Journal of Medical Hypotheses and Ideas
Volume:6 Issue: 1, 2012

Insulin dependent diabetes mellitus (IDDM) is a global disease with high economic and social burden. A potential cure for type 1 diabetes is pancreatic islet transplantation. Despite recent improvements, islets are faced with various types of stress related to the isolation and transplantation procedure. Oxidative stress plays an essential role in cell damage during islet isolation and transplantation procedures. In this article, we hypothesise that a combination of cerium and yttrium oxide nanoparticles, as a power antioxidant with free-radical-scavenging activity, because of enhancing the survival or viability of cells in vitro can improve islet transplantation. No doubt, administration of this improvement can be used in diabetes treatment.

Reconstruction of the extrahepatic bile duct following bile duct injury or defect is one of the most common challenges for hepatobiliary surgeons. There are currently a number of surgical strategies such as biliary-enteric anastomosis, end-to-end anastomosis and autologous tissue substitute. However, sphincter of Oddi dysfunction as well as biliary stricture may occur after surgical anastomosis. Also, insufficient tissue quantity remains a problem associated with the application of tissue substitute. Therefore, considerable attention has been attracted to explore a new replacement material of the bile duct for biliary reconstruction. The human umbilical cord (HUC) is abundant in resource and is convenient to collect, including two arteries and one vein, whose diameters are close to that of the common bile duct. In order to reduce immunogenicity (foreign-body reaction), cells and major histocompatibility complex (MHC) antigens can be removed from the HUC and the remaining tissue (extracellular matrix, ECM) can be used as a scaffold. The HUC provides a rich source of mesenchymal stem cells (MSCs). A current study has demonstrated that MSCs are able to differentiate into biliary epithelial cells in vivo and in vitro with low immunogenicity, which can be used as seed cells. The HUC might be a promising composite material of a scaffold (ECM) and seed cells (biliary epithelial cells), for bile duct replacement in situ without removal of sphincter of Oddi, or biliary stricture. In addition, the patients’ own umbilical cord without any foreign-body reaction can be directly banked for possible future use in bile duct reconstruction. Therefore, we hypothesise that the HUC may be a novel substitute for reconstruction of the extrahepatic bile duct.

Tolerability is an essential part of drug therapy and can affect health and economic outcomes. Withdrawal due to adverse reactions of medicines or lack of effectiveness is a major concern in long-term treatments that influences cost-effectiveness analysis. In case of possibility of stopping and switch to other interventions in decision analysis model, overhead costing may affect results and decision-making processes. Thus, modifying of classic decision analysis model seems to be necessary in such cases. My hypothesis is that by the use of a new decision model that can make links between different Markov-like models accurate cost calculation could be achieved. The appearance of model is going to be like a semicycle net. Considering the probability of switching from one treatment strategy to another, one could give more precise economic evaluation results. In the first step, this model needs to be tested and compared with the conventional model. In the second step, the impact of these differences has to be examined in the practical field of health, drug policy and supply management. By applying this new decision model in total health budget, threshold and its consequences on national health accounts and share of health in gross domestic product should be tested.

Leakage from anastomosis site and low anterior resection syndrome are serious complications that may occur after low anterior resection for low rectal cancers. Although surgeons recommended different surgical and medical solutions for decreasing these complications, they are not successful in some cases. We think using the ileal pouch with vascular pedicle instead of devascularised and denervated left colon to anastomosis to anal canal may diminish these two problems. It needs more animal studies and then clinical trials to evaluate this new technique.

