Mechanobiology of Bone Development and Computational Simulations

Bone is important because it provides the skeleton structural integrity and enables movement and locomotion. Its development and morphology follow its function. It adapts to changes of mechanical loading and has the ability to repair itself after damage or fracture. The processes of bone development, bone adaptation, and bone regeneration in fracture healing are regulated, in part, by mechanical stimuli that result when the bone is loaded.

A phenomenological explication of dream interpretation among rural and urban Nguni people

Psychologists investigating dreams in non-Western cultures have generally not considered the meanings of dreams within the unique meaning-structure of the person in his or her societal context. The majority of dream studies in African societies are no exception. Researchers approaching dreams within rural Xhosa and Zulu speaking societies have either adopted an anthropological or a psychodynamic orientation. The latter approach particularly imposes a Western perspective in the interpretation of dream material. There have been no comparable studies of dream interpretation among urban blacks participating in the African Independent Church Movement. The present study focuses on the rural Xhosa speaking people and the urban black population who speak one of the Nguni languages and identify with the African Independent Church Movement. The study is concerned with understanding the meanings of dreams within the cultural context in which they occur. The specific aims of the study are: 1. To explicate the indigenous system of dream interpretation as revealed by acknowledged dream experts. 2. To examine the commonalities and the differences between the interpretation of dreams in two groups, drawn from a rural and urban setting respectively. 3. To elaborate upon the life-world of the participants by the interpretations gained from the above investigation. One hundred dreams and interpretations are collected from two categories of participants referred to as the Rural Group and the Urban Group. The Rural Group is made up of amagqira [traditional healers] and their clients, while the Urban Group consists of prophets and members of the African Independent Churches. Each group includes acknowledged dream experts. A phenomenological methodology is adopted in explicating the data. The methodological precedure involves a number of rigorous stages of expl ication whereby the original data is reduced to Constituent Profiles leading to the construction of a Thematic Index File. By searching and reflect ing upon the data, interpretative themes are identified. These themes are explicated to provide a rigorous description of the interpretative-reality of each group. Themes explicated w i thin the Rural Group are: the physiognomy of the dreamer's life-world as revealed by ithongo, the interpretation of ithongo as revealed through action, the dream relationship as an anticipatory mode-of-existence, iphupha as disclosing a vulnerable mode-of-being, human bodiliness as revealed in dream interpretations and the legitimation of the interpretative-reality within the life-world. Themes explicated within the Urban Group are: the phys iognomy of the dreamer's life-world revealed in their dream-existence, the interpretative-reality revealed through the enaction of dreams, tension between the newer Christian-based cosomology and the traditional cultural-based cosmology, a moral imperative, prophetic perception and human bodiliness, as revealed in dream interpretations and the legitimation of the interpretative-reality within the life-world. The essence of the interpretative-reality of both groups is very similar and is expressed in the notion of relatedness to a cosmic mode-of-being. The cosmic mode-of-being includes a numinous dimension which is expressed through divine presence in the form of ancestors, Holy Spirit or God. These notions cannot be apprehended by theoretical constructs alone but may be grasped and given form in meaning-disclosing intuitions which are expressed in the lifeworld in terms of bodiliness, revelatory knowledge, action and healing. Some differences b e tween the two groups are evident and reveal some conflict between the monotheistic Christian cosmology and the traditional cosmology. Unique aspects of the interpetative-reality of the Urban Group are expressed in terms of difficulties in the urban social environment and the notion of a moral imperative. It is observed that cul tural self-expression based upon traditional ideas continues to play a significant role in the urban environment. The apparent conflict revealed between the respective cosmologies underlies an integration of the aditional meanings with Christian concepts. This finding is consistent with the literature suggesting that the African Independent Church is a syncretic movement. The life-world is based upon the immediate and vivid experience of the numinous as revealed in the dream phenomenon. The participants' approach to dreams is not based upon an explicit theory, but upon an immediate and pathic understanding of the dream phenomenon. The understanding is based upon the interpreter's concrete understanding of the life-world, which includes the possibility of cosmic integration and continuity between the personal and transpersonal realms of being. The approach is characterized as an expression of man's primordial attunement with the cosmos. The approach of the participants to dreams may not b e consistent with a Western rational orientation, but neverthele ss, it is a valid approach . The validity is based upon the immediate life-world of experience which is intelligible, coherent, and above all, it is meaning-giving in revealing life-possibility within the context of human existence.

