The whole body donation program at the university of Bologna: A report based on the experience of one of the oldest university in Western world.

Human body dissection is fundamental in medical education, as it allows future physicians to learn about the body's morphology in three dimensions, to recognize anatomical variations and to develop and increase the essential qualities of respect, compassion and empathy for patients. It is equally important in clinical training as it allows surgeons to improve their manual dexterity and practical skills and to test innovative surgical techniques and devices. In Italy prior to 2020, body acquisition and use for study and research purposes were regulated by a generic set of old directives and national decrees which dealt only marginally with these issues. However, in 2013, a whole body donation program was officially set up at the Institute of Human Anatomy of the University of Bologna. Completely free and voluntary informed consent has always been regarded as a core prerequisite and, since its inception, the program exclusively accepted bequeathed bodies. On February 10, 2020, a specific law governing the disposition of post mortem human body and tissues for study, training and scientific research purposes was definitively enacted. The present work traces the University of Bologna's experience leading to the whole body donation program and the brand new dissecting room. It describes the program of Bologna as an example of "good practice" in body donation, aimed at ensuring education and clinical training by means of both traditional gross anatomy and innovative technology. Moreover, it analyzes the results achieved in terms of increased donor enrollment and improved teaching/training quality and the strengths of this program in light of the provisions enshrined in the new law.

Near-Peer Teaching in Human Anatomy from a Tutors' Perspective: An Eighteen-Year-Old Experience at the University of Bologna.

The University of Bologna School of Medicine in 2003 adopted a near-peer teaching (NPT) program with senior medical students teaching and assisting younger students in human anatomy laboratories. This study aimed to evaluate the effectiveness and outcomes of this program-unique on the Italian academic panorama-from the tutors' perspective. An anonymous online survey was administered to all those who acted as peer tutors in the period from 2003 to 2021; it evaluated tutors' perceptions regarding the influence of the tutoring experience on their skillset gains, academic performance, and professional career. Furthermore, tutors were asked to express their views on the value of cadaver dissection in medical education and professional development. The overall perception of the NPT program was overwhelmingly positive and the main reported benefits were improved long-term knowledge retention and academic performance, improved communication, team-working and time management skills, and enhanced self-confidence and motivation. Most tutors strongly believed that cadaver dissection was an invaluable learning tool in medical education, helped them to develop professionalism and human values, and positively influenced the caring of their future patients. Nearly all the participants highlighted the importance of voluntary body donation for medical education and research. The present results supported the thesis that tutors themselves benefited from the act of teaching peers; this impactful experience equipped them with a wide range of transferable skills that they could draw on as future educators and healthcare professionals.

An early scientific report on acromegaly: solving an intriguing endocrinological (c)old case?

We present and discuss a late-nineteenth century clinical case described by Professor Taruffi in a scientific paper titled "Scheletro con prosopoectasia e tredici vertebre dorsali" (Skeleton with prosopoectasia and thirteen thoracic vertebrae). Taruffi could not explain the disproportionate skeletal and visceral growth, and the case could therefore be considered an unrecognized case of acromegaly. The anatomopathological specimens and the wax model cited in the paper are currently hosted at the "Luigi Cattaneo" Anatomical Wax Collection of Bologna University; however, some inaccuracies and uncertainties as to their attribution to the same case have remained to this day. The skeletal remains were examined macroscopically to investigate any structural abnormalities and pathological changes. In addition, thanks to archival, museum inventory and literature research, we documented the systematic relationship between the paper and the samples and were able to ascribe the abnormally dilated dried stomach, currently displayed in a different showcase, to the same case. This is, to our knowledge, the first case of acromegaly in the history of medical literature which also includes a visceral specimen. As far as we know, there are no reports of the occurrence of severe gastromegaly in patients with acromegaly. In view of this rare association and, to date, endocrinological research, we hypothesize a further pathogenic mechanism by which acromegaly could have induced this massive dilatation. Taruffi's work represents an immensely valuable scientific/artistic heritage and is still cited in contemporary endocrinological literature, demonstrating its relevant contribution to the historical evolution of the disease through the nineteenth and twentieth centuries.