The anticancer activity demonstrated by genetically attenuated invasive Shigella flexneri contradicts the long-held understanding of bacterial infection-mediated anticancer activity (BIMAc), as a ‘by-stander effect’ caused by an immune response against any invading pathogen as a reason for tumour regression. Similarly, the selective tumouricidal effect by Salmonella A1 auxotrophic mutant in nude mice is another observation where the current theory fails. Considering these flaws, we set to re-examine the mechanisms behind BIMAc independent of immune response, on the basis of molecular understanding about the initial colonisation of gut epithelium by S. flexneri and its production of cell-cycle-inhibiting proteins called cyclomodulins. During infection, S. flexneri injects OspE effector protein into the gut epithelium. The resulting interaction of OspE with ILK prevents epithelial cell exfoliation and facilitates the pathogen’s colonisation of the gut. This interaction is also shown to enhance membrane retention of ILK in these infected cells. Correspondingly, another study reports the indispensable role of ILK in survival of cancer cells with supernumerary centrosomes by localising it to the centrosomes and clustering them into a bipolar spindle. Knockdown of ILK in these cells leads to apoptosis due to multipolar mitosis. From these cumulative facts we hypothesised that enhanced membrane retention of ILK in Shigella-infected cancer cells prevents localisation of ILK to centrosomes and provokes multipolar mitosis and therefore cell death in cancer subpopulations with supernumerary centrosomes. This interaction may also be metastasis suppressive, because of its inhibitory effect on the focal adhesion turnover of gut epithelium, which is quintessential for any form of cell migration. Apart from these, Shigella also encodes potent cell-cycle-inhibiting effector molecules such as cyclomodulins. The additive action of these cyclomodulins along with the OspE–ILK interaction may be considered as the reason behind the anticancer activity mediated by Shigella infection.

Behçet’s disease (BD) is a systemic vasculitis which is characterised by oral, aphthous ulcers, genital ulcers, skin lesions and ocular manifestations. Although the aetiopathogenesis of BD is still unknown, the critical role of Th1 immune responses, neutrophil hyperactivation alongside overproduction of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-8, tumour necrosis factor-alpha (TNFα) and particularly IL-17 have been demonstrated in the immunopathogenesis of the disease. Despite significant progress in understanding of the aetiology of the disease, its treatment remains intricate, and is still treated with immune-suppressive drugs and biological agents with probable systemic side effects. Accordingly, there is a necessity to establish the more efficient and less toxic therapeutic methods which may offer a long-time remission of BD.Mesenchymal stem cells (MSCs) are non-haematopoietic and multipotential stem cells with immunosuppressive capacities in innate and acquired immune systems. MSCs can migrate to damaged tissues and prevent secretion of proinflammatory cytokines and other immunomodulatory effectors, increasing the survival of damaged cells, although the exact underlying mechanisms are still unknown. For this purpose, numerous herpes simplex viruses are injected into C57BL/6 mice to produce Behçet’s mouse model and transferring a certain number of MSCs may have therapeutic value for control of Behçet’s animal model, so researchers could deliberate the function of MSCs and proinflammatory cytokines particularly IL-17A-F, TNF-α, interferon gamma (IFN-γ), IL-2, IL-6 and IL-8 in an experimental model.The aim of this hypothesis is to evaluate immunosuppressive and immunomodulatory properties of MSCs in syngeneic animal model for BD, in order to clarify the mechanisms of MSCs in BD management, as a broad and more confident treatment in clinical application.

Caesarean rate has been increasing year by year in China and other countries in the world. In fact, caesarean section is associated with increased risk of maternal mortality and serious foetal pulmonary morbidity. To reduce caesarean rate, obstetricians in physician-based birth units get used to take early intervention for any delay in labour progress that could cause dystocia. However, standard obstetric care enhanced by obstetric power has not consistently been shown to reduce rate of caesarean delivery. Other than physician-based model, midwife-led model of care is aiming to promote normal birth by use of midwives’ skills as well as continuous support rather than augmentation of labour through excessive medical treatment. Midwife-led care model is novel to worldwide birth units where standard obstetric care still dominates. It has made some headway in efforts to reduce caesarean rate. The fact that standard obstetric care of childbirth have not consistently reduced rate of caesarean delivery encourages us for creating the hypotheses that midwife-led care model satisfying puerpera with care and support could minimise unnecessary obstetric intervention and facilitate vaginal birth, and finally reduces caesarean rate. This hypothesis, if confirmed, might have the potential to be disseminated elsewhere in the world, where most women still take standard obstetric care. Moreover, it has political implications for the national health-care policymaking.