Establishment of a mouse model of colitis and its use to evaluate the anti-inflammatory effects of two ghrelin peptides

Ghrelin is a gut-brain peptide hormone that induces appetite, stimulates the release of growth hormone, and has recently been shown to ameliorate inflammation. Recent studies have suggested that ghrelin may play a potential role in inflammation-related diseases such as inflammatory bowel diseases (IBD). A previous study with ghrelin in the TNBS mouse model of colitis demonstrated that ghrelin treatment decreased the clinical severity of colitis and inflammation and prevented the recurrence of disease. Ghrelin may be acting at the immunological and epithelial level as the ghrelin receptor (GHSR) is expressed by immune cells and intestinal epithelial cells. The current project investigated the effect of ghrelin in a different mouse model of colitis using dextran sodium sulphate (DSS) – a luminal toxin. Two molecular weight forms of DSS were used as they give differing effects (5kDa and 40kDa). Ghrelin treatment significantly improved clinical colitis scores (p=0.012) in the C57BL/6 mouse strain with colitis induced by 2% DSS (5kDa). Treatment with ghrelin suppressed colitis in the proximal colon as indicated by reduced accumulative histopathology scores (p=0.03). Whilst there was a trend toward reduced scores in the mid and distal colon in these mice this did not reach significance. Ghrelin did not affect histopathology scores in the 40kDa model. There was no significant effect on the number of regulatory T cells or TNF-α secretion from cultured lymph node cells from these mice. The discovery of C-terminal ghrelin peptides, for example, obestatin and the peptide derived from exon 4 deleted proghrelin (Δ4 preproghrelin peptide) have raised questions regarding their potential role in biological functions. The current project investigated the effect of Δ4 peptide in the DSS model of colitis however no significant suppression of colitis was observed. In vitro epithelial wound healing assays were also undertaken to determine the effect of ghrelin on intestinal epithelial cell migration. Ghrelin did not significantly improve wound healing in these assays. In conclusion, ghrelin treatment displays a mild anti-inflammatory effect in the 5kDa DSS model. The potential mechanisms behind this effect and the disparity between these results and those published previously will be discussed.

Resolving painful emotional experience during psychodrama

Unresolved painful emotional experiences such as bereavement, trauma and disturbances in core relationships, are common presenting problems for clients of psychodrama or psychotherapy more generally. Emotional pain is experienced as a shattering of the sense of self and disconnection from others and, when unresolved, produces avoidant responses which inhibit the healing process. There is agreement across therapeutic modalities that exposure to emotional experience can increase the efficacy of therapeutic interventions. Moreno proposes that the activation of spontaneity is the primary curative factor in psychodrama and that healing occurs when the protagonist (client) engages with his or her wider social system and develops greater flexibility in response to that system. An extensive case-report literature describes the application of the psychodrama method in healing unresolved painful emotional experiences, but there is limited empirical research to verify the efficacy of the method or to identify the processes that are linked to therapeutic change. The purpose of this current research was to construct a model of protagonist change processes that could extend psychodrama theory, inform practitioners’ therapeutic decisions and contribute to understanding the common factors in therapeutic change. Four studies investigated protagonist processes linked to in-session resolution of painful emotional experiences. Significant therapeutic events were analysed using recordings and transcripts of psychodrama enactments, protagonist and director recall interviews and a range of process and outcome measures. A preliminary study (3 cases) identified four themes that were associated with helpful therapeutic events: enactment, the working alliance with the director and with group members, emotional release or relief and social atom repair. The second study (7 cases) used Comprehensive Process Analysis (CPA) to construct a model of protagonists’ processes linked to in-session resolution. This model was then validated across four more cases in Study 3. Five meta-processes were identified: (i) a readiness to engage in the psychodrama process; (ii) re-experiencing and insight; (iii) activating resourcefulness; (iv) social atom repair with emotional release and (v) integration. Social atom repair with emotional release involved deeply experiencing a wished-for interpersonal experience accompanied by a free flowing release of previously restricted emotion and was most clearly linked to protagonists’ reports of reaching resolution and to post session improvements in interpersonal relationships and sense of self. Acceptance of self in the moment increased protagonists’ capacity to generate new responses within each meta-process and, in resolved cases, there was evidence of spontaneity developing over time. The fourth study tested Greenberg’s allowing and accepting painful emotional experience model as an alternative explanation of protagonist change. The findings of this study suggested that while the process of allowing emotional pain was present in resolved cases, Greenberg’s model was not sufficient to explain the processes that lead to in-session resolution. The protagonist’s readiness to engage and activation of resourcefulness appear to facilitate the transition from problem identification to emotional release. Furthermore, experiencing a reparative relationship was found to be central to the healing process. This research verifies that there can be in-session resolution of painful emotional experience during psychodrama and protagonists’ reports suggest that in-session resolution can heal the damage to the sense of self and the interpersonal disconnection that are associated with unresolved emotional pain. A model of protagonist change processes has been constructed that challenges the view of psychodrama as a primarily cathartic therapy, by locating the therapeutic experience of emotional release within the development of new role relationships. The five meta-processes which are described within the model suggest broad change principles which can assist practitioners to make sense of events as they unfold and guide their clinical decision making in the moment. Each meta-process was linked to specific post-session changes, so that the model can inform the development of therapeutic plans for individual clients and can aid communication for practitioners when a psychodrama intervention is used for a specific therapeutic purpose within a comprehensive program of therapy.

