poly(ADP-ribose) polymerase expression.

The obligate intracellular protozoan parasite Toxoplasma gondii has been shown to protect different cell types from apoptosis induced by a variety of pro-apoptotic treatments. However, the precise cell biological mechanisms of this inhibition remained unknown. As shown in this study, apoptosis in human-derived HL-60 and U937 cells induced by treatment with actinomycin D or TNF-alpha in combination with cycloheximide, respectively, was indeed dose-dependently downregulated by prior infection with T. gondii, as determined by DNA fragmentation assays. Cleavage of caspase 3 and caspase 9 after treatment with pro-apoptotic stimuli was considerably diminished by T. gondii. Furthermore, release of mitochondrial cytochrome c during apoptosis in HL-60 cells was prevented by intracellular parasites and this was correlated with the absence of DNA strand breaks on the single cell level. Inhibition of cytochrome c release coincided with a twofold upregulation of Mcl-1 protein levels in HL-60 and U937 cells, while Bcl-2 expression did not increase after infection. Parasitic interference with the caspase cascade led to a reduced proteolytic cleavage of the nuclear target molecule protein kinase C delta. In parallel, poly(ADP-ribose) polymerase protein levels were prominently downregulated by T. gondii, irrespective of whether HL-60 and U937 cells had been treated with pro-apototic stimuli or left untreated. However, poly(ADP-ribose) polymerase mRNA levels remained unchanged after infection as determined by RT-PCR analyses. These observations suggest that T. gondii has evolved different mechanisms that may contribute to downregulation of host cell apoptosis, namely inhibition of cytochrome c release and subsequent caspase activation as well as downregulation of poly(ADP-ribose) polymerase protein levels.

Toxoplasma gondii and MHC-restricted antigen presentation: on degradation, transport and modulation.

Resistance against Toxoplasma gondii, an obligate intracellular protozoan parasite surrounded by a parasitophorous vacuolar membrane, is mediated by the cellular arm of the immune system, namely CD8+ and CD4+ T cells. Thus, priming and activation of these cells by presentation of antigenic peptides in the context of major histocompatibility complex class I and class II molecules have to take place. This is despite the fact that the vacuolar membrane avoids fusion with the endocytic compartment and acts like a molecular sieve, restricting passive diffusion of larger molecules. This raises several cell biological and immunological questions which will be discussed in this review in the context of our current knowledge about major histocompatibility complex-restricted antigen presentation in other systems: (1) By which pathways are parasite-derived antigens presented to T cells? (2) Has the parasite evolved mechanisms to interfere with major histocompatibility complex-restricted antigen presentation in order to avoid immune recognition? (3) To what extent and by which mechanism is antigenic material, originating from the parasite, able to pass through the vacuolar membrane into the cytosol of the infected cell and is it then accessible to the antigen presentation machinery of the infected cell? (4) What are the actual antigen-presenting cells which prime specific T cells in lymphoid organs? An understanding of these mechanisms will not only provide new insights into the pathogenesis of Toxoplasma gondii and possibly other intravacuolar parasites, but will also improve vaccination strategies.