An increased expression of PI-PLCß1 is associated with myeloid differentiation and a longer response to azacitidine in myelodysplastic syndromes.

This study tested the hypothesis that PI-PLCß1 is associated with myeloid differentiation and that its expression could be useful for predicting the response of MDS patients to azacitidine, as the clinical effect of epigenetic treatments is often detectable only after several cycles of therapy. To this end, PI-PLCß1 was quantified on 70 MDS patients (IPSS risk: 13 Low, 20 Int-1, 31 Int-2, 6 High) at baseline and during the first 3 cycles of azacitidine. Results were then compared with the hematologic response, as assessed after the sixth cycle of azacitidine therapy. Overall, 60 patients completed 6 cycles of azacitidine, and for them, a clinical and molecular evaluation was possible: 37 of these patients (62%) showed a specific increase of PI-PLCß1 mRNA within the first 3 cycles, which was associated with a longer duration of response and with an increased myeloid differentiation, as evidenced by PI-PLCγ2 induction and the recruitment of specific myeloid-associated transcription factors to the PI-PLCß1 promoter during azacitidine response. Moreover, the increase of cyclin D3 gene expression throughout all of the therapy showed that PI-PLCß1-dependent signaling is indeed activated in azacitidine responder patients. Taken together, our results show that PI-PLCß1 quantification in MDS predicts the response to azacitidine and is associated with an increased myeloid differentiation.

Collagen fibre and fibril ultrastructural arrangement of the superficial medial collateral ligament in the human knee.

PURPOSE: The aim of the study was to investigate the collagen fibre ultrastructural arrangement and collagen fibril diameters in the superficial medial collateral ligament (sMCL) in the human knee. Considering sMCL's distinctive functions at different angles of knee flexion, it was hypothesized a significant difference between the collagen fibril diameters of each portion of the sMCL. METHODS: Fourteen sMCL from seven fresh males (by chance because of the availability) cadavers (median age 40 years, range 34-59 years) were harvested within 12 h of death. sMCLs were separated into two orders of regions for analysis. The first order (divisions) was anterior, central and posterior. Thereafter, each division was split into three regions (femoral, intermediate and tibial), generating nine portions. One sMCL from each cadaver was used for transmission electron microscopy (TEM) and morphometric analyses, whereas the contralateral sMCL was processed for light microscopy (LM) or scanning electron microscopy (SEM). RESULTS: LM and SEM analyses showed a complex tridimensional architecture, with the presence of wavy collagen fibres or crimps. TEM analysis showed significant differences in median collagen fibril diameter among portions inside the anterior, central and posterior division of the sMCL (p < 0.0001 within each division). Significant differences were also present among the median [interquartile range] collagen fibril diameters of anterior (39.4 [47.8-32.9]), central (38.5 [44.4-34.0]) and posterior (41.7 [52.2-35.4]) division (p = 0.0001); femoral (38.2 [45.0-32.7]), intermediate (40.3 [47.3-36.1]) and tibial (40.7 [55.0-32.2]) region (p = 0.0001). CONCLUSIONS: Human sMCL showed a complex architecture that allows restraining different knee motions at different angles of knee flexion. The posterior division of sMCL accounted for the largest median collagen fibril diameter. The femoral region of sMCL accounted for the smallest median collagen fibril diameter. The presence of crimps in the medial collateral ligament, previously identified in the rat, was confirmed in humans (taking into consideration differences between these two species).

Strategic Role of Nuclear Inositide Signalling in Myelodysplastic Syndromes Therapy.