The evaluation of a biphasic osteochondral implant coupled with an electrospun membrane in a large animal model

Conventional clinical therapies are unable to resolve osteochondral defects adequately, hence tissue engineering solutions are sought to address the challenge. A biphasic implant which was seeded with Mesenchymal Stem Cells (MSC) and coupled with an electrospun membrane was evaluated as an alternative. This dual phase construct comprised of a Polycaprolactone (PCL) cartilage scaffold and a Polycaprolactone - Tri Calcium Phosphate (PCL - TCP) osseous matrix. Autologous MSC was seeded into the entire implant via fibrin and the construct was inserted into critically sized osteochondral defects located at the medial condyle and patellar groove of pigs. The defect was resurfaced with a PCL - collagen electrospun mesh that served as a substitute for periosteal flap in preventing cell leakage. Controls either without implanted MSC or resurfacing membrane were included. After 6 months, cartilaginous repair was observed with a low occurrence of fibrocartilage at the medial condyle. Osteochondral repair was promoted and host cartilage degeneration was arrested as shown by the superior Glycosaminoglycan (GAG) maintenance. This positive morphological outcome was supported by a higher relative Young's modulus which indicated functional cartilage restoration. Bone in growth and remodeling occurred in all groups with a higher degree of mineralization in the experimental group. Tissue repair was compromised in the absence of the implanted cells or the resurfacing membrane. Moreover healing was inferior at the patellar groove as compared to the medial condyle and this was attributed to the native biomechanical features.

Coating of biomaterial scaffolds with the collagen-mimetic peptide GFOGER for bone defect repair

Healing large bone defects and non-unions remains a significant clinical problem. Current treatments, consisting of auto and allografts, are limited by donor supply and morbidity, insufficient bioactivity and risk of infection. Biotherapeutics, including cells, genes and proteins, represent promising alternative therapies, but these strategies are limited by technical roadblocks to biotherapeutic delivery, cell sourcing, high cost, and regulatory hurdles. In the present study, the collagen-mimetic peptide, GFOGER, was used to coat synthetic PCL scaffolds to promote bone formation in critically-sized segmental defects in rats. GFOGER is a synthetic triple helical peptide that binds to the [alpha]2[beta]1 integrin receptor involved in osteogenesis. GFOGER coatings passively adsorbed onto polymeric scaffolds, in the absence of exogenous cells or growth factors, significantly accelerated and increased bone formation in non-healing femoral defects compared to uncoated scaffolds and empty defects. Despite differences in bone volume, no differences in torsional strength were detected after 12 weeks, indicating that bone mass but not bone quality was improved in this model. This work demonstrates a simple, cell/growth factor-free strategy to promote bone formation in challenging, non-healing bone defects. This biomaterial coating strategy represents a cost-effective and facile approach, translatable into a robust clinical therapy for musculoskeletal applications.

