Journal of Medical Hypotheses and Ideas最新文献

Cerebral arteriovenous malformations (AVMs) occur universally in 1.1 per 100,000 people. These malformations are the cause of serious neurological morbidity or even death when they bleed. AVMs are not necessarily static congenital abnormalities. They can undergo internal changes due to angiogenesis resulting in vascular remodelling. They can even regrow after successful therapy. Vascular endothelial growth factors (VEGFs) play an important role in angiogenesis. Drugs that block the action of VEGF on vascular endothelial growth factor receptors (VEGFRs) on the endothelial cell surface are available. This blockade causes an anti-angiogenetic effect. Anti-angiogenic drugs are widely used as adjuvant therapy in the management of cancers because they suppress the formation of new blood vessels required by the tumour for growth. For similar reasons, they are used in the treatment of age-related macular degeneration.

The present treatment options for AVMs are surgery, embolisation and irradiation either on their own or in combination. Irradiation with stereotactic radiosurgery (SRS) offers the advantage of being non-invasive, but it relies on the late radiation effects to achieve its therapeutic goal of complete obliteration. This latent time (1–3 years), during which the risk for a bleed remains, is an inherent drawback of SRS. The histopathology of surgical specimens of post-SRS AVMs demonstrates a role of endothelial cells in repairing the radiation damage. Suppressing their activity post SRS by a VEGF blockade has the potential to enhance the radiation damage and hence speed up the obliteration process and reduce the latent time. It is postulated that such a ‘VEGF blockade’ could be useful as an adjuvant therapy to SRS. In addition, there is also the potential for a neo-adjuvant use, whereby a VEGF blockade could cause regression in the size of the AVM, making definite therapy easier. The rationale for the VEGF-blockade concept is presented and discussed.

Brahimi et al. in this journal formed a hypothesis that “the platelet count is underestimated, by an automated cell counter, each time platelet aggregates are present in the sample tube.” The addition of a platelet agonist to a stimulated sample tube will lead to the formation of platelet aggregates and hence to a drop in the platelet count. In the case of a hereditary platelet dysfunction, platelet aggregates cannot be formed upon addition of a platelet agonist and the platelet count will remain unchanged. The authors propose a hypothesis to develop “a more accessible screening technique for these hereditary platelet dysfunctions.” In our reply, we critically evaluate this screening method and focus on the importance of the differences between impedance aggregometry in whole blood versus aggregometry in platelet-rich plasma.

Neural stem cell (NSC) transplantation is an effective method of giving a supplement of cells lost and promoting functional recovery after spinal cord injury (SCI). Nonetheless, owing to hostile environments at the injury site, such as ischaemic hypoxia conditions and inflammatory cytokines, poor cell survival and uncontrolled differentiation are consistent problems encountered following NSC transplantation in ischaemic neural tissue. Hypoxia-inducible factor-1a (HIF-1α) provides profound protection to NSCs against negative factors at the injury site. On the other hand, HIF-1 can induce NSCs to differentiate into neurons. We predict that transplanted NSCs modified by an HIF-1α gene would have a better efficacy for promoting neural regeneration and functional reconstruction.

There are controversies about the effects of amniotic membrane (AM) on angiogenesis. It was recently hypothesised that denuded AM (without epithelial cells) can induce angiogenesis. The results from the dorsal skinfold chamber method in an animal model and aortic ring assay showed that the epithelial side of the AM inhibits vessel sprouting and reduces capillary numbers, while the mesenchymal side of the AM increases angiogenesis. These data answered the controversies about the angiogenic capability of the AM and raised some questions about the mechanisms by which the AM affects angiogenesis. In this article, mechanism(s) by which the AM affects angiogenesis and viability state of amniotic cells and its effect on angiogenesis have been propounded.

Trauma is the leading cause of temporomandibular joint (TMJ) bony ankylosis. The treatment of the condition poses a significant challenge because of the high incidence of recurrence. We previously proposed a new view that the development of traumatic TMJ bony ankylosis may be a course similar to hypertrophic nonunion, and the ensuing animal experiments preliminarily verified this view through histological analysis and molecular biology examination. In view of the similarity between bone healing and bony ankylosis, and the importance of recruitment and differentiation of mesenchymal stem cells (MSCs) during the course of bone healing, it is reasonable to select MSCs as the breakthrough point for prevention of bony ankylosis. Recent studies reveal that fibroblast growth factor 21 (FGF21), a key mediator of peroxisome proliferator-activated receptor-γ (PPARγ), can promote adipocyte differentiation, inhibit osteoblast differentiation of MSCs and stimulate osteoclast activity by activation of PPARγ. Therefore, we hypothesize that local FGF21 injection may prohibit the onset of traumatic TMJ bony ankylosis through formation of a fat pad separating the condyle from the glenoid fossa, inhibition of new bone formation and promotion of bone resorption in the joint space, which thus may be a potential novel treatment for TMJ bony ankylosis.