Nuclear inositide signalling is implicated in normal and pathological cell proliferation and differentiation in several distinct models. Among the key molecules of nuclear inositide pathways, phosphoinositide-phospholipase (PI-PLC) C β1 is essential for regulating hematopoiesis, particularly along myeloid and erythroid lineage. Moreover, Akt activation is associated with protein synthesis, via mTOR pathway, and with erythroid induction, through PI-PLCγ1 activation. Myelodysplastic syndromes (MDS) are a series of heterogeneous diseases characterized by ineffective hemopoiesis, with a variable risk of evolution into acute myeloid leukemia (AML). Therapeutic approaches for MDS include demethylating agents, such as azacitidine, aiming at reducing cell proliferation, and erythropoietin, useful for sustaining a normal erythropoiesis. In the last few years, a role for nuclear inositide signalling as a therapeutic target in MDS has been disclosed, in that PI-PLCβ1 increase is associated with azacitidine responsiveness, even when this drug is used in combination with other agents, and Akt is specifically activated in MDS at higher risk of AML evolution. On the other hand, recent data demonstrated that inositide signalling can also be involved in erythroid therapy, given the inhibitory effect of erythropoietin on PI-PLCβ1 and the activation of Akt/PI-PLCγ1 pathway, following the administration of erythropoietin. Here, we review the strategic role of nuclear inositide signalling in MDS, in pathogenesis and therapy.

Early healing events around titanium implant devices with different surface microtopography: a pilot study in an in vivo rabbit model.

In the present pilot study, the authors morphologically investigated sandblasted, acid-etched surfaces (SLA) at very early experimental times. The tested devices were titanium plate-like implants with flattened wide lateral sides and jagged narrow sides. Because of these implant shape and placement site, the device gained a firm mechanical stability but the largest portion of the implant surface lacked direct contact with host bone and faced a wide peri-implant space rich in marrow tissue, intentionally created in order to study the interfacial interaction between metal surface and biological microenvironment. The insertion of titanium devices into the proximal tibia elicited a sequence of healing events. Newly formed bone proceeded through an early distance osteogenesis, common to both surfaces, and a delayed contact osteogenesis which seemed to follow different patterns at the two surfaces. In fact, SLA devices showed a more osteoconductive behavior retaining a less dense blood clot, which might be earlier and more easily replaced, and leading to a surface-conditioning layer which promotes osteogenic cell differentiation and appositional new bone deposition at the titanium surface. This model system is expected to provide a starting point for further investigations which clarify the early cellular and biomolecular events occurring at the metal surface.

Contribution of glycosaminoglycans to the microstructural integrity of fibrillar and fiber crimps in tendons and ligaments.

The biomechanical roles of both tendons and ligaments are fulfilled by the extracellular matrix of these tissues. In particular, tension is mainly transmitted and resisted by protein (collagen, elastin) fibers, whereas compression is opposed by water-soluble glycosaminoglycans (GAGs). GAGs spanning the interfibrillar spaces and interacting with fibrils through the interfibrillar proteoglycans also seem to play a part in transmitting and resisting tensile stresses. Both tendons and ligaments showing similar composition, but different functional roles and collagen array, exhibit periodic undulations of collagen fibers or crimps. Each crimp is composed of many knots of each single fibril or fibrillar crimps. Fibrillar and fiber crimps play a mechanical role in absorbing the initial loading during elongation of both tendons and ligaments, and in recoiling fibrils and fibers when tissues have to return to their original length. This study investigated whether GAGs covalently attached to proteoglycan core proteins directly affect the 3D microstructural integrity of fibrillar crimp regions and fiber crimps in both tendons and ligaments. Achilles tendons and medial collateral ligaments of the knee from eight female Sprague-Dawley rats (90 days old) incubated in a chondroitinase ABC solution to remove GAGs were observed under a scanning electron microscope (SEM). In addition, isolated fibrils of these tissues obtained by mechanical disruption were analyzed by a transmission electron microscope (TEM). Both Achilles tendons and medial collateral ligaments of the rats after chemical or mechanical removal of GAGs still showed crimps and fibrillar crimps comparable to tissues with a normal GAG content. All fibrils in the fibrillar crimp region always twisted leftwards, thus changing their running plane, and then sharply bent, changing their course on a new plane. These data suggest that GAGs do not affect structural integrity or fibrillar crimp functions that seem mainly related to the local fibril leftward twisting and the alternating handedness of collagen from a molecular to a supramolecular level.