Reempowering ourselves: Australian Aboriginal women

The arrival of the colonists, the invasion of Aboriginal lands and the subsequent colonization of Australia had a disastrous effect on Aboriginal women, including on-going dispossession and disempowerment. Aboriginal women’s lives and gendered realities were forever changed in most communities. The system of colonization deprived Aboriginal women of land and personal autonomy and restricted the economic, political, social, spiritual and ceremonial domains that had existed prior to colonization. It also involved the implementation of overriding patriarchal systems. This is why Aboriginal women may find understanding within the women’s movement and why feminism might offer them a source of analysis. There are some connections in the various forms of social oppression, which give women connection and a sharing on some issues. However, imperialism and colonialism are also part of the women’s movement and feminism. This essay demonstrates why attempts to engage with feminism and to be included in women-centred activities might result in the denial and sidelining of Aboriginal sovereignty and further oppression and marginalisation of Aboriginal women. Moreover, strategies employed by non-Indigenous feminists can result in the maintenance of white women’s values and privileges within the dominant patriarchal white society. By engaging in these strategies feminists can also act in direct opposition to Aboriginal sovereignty and Aboriginal women. This essay states clearly that women who do not express positions or opinions in outright support of these activities still benefit from their position by proxy and contribute to the cultural dominance of non-Indigenous women. I argue that Aboriginal women need to define what empowerment might mean to themselves, and I suggest re-empowerment as an act of Aboriginal women’s healing and resistance to the on-going processes and impacts of colonization.

Factors associated with recurrence of venous leg ulcers : a survey and retrospective chart review

Background: Chronic venous leg ulcers have a significant impact on older individuals’ well-being and health care resources. Unfortunately after healing, up to 70% recur. ----- Objective: To examine the relationships between leg ulcer recurrence and physical activity, compression, nutrition, health, psychosocial indicators and self-care activities in order to provide information for preventive strategies. ----- Design: Survey and retrospective chart review Settings: Two metropolitan hospital and three community-based leg ulcer clinics. ----- Subjects: A sample of 122 community living patients with leg ulcer of venous aetiology which had healed between 12 and 36 months prior to the survey. ---- Methods: Data were collected from medical records on demographics, medical history and previous ulcer history and treatments; and from self-report questionnaires on physical activity, nutrition, psychosocial measures, ulcer recurrences and history, compression and other self-care activities. All variables significantly associated with recurrence at the bivariate level were entered into a logistic regression model to determine their independent influences on recurrence. ----- Results: Median follow-up time was 24 months (range 12–40 months). Sixty-eight percent of participants had recurred. Bivariate analysis found recurrence was positively associated with ulcer duration, cardiac disease, a Body Mass Index ≤20, scoring as at-risk of malnutrition and depression; and negatively associated with increased physical activity, leg elevation, wearing Class 2 (20–25mmHg) or Class 3 (30–40mmHg) compression hosiery, and higher self-efficacy scores. After adjusting for all variables, an hour/day of leg elevation (OR=0.04, 95% CI=0.01–0.17), days/week in Class 2 or 3 compression hosiery (OR=0.53, 95% CI=0.34–0.81), Yale Physical Activity Survey score (OR=0.95, 95% CI=0.92–0.98), cardiac disease (OR=5.03, 95% CI=1.01–24.93) and General Self-Efficacy scores (OR=0.83, 95% CI=0.72–0.94) remained significantly associated (p<0.05) with recurrence. ----- Conclusions: Results indicate a history of cardiac disease is a risk factor for recurrence; while leg elevation, physical activity, compression hosiery and strategies to improve self-efficacy are likely to prevent recurrence.

Runx2 overexpression in bone marrow stromal cells accelerates bone formation in critically-sized femoral defects

The repair of large non-unions in long bones remains a significant clinical problem due to high failure rates and limited tissue availability for auto- and allografts. Many cell-based strategies for healing bone defects deliver bone marrow stromal cells to the defect site to take advantage of the inherent osteogenic capacity of this cell type. However, many factors, including donor age and ex vivo expansion of the cells, cause bone marrow stromal cells to lose their differentiation ability. To overcome these limitations, we have genetically engineered bone marrow stromal cells to constitutively overexpress the osteoblast specific transcription factor Runx2. In the present study, we examined Runx2-modified bone marrow stromal cells, delivered via poly(caprolactone) scaffolds loaded with type I collagen meshes, in critically-sized segmental defects in rats compared to unmodified cells, cell-free scaffolds and empty defects. Runx2 expression in bone marrow stromal cells accelerated healing of critically-sized defects compared to unmodified bone marrow stromal cells and defects receiving cell-free treatments. These findings provide an accelerated method for healing large bone defects which may reduce recovery time and the need for external fixation of critically-sized defects.