Metal phosphides in general are potent pesticides that are a common cause of human poisoning. Various salts of phosphides produce highly toxic phosphine in exposure to gastric acid that results in multi-organ damage and death. There is no antidote for phosphine poisoning and most of human poisoned cases do not survive. All we know so far is that phosphine is a mitochondrial toxin that inhibits cellular respiration and induces oxidative stress. Mechanistically, phosphine as a reducing agent interacts with metal ion cofactors at the active site of enzymes and inhibits key enzymes such as cytochrome C oxidase that lead to inhibition of mitochondrial respiration. Phosphine (E0 = −1.18 V) as a reducing agent gives electrons to cytochrome C oxidase (E0 = +0.29 V). Metal phosphides with lower reduction potential are stronger electron donors and thus stronger poisons. Our hypothesis is that if an electron receiver stronger than cytochrome C oxidase is used then it would compete with cytochrome C oxidase in interaction with phosphine. This competition might prevent or reduce the inhibition of cellular respiration. This idea can be tested in an animal model of phosphine toxicity by monitoring cardiovascular state and measuring the cardiac mitochondrial function.

Child labour is an immense problem in Pakistan. As labour boys are put under persistent/severe physical stress, we hypothesised, that it may result in higher levels of cortisol and exhaust glycogen, fats and protein. Depletion of fats may result in lower body weight, and insufficient leptin concentrations could excite gonadotropic releasing hormone (GnRH) at normal time of puberty in working boys. Moreover, lower testosterone levels in working boys, due to delayed puberty, may result in suppression of somatotropic axis. Short/weak stature and failure of onset of puberty may cause poor performance, inferiority complex and psychological disorders. Therefore, the present study is designed to find out the timing of onset of puberty in working boys. The study will include 10–18 years of working boys as case and non-working boys of the same age group as control. Working boys will be labour boys, while the control group will not be involved in physical work. A questionnaire will be used to record socioeconomic status, major diseases, nutritional status, type and duration of work and family history of puberty, growth and obesity of subjects. Boys with familial history of pubertal delay, obesity, malnutrition, mental disorders, haematological diseases and severe/chronic diseases will be excluded. The intensity of physical working stress will be determined by a grading scale. The anthropometric data including height, weight, body mass index (BMI), bone age and tests of adiposity will be collected from subjects. The stages of pubertal onset will be determined by Tanner staging. Serum concentrations of hormones of growth, thyroid, adrenal, brain–gut and gonadal axis will be determined in non-working and working boys. Physical and hormonal tests of the working boys and the comparison with non-working boys are sufficient to test the idea.

Autism is a neurodevelopment disorder. Its aetiology and pathophysiology are not clearly known. However, mitochondria may play a significant role at least in some cases of autism. There is no therapeutic approach for autism. Moreover, there are only few Food and Drug Administration (FDA)-approved medications for autism. Therefore, providing novel therapeutic approaches are highly required. Oxidative stress is suggested as an important factor in the aetiology of autism. Already some interventions targeting oxidative stress in autism are suggested.This article reviews evidence about the possible role of gold nanoparticles and lipoic acid (LA) as anti-inflammatory agents. It mentions some evidence about the possible role of oxidative stress. Then, the role of gold nanoparticles and LA for the management of autism is discussed.According to the above-mentioned evidence, it is hypothesised that gold nanoparticles and LA may reduce neuro-inflammation in autism.Controlled experimental studies are needed to test whether gold nanoparticles plus LA enhance antioxidative stress system leading to the improvement of autism clinical symptoms.

The blockage of cancer cell growth and division is the prime objective in clinical cancer therapy both at early stages and for inhibition of minimal residual disease and relapse. The failure of conventional therapies in treating breast cancer (BC) has prompted dissection of signalling pathways involved in BC cell growth and characterisation of cellular receptors. Specific sets of membrane-bound receptors promote disarrayed self-renewal of BC stem cells and deregulated BC cell proliferation. Individual blockage of each receptor promotes only incomplete inhibition of BC cell growth and partial regression of metastasis. Such monotherapies are based on either chemotherapy or monoclonal antibodies. However, they do not provide long-lasting benefits and are further compromised by increasing resistance the cancer cells acquire against therapeutic agents, by their evasion of receptor blockage and by adoption of alternative growth routes that are induced by cross-talks between key receptors. On the other hand, dual targeting approaches, including receptor blockage combined with chemotherapy, produce prolonged overall survival but, nevertheless, complicate treatment by inducing side effects. Based on the complex nature of BC, combined targeted strategies that potentially confer maximum coverage for treatment cannot be effective without overcoming drug resistance initiated and further induced by inter-receptor communications. This implies that a comprehensive strategy based on concomitant inhibition of key receptors could provide an ultimate solution for effective treatment of aggressive types of BC. Such a strategy would likely be capable of targeting breast tumour cells and BC stem cells alike eventually forcing the cancer to regress.