Collagen fibre arrangement and functional crimping pattern of the medial collateral ligament in the rat knee.

Ligaments have been described as multifascicular structures with collagen fibres cross-connecting to each other or running straight and parallel also showing a waviness or crimping pattern playing as a shock absorber/recoiling system during joint motions. A particular collagen array and crimping pattern in different ligaments may reflect different biomechanical roles and properties. The aim of the study was to relate the 3D collagen arrangement in the crimping pattern of the medial collateral ligament (MCL) to its functional role. The MCL is one of the most injured ligaments during sports activities and an experimental model to understand the rate, quality and composition of ligaments healing. A deep knowledge of structure-function relationship of collagen fibres array will improve the development of rehabilitation protocols and more appropriate exercises for recovery of functional activity. The rat MCL was analysed by polarized light microscopy, confocal laser microscopy and scanning electron microscopy (SEM). Histomorphometric analysis demonstrated that MCL crimps have a smaller base length versus other tendons. SEM observations demonstrated that collagen fibres showing few crimps were composed of fibrils intertwining and crossing one another in the outer region. Confocal laser analyses excluded a helical array of collagen fibres. By contrast, in the core portion, densely packed straight collagen fibres ran parallel to the main axis of the ligament being interrupted both by planar crimps, similar to tendon crimps, and by newly described right-handed twisted crimps. It is concluded that planar crimps could oppose or respond exclusively to tensional forces parallel to the main ligament axis, whereas the right-handed twisted crimps could better resist/respond to a complex of tensional/rotational forces within the ligament thus opposing to an external rotation of tibia.

Structure relates to elastic recoil and functional role in quadriceps tendon and patellar ligament.

Tendons and ligaments have similar but slightly different structure and composition. Crimps of tendons and ligaments are morphological structures related to the elastic functional properties of these connective tissues. Aim of this study was to investigate the morphological arrangement of collagen fibres, fibrils and crimping pattern of suprapatellar (rectus femoris tendon-RFT and vastus intermedius tendon-VIT) and infrapatellar connective tissues (patellar ligament-PL) to relate their structural aspects to their common function role of leg extension. RFT, VIT and PL were removed from knees of Sprague-Dawley rats and light and electron microscopy (TEM and SEM) performed. Sagittal sections showed that collagen array and crimping pattern were similar in RFT and PL but differed from VIT. Morphometric analysis confirmed that crimp number was about the same in RFT and PL (5.4+/-1.4 and 6.1+/-2.8 respectively), but it was almost three times higher in VIT (14.5+/-4.7). Similarly crimp top angle in RFT and PL (141.5+/-15.0 degrees and 146.2+/-12.2 degrees respectively) was significantly higher than in VIT (122.3+/-14.8 degrees ) and the crimp base length was more than twice as wide in RFT (75.5+/-22.6microm) and PL (72.3+/-28.9microm) than in VIT (36+/-14.1microm). The smaller, fewer and most crimped crimps in VIT show that this tendon has a greater elastic recoil and responds to higher forces as among quadriceps muscles the vastus intermedius belly contributes the most during knee extension. By contrast, RFT acting as a "stopper" tendon also plays a ligament role by limiting an excessive flexion of the joint during postural rest position of the knee.

Different crimp patterns in collagen fibrils relate to the subfibrillar arrangement.

Collagen fibril ultrastructure and course were examined in different connective tissues by PLM, SEM, TEM, and AFM. In tendons, collagen fibrils were large and heterogeneous with a straight subfibrillar arrangement. They ran densely packed, parallel, and straight changing their direction only in periodic crimps where fibrils showed a local deformation (fibrillar crimps). Other tissues such as aponeurosis, fascia communis, skin, aortic wall, and tendon and nerve sheaths showed thinner uniform fibrils with a helical subfibrillar arrangement. These fibrils appeared in parallel or helical arrangement following a wavy, undulating course. Ligaments showed large fibrils as in tendon, with fibrillar crimps but less packed. Thinner uniform-sized fibrils also were observed. Fibrillar crimps seem to be related to the subfibrillar arrangement being present only in large fibrils with a straight subfibrillar arrangement. These stiffer fibrils respond mainly to unidirectional tensional forces, whereas the flexible thinner fibrils with helical subfibrils can accommodate extreme curvatures without harm, thus responding to multidirectional loadings.