Enhancing in vivo vascularized bone formation by cobalt chloride-treated bone marrow stromal cells in a tissue engineered periosteum model

The periosteum plays an indispensable role in both bone formation and bone defect healing. In this study we constructed an artificial in vitro periosteum by incorporating osteogenic differentiated bone marrow stromal cells (BMSCs) and cobalt chloride (CoCl(2))-treated BMSCs. The engineered periostea were implanted both subcutaneously and into skull bone defects in SCID mice to investigate ectopic and orthotopic osteogenesis and vascularization. After two weeks in subcutaneous and four weeks in bone defect areas, the implanted constructs were assessed for ectopic and orthotopic osteogenesis and vascularization by micro-CT, histomorphometrical and immunohistochemical methods. The results showed that CoCl(2) pre-treated BMSCs induced higher degree of vascularization and enhanced osteogenesis within the implants in both ectopic and orthotopic areas. This study provided a novel approach using BMSCs sourced from the same patient for both osteogenic and pro-angiogenic purposes in constructing tissue engineered periosteum to enhance vascularized osteogenesis.

Bioactive mesopore-glass microspheres with controllable protein-delivery properties by biomimetic surface modification

Microsphere systems with the ideal properties for bone regeneration need to be bioactive, and at the same time possess the capacity for controlled protein/drug-delivery; however, the current crop of microsphere system fails to fulfill these properties. The aim of this study was to develop a novel protein-delivery system of bioactive mesoporous glass (MBG) microspheres by a biomimetic method through controlling the density of apatite on the surface of microspheres, for potential bone tissue regeneration. MBG microspheres were prepared by using the method of alginate cross-linking with Ca2+ ions. The cellular bioactivity of MBG microspheres was evaluated by investigating the proliferation and attachment of bone marrow stromal cell (BMSC). The loading efficiency and release kinetics of bovine serum albumin (BSA) on MBG microspheres were investigated after coprecipitating with biomimetic apatite in simulated body fluids (SBF). The results showed that MBG microspheres supported BMSC attachment and the Si containing ionic products from MBG microspheres stimulated BMSCs proliferation. The density of apatite on MBG microspheres increased with the length of soaking time in SBF. BSA-loading efficiency of MBG was significantly enhanced by co-precipitating with apatite. Furthermore, the loading efficiency and release kinetics of BSA could be controlled by controlling the density of apatite formed on MBG microspheres. Our results suggest that MBG microspheres are a promising protein-delivery system as a filling material for bone defect healing and regeneration.

Sustained release and osteogenic potential of heparan sulfate-doped fibrin glue scaffolds within a rat cranial model

This paper explores the potential therapeutic role of the naturally occurring sugar heparan sulfate (HS) for the augmentation of bone repair. Scaffolds comprising fibrin glue loaded with 5 lg of embryonically derived HS were assessed, firstly as a release-reservoir, and secondly as a scaffold to stimulate bone regeneration in a critical size rat cranial defect. We show HS-loaded scaffolds have a uniform distribution of HS, which was readily released with a typical burst phase, quickly followed by a prolonged delivery lasting several days. Importantly, the released HS contributed to improved wound healing over a 3-month period as determined by microcomputed tomography (lCT) scanning, histology, histomorphometry, and PCR for osteogenic markers. In all cases, only minimal healing was observed after 1 and 3 months in the absence of HS. In contrast, marked healing was observed by 3 months following HS treatment, with nearly full closure of the defect site. PCR analysis showed significant increases in the gene expression of the osteogenic markers Runx2, alkaline phosphatase, and osteopontin in the heparin sulfate group compared with controls. These results further emphasize the important role HS plays in augmenting wound healing, and its successful delivery in a hydrogel provides a novel alternative to autologous bone graft and growth factorbased therapies.