Coeliac disease is a chronic intestinal inflammatory condition, which is caused by an inappropriate immune response to components of wheat family cereals in a genetically susceptible host. Gliadins are the major pathogenic constituent of wheat; their toxicity and immunogenicity depend on their amino acid sequence. They are known to initiate the innate and the adaptive immune response. Nevertheless, it is not yet known how they are recognised by the intestinal epithelium and immune cells. Toll-like receptors (TLRs) are the best-studied group of pattern recognition receptors, which play a critical role in the initiation of innate immunity through the recognition of pathogen- and damage-associated molecular patterns. Exogenous food-derived proteins are not yet recognised as TLR ligands. Gliadin can activate TLR signalling pathway in vitro. The existing evidence is suggestive of the direct contribution of gliadin and/or other wheat components to activating TLR signalling. However, the data available so far are controversial and are mainly focussed on TLR 2 and TLR4. It is hypothesised that gliadin is a direct ligand for one of the TLRs. If indeed gliadin is proven to be a direct ligand of TLRs, our understanding of the pathogenesis of gastrointestinal diseases, such as colorectal cancer, will also be greatly influenced. In order to fully appreciate the role of gliadin as a direct TLR ligand, it should be proven to interact physically with and bind to one or more of the TLR molecules. Furthermore, it should be documented that TLR pathway activation is the downstream effect of gliadin/TLR binding.

Liver transplantation is the only choice for patients with end-stage liver diseases. Hepatocyte transplantation is a promising alternative for treatment of these groups. However, the major challenge is insufficiency of donor organs that can provide good-quality cells. Therefore, numerous experimental and clinical studies have evaluated the potential of different sources of adult stem cells, which differentiate into hepatocytes, for cell therapy. Endometrial (stem) stromal cells are readily isolated and expandable; moreover, these cells have more clonogenicity and pose less technical problems, so they are considered to possess great autologous therapeutic potential.

We propose that endometrial stem (stromal) cells could be an invaluable and realistic source in this regard.

Corneal neo-vascularisation (NV) is a major sight-threatening condition and is caused by infections, degenerative disorders, inflammation and long-time contact lens wear. Corneal NV occurs when the balance between angiogenic and antiangiogenic factors is tipped towards angiogenic molecules. The abnormal vessels may decrease corneal clarity and vision, lead to inflammation and corneal scarring and worsen the prognosis of penetrating keratoplasty if needed.

There is no definite therapeutic approach for cornea NV. Medical and surgical therapies used to reduce corneal NV include corticosteroids and non-steroidal anti-inflammatory agents, laser photocoagulation and needle diathermy. Many of these therapies not only have demonstrated limited success but also have associated adverse effects. Therefore, it is very necessary to provide novel therapeutic approaches. Recently, anti-vascular endothelial growth factor (anti-VGEF) therapy has been introduced for the management of corneal NV.

Herein, we hypothesise the use of silicate nanoparticles (SiNPs) as a novel treatment for corneal NV. The penetration rate of SiNPs into the cornea is attributed to the size of nanoparticles. Therefore, different sizes of SiNPs (20–50 nm) would be prepared and loaded onto the tissue to determine corneal permeability towards them. In addition, SiNPs would be administered into the eye by topical, subconjunctival and corneal intrastromal injection and accumulate in newly formed vessels. This hypothesis has been developed by emphasising on the synthesis of SiNPs, characterisation of size-dependent properties and surface modification for the preparation of homogeneous nanocomposites, generated by a reverse micro-emulsion method. As the importance of concentration, shape and/or size of SiNPs could be key factors exerting their antiangiogenic effects, we suggest using 20–30-nm SiNPs to enhance their ability to penetrate into the corneal epithelium. We hypothesise that topical, subconjunctival and corneal intrastromal injections of SiNPs may effectively inhibit and treat corneal NV. Controlled experimental studies on rabbits are needed to test whether SiNPs are able to effectively inhibit VEGF-induced angiogenesis in every segment of the eye including anterior, middle (ciliary body and trabecular mesh work) and posterior segments.