Proteoglycan fragmentation and respiratory mechanics in mechanically ventilated healthy rats.

This research investigated whether stretching of lung tissue due to increased positive alveolar pressure swings during mechanical ventilation (MV) at various tidal volumes (V(T)) might affect the composition and/or structure of the glycosaminoglycan (GAG) components of pulmonary extracellular proteoglycans. Experiments were performed in 30 healthy rats: 1) anesthetized and immediately killed (controls, C-0); 2) anesthetized and spontaneously breathing for 4 h (C-4h); and 3) anesthetized, paralyzed, and mechanically ventilated for 4 h with air at 0-cmH(2)O end-expiratory pressure and V(T) of 8 ml/kg (MV-1), 16 ml/kg (MV-2), 24 ml/kg (MV-3), or 32 ml/kg (MV-4), adjusting respiratory rates at a minute ventilation of 270 ml/min. Compared with C-0 and C-4h, a significant reduction of dynamic and static compliance of the respiratory system and of the lung was observed only in MV-4, while extravascular lung water significantly increased in MV-3 and MV-4, but not in MV-1 and MV-2. However, even in MV-1, MV induced a significant fragmentation of pulmonary GAGs. Extraction of covalently bound GAGs and wash out of loosely bound or fragmented GAGs progressively increased with increasing V(T) and was associated with increased expression of local (matrix metalloproteinase-2) and systemic (matrix metalloproteinase-9) activated metalloproteases. We conclude that 1) MV, even at "physiological" low V(T), severely affects the pulmonary extracellular architecture, exposing the lung parenchyma to development of ventilator-induced lung injury; and 2) respiratory mechanics is not a reliable clinical tool for early detection of lung injury.

Collagen structure of tendon relates to function.

A tendon is a tough band of fibrous connective tissue that connects muscle to bone, designed to transmit forces and withstand tension during muscle contraction. Tendon may be surrounded by different structures: 1) fibrous sheaths or retinaculae; 2) reflection pulleys; 3) synovial sheaths; 4) peritendon sheaths; 5) tendon bursae. Tendons contain a) few cells, mostly represented by tenoblasts along with endothelial cells and some chondrocytes; b) proteoglycans (PGs), mainly decorin and hyaluronan, and c) collagen, mostly type I. Tendon is a good example of a high ordered extracellular matrix in which collagen molecules assemble into filamentous collagen fibrils (formed by microfibrils) which aggregate to form collagen fibers, the main structural components. It represents a multihierarchical structure as it contains collagen molecules arranged in fibrils then grouped in fibril bundles, fascicles and fiber bundles that are almost parallel to the long axis of the tendon, named as primary, secondary and tertiary bundles. Collagen fibrils in tendons show prevalently large diameter, a D-period of about 67 nm and appear built of collagen molecules lying at a slight angle (< 5 degrees). Under polarized light microscopy the collagen fiber bundles appear crimped with alternative dark and light transverse bands. In recent studies tendon crimps observed via SEM and TEM show that the single collagen fibrils suddenly changing their direction contain knots. These knots of collagen fibrils inside each tendon crimp have been termed "fibrillar crimps", and even if they show different aspects they all may fulfil the same functional role. As integral component of musculoskeletal system, the tendon acts to transmit muscle forces to the skeletal system. There is no complete understanding of the mechanisms in transmitting/absorbing tensional forces within the tendon; however it seems likely that a flattening of tendon crimps may occur at a first stage of tendon stretching. Increasing stretching, other transmission mechanisms such as an interfibrillar coupling via PGs linkages and a molecular gliding within the fibrils structure may be involved.

Crimp morphology in relaxed and stretched rat Achilles tendon.