Meniscal repair in the elite athlete : results of 45 repairs with a minimum 5-year follow-up

Background The preservation of meniscal tissue is important to protect joint surfaces. Purpose We have an aggressive approach to meniscal repair, including repairing tears other than those classically suited to repair. Here we present the medium- to long-term outcome of meniscal repair (inside-out) in elite athletes. Study Design Case series; Level of evidence, 4. Methods Forty-two elite athletes underwent 45 meniscal repairs. All repairs were performed using an arthroscopically assisted inside-out technique. Eighty-three percent of these athletes had ACL reconstruction at the same time. Patients returned a completed questionnaire (including Lysholm and International Knee Documentation Committee [IKDC] scores). Mean follow-up was 8.5 years. Failure was defined by patients developing symptoms of joint line pain and/or locking or swelling requiring repeat arthroscopy and partial meniscectomy. Results The average Lysholm and subjective IKDC scores were 89.6 and 85.4, respectively. Eighty-one percent of patients returned to their main sport and most to a similar level at a mean time of 10.4 months after repair, reflecting the high level of ACL reconstruction in this group. We identified 11 definite failures, 10 medial and 1 lateral meniscus, that required excision; this represents a 24% failure rate. We identified 1 further patient who had possible failed repairs, giving a worst-case failure rate of 26.7% at a mean of 42 months after surgery. However, 7 of these failures were associated with a further injury. Therefore, the atraumatic failure rate was 11%. Age and size and location of the tears were not associated with a higher failure rate. Medial meniscal repairs were significantly more likely to fail than lateral meniscal repairs, with a failure rate of 36.4% and 5.6%, respectively (P < .05). Conclusion Meniscal repair and healing are possible, and most elite athletes can return to their preinjury level of activity.

A hydrogen tethered inhibitor of matrix metalloproteinases

During wound repair, the balance between matrix metalloproteinases (MMPs) and their natural inhibitors (the TIMPs) is crucial for the normal extra cellular matrix turnover. However, the over expression of several MMPs including MMP-1, 2, 3, 8, 9 and MMP-10, combined with abnormally high levels of activation or low expression of TIMPs, may contribute to excessive degradation of connective tissue and formation of chronic ulcers. There are many groups exploring strategies for promoting wound healing involving delivery of growth factors, cells, ECM components and small molecules. Our approach for improving the balance of MMPs is not to add anything more to the wound, but instead to neutralise the over-expressed MMPs using inhibitors tethered to a bandage-like hydrogel. Our in vitro experiments using designed synthetic pseudo peptide inhibitors have been demonstrated to inhibit MMP activity in standard solutions. These inhibitors have also been tethered to polyethylene glycol hydrogels using a facile reaction between the linker unit on the inhibitor and the gel. After tethering the inhibition of MMPs diminishes to some extent and we postulate that this arises due to poor diffusion of the MMPs into the gels. When the tethered inhibitors were tested against chronic wound fluid obtained against patients we observed over 40% inhibition in proteolytic activity suggesting our approach may prove useful in rebalancing MMPs within chronic wounds.

A new future for growth factor complexes as wound therapies?

Background: Topical administration of growth factors (GFs) has displayed some potential in wound healing, but variable efficacy, high doses and costs have hampered their implementation. Moreover, this approach ignores the fact that wound repair is driven by interactions between multiple GFs and extracellular matrix (ECM) proteins. The Problem: Deep dermal partial thickness burn (DDPTB) injuries are the most common burn presentation to pediatric hospitals and also represent the most difficult burn injury to manage clinically. DDPTB often repair with a hypertrophic scar. Wounds that close rapidly exhibit reduced scarring. Thus treatments that shorten the time taken to close DDTPB’s may coincidently reduce scarring. Basic/Clinical Science Advances: We have observed that multi-protein complexes comprised of IGF and IGF-binding proteins bound to the ECM protein vitronectin (VN) significantly enhance cellular functions relevant to wound repair in human skin keratinocytes. These responses require activation of both the IGF-1R and the VN-binding αv integrins. We have recently evaluated the wound healing potential of these GF:VN complexes in a porcine model of DDTPB injury. Clinical Care Relevance: This pilot study demonstrates that GF:VN complexes hold promise as a wound healing therapy. Enhanced healing responses were observed after treatment with nanogram doses of the GF:VN complexes in vitro and in vivo. Critically healing was achieved using substantially less GF than studies in which GFs alone have been used. Conclusion: These data suggest that coupling GFs to ECM proteins, such as VN, may ultimately prove to be an improved technique for the delivery of novel GF-based wound therapies.