Cancer is a leading cause of death worldwide. Interventional cancer therapy made huge progress in the past few decades; however, traditional interventional therapy, for example, transarterial embolisation and transarterial chemoembolisation, remains to be developed for its potential limitations. Numerous studies in the past half century demonstrated that tissue injury accelerated after ischaemia reperfusion. Reactive oxygen species (ROS) production, cell death and inflammatory factors involved in the development of ischaemia reperfusion injury. As outlined above, we hypothesise that reperfusing the tumour lesion with high oxygen, high calcium and high pH fluid together with ROS-generating agents and/or inhibitor of antioxidant system, with or without traditional chemotherapeutic agents after a short-time arterial embolisation, can effectively induce cancer cell death, and it might be a new attempt in cancer interventional therapy.

Organophosphate pesticides (OPs) inhibit both true and pseudo-cholinesterases by reaction with the hydroxyl group of serine in their active sites. Poisoning with OPs is commonly seen in clinics. A common antidote for OP poisoning is atropine but, after ageing and OP dealkylation, even oximes could not be effective. It has been shown that oximes are not always useful in management of OP poisoning. On the other hand, magnesium has been found effective in both clinical and experimental studies. Studies to find more effective antidotes for OP poisoning are in progress. Presently, the possible role of magnesium ion in catalysis of reaction of dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP), a water-soluble OP, with serine is proposed. The hydroxyl group of serine could be a target to which DDVP can react. Nucleophilic attack of pralidoxime to DDVP was previously investigated. To confirm the idea, data were derived from recent and previous research on the role of magnesium in phosphoryl group transfer reactions. Possible reactions of serine and pralidoxime with DDVP in the absence and the presence of magnesium ion were separately investigated theoretically.

The brown adipose tissue (BAT) is an organ with the specialised function of intracellular fat oxidation; in other words, brown fat points to a potential natural tool by which energy expenditure is being stimulated. Obesity is a serious illness which can lead to many medical complications such as cardiovascular disorders. The BAT production, therefore, could be a promising therapeutic strategy for managing obesity. While different approaches have been examined to generate brown adipocytes from various precursor cells, no study has proposed an efficient procedure for direct trans-differentiation of white to brown adipocytes. Bone morphogenic protein (BMP)-7 is a possible potential agent by which most of the main factors involved in induction of brown adipocytogenesis such as early regulators of brown fat fate, positive regulatory domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1α) are stimulated, but the rate of success was not so promising. It has been documented that mature white adipocytes exert endoplasmic reticulum stress response (ESR) and consequently unfolded protein response (UPR) becomes activated for the purpose of ESR recovery since the ESR exceeds the capacity of UPR to overcome the imposed stress, and in turn disables the cell to manage the protein synthesis cascade including those required for BMP-7 induction of brown adipogenesis. This was performed using three main ESR sensors: PKR-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme-1 (IRE-1) and activating transcription factor 6 alpha (ATF-6α) resulting in attenuation of protein translation by blocking the activation of transcriptional machinery of UPR genes and the cell behaviour would also be changed towards apoptosis.

Paraquat dichloride (PQ) is an effective and widely used herbicide for eliminating weeds. However, once being accidentally or voluntarily ingested, PQ-poisoned patients have the very high incidence of adult respiratory distress syndrome because lung can actively absorb PQ. Since the 1970s, evidence suggested that polyamine competitively inhibited uptake of PQ into lung tissue; therefore, polyamine transport system has been regarded as an important vehicle for PQ uptake into lung. However, so far, we cannot clone or detect the polyamine transport system in mammalian animal. Recent evidence from diverse sources has suggested that caveola may be an important vehicle for polyamine absorption into lung. Herein we hypothesise that caveola is a key vehicle for PQ uptake in lung and hence blocking the expression of caveola may serve as new targets for treatment of PQ poisoning.