Fibrous extracellular matrix of tendon is considered to be an inextensible anatomical structure consisting of type I collagen fibrils arranged in parallel bundles. Under polarized light microscopy the collagen fibre bundles appear crimped with alternating dark and light transverse bands. This study describes the ultrastructure of the collagen fibrils in crimps of both relaxed and in vivo stretched rat Achilles tendon. Under polarized light microscopy crimps of relaxed Achilles tendons appear as isosceles or scalene triangles of different size. Tendon crimps observed via SEM and TEM show the single collagen fibrils that suddenly change their direction containing knots. The fibrils appear partially squeezed in the knots, bent on the same plane like bayonets, or twisted and bent. Moreover some of them lose their D-period, revealing their microfibrillar component. These particular aspects of collagen fibrils inside each tendon crimp have been termed 'fibrillar crimps' and may fulfil the same functional role. When tendon is physiologically stretched in vivo the tendon crimps decrease in number (46.7%) (P<0.01) and appear more flattened with an increase in the crimp top angle (165 degrees in stretched tendons vs. 148 degrees in relaxed tendons, P<0.005). Under SEM and TEM, the 'fibrillar crimps' are still present, never losing their structural identity in straightened collagen fibril bundles of stretched tendons even where tendon crimps are not detectable. These data suggest that the 'fibrillar crimp' may be the true structural component of the tendon crimp acting as a shock absorber during physiological stretching of Achilles tendon.

Osteogenesis and morphology of the peri-implant bone facing dental implants.

This study investigated the influence of different implant surfaces on peri-implant osteogenesis and implant face morphology of peri-implant tissues during the early (2 weeks) and complete healing period (3 months). Thirty endosseous titanium implants (conic screws) with differently treated surfaces (smooth titanium = SS, titanium plasma sprayed = TPS, sand-blasted zirconium oxide = Zr-SLA) were implanted in femur and tibiae diaphyses of two mongrel sheep. Histological sections of the implants and surrounding tissues obtained by sawing and grinding techniques were observed under light microscopy (LM). The peri-implant tissues of other samples were mechanically detached from the corresponding implants to be processed for SEM observation. Two weeks after implantation, we observed osteogenesis (new bone trabeculae) around all implant surfaces only where a gap was present at the host bone-metal interface. No evident bone deposition was detectable where threads of the screws were in direct contact with the compact host bone. Distance osteogenesis predominated in SS implants, while around rough surfaces (TPS and Zr-SLA), both distance and contact osteogenesis were present. At SEM analysis 2 weeks after implantation, the implant face of SS peri-implant tissue showed few, thin, newly formed, bone trabeculae immersed in large, loose, marrow tissue with blood vessels. Around the TPS screws, the implant face of the peri-implant tissue was rather irregular because of the rougher metal surface. Zr-SLA screws showed more numerous, newly formed bone trabeculae crossing marrow spaces and also needle-like crystals in bone nodules indicating an active mineralising process. After 3 months, all the screws appeared osseointegrated, being almost completely covered by a compact, mature, newly formed bone. However, some marrow spaces rich in blood vessels and undifferentiated cells were in contact with the metal surface. By SEM analysis, the implant face of the peri-implant tissue showed different results. Around the SS screws, the compact bone with areas of different mineralisation rate appeared very smooth, while around the rougher TPS screws, the bone still showed an irregular surface corresponding to the implant macro/microroughness. Around the Zr-SLA screws, a more regular implant-bone surface and sparse, calcified marrow spaces were detectable. Results from this research suggest that 2 weeks after implantation, trabecular bone represents the calcified healing tissue, which supports the early biological fixation of the implants. The peri-implant marrow spaces, rich in undifferentiated cells and blood vasculature, observed both 2 weeks and 3 months after surgery, favour the biological turnover of both early and mature peri-implant bone. The implant surface morphology strongly influences the rate and the modality of peri-implant osteogenesis, as do the morphology and arrangement of the implant face in peri-implant bone both during early healing (after 2 weeks) and when the implant is just osseointegrated; rough surfaces, and in particular Zr-SLA, seem to better favour bone deposition on the metal surface.