The goal of primary chemoprevention is to decrease the incidence of a given cancer, simultaneously reducing treatment-related adverse events, cost of treatment of the disease and mortality. Prostate cancer is an attractive and appropriate target for primary prevention because of its high incidence and prevalence, increased disease-related mortality, long latency and molecular pathogenesis and epidemiological data indicating that modifiable environmental factors may decrease risk. Various agents have been suggested to prevent prostate cancer and many clinical trials are currently on. Ultimately the adoption of a preventive strategy hinges on its potential benefits weighed against the potential risks of the specific agents used. This article is aimed to examine the experimental and epidemiological data spanning a period of 1998 to 2007, demonstrating the chemopreventive activity, safety and toxicity of various nutritional elements and other agents that can help prevent prostate cancer and/or slow disease progression. Prostate cancer is a slow-growing tumor of older men, constituting the most common type of non-skin cancer and the second leading cause of cancer-related deaths in American men. In the late 80s and early 90s great attention was given to screening asymptomatic men by measuring concentration of prostate specific antigen (PSA), which eventually led to a significant increase in the detection of clinically insignificant tumors. Despite this increase, mortality due to prostate cancer has decreased every year since 1992. Though the exact pathogenesis is not clear, epidemiological evidence supports a relationship between prostate cancer and serum levels of testosterone.[Although controversial, strategies for decreasing prostate cancer mortality have focused on early detection. The most important tumor marker for detection and post-treatment monitoring of prostate cancer is PSA level. However, PSA levels have fallacies. Increased levels of serum PSA can occur in prostate cancer, benign prostatic hyperplasia and prostatitis. Conversely, treatment with 5 alpha reductase inhibitors lowers PSA levels to approximately 50%. However, PSA assessment still remains the best method to detect cancers at a pre-symptomatic stage. Newer methods for increasing the sensitivity and specificity of PSA screening tool are currently being adopted.To identify the various strategies for prostate cancer chemoprevention, a MEDLINE search (from 1970 to 2007) and bibliographic search of the English language literature was conducted.Carcinogenesis is a multi-step molecular process induced by genetic and epigenetic changes that disrupt the balance between cell proliferation, apoptosis, differentiation, senescence and the pathways controlling these cellular processes. Precursor lesions that represent intermediate stages between normal and malignant cells can arise as long as 20 years before the appearance of cancer. Chemoprevention is defined as the use of natural or synthetic agents that reverse, inhibit or prevent the development of cancer in cancer-free individuals. Importan6Evidence from epidemiological studies suggests associations between exposure to a variety of dietary nutrients and certain cancers including lung, colon, breast and prostate. The roleThere are a number of carotenoids with antioxidative activity. Lycopene is a red-orange, highly unsaturated, acyclic isomer of beta-carotene found primarily in tomatoes and tomato-derived products and in other red fruits and vegetables. Lycopene possesses significant antioxidant properties that may confer some antineoplastic activity. Studies have found out that increased lycopene intake was associated with a decreased risk of prostate cancer.–12 HowevSeveral studies support a positive correlation between some aspect or component of animal fat and prostate cancer risk.18 PopulaConsumption of oily fish and other foods rich in omega-3 fatty acids may help prevent the spread of carcinoma prostate. The omegThe diet in many Asian countries is especially high in plant products including soy. Higher c2528Epidemiological studies have shown that there is a low incidence of prostate cancer among native Asian men with a high dietary intake of green tea and hence the polyphenols contained in green tea have been proposed as chemopreventive. Prostateα-tocopherol is the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts and other foods. It is a potent antioxidant and has been suggested as a potential preventative of several cancers, particularly lung cancer. In the ASelenium found in many vegetables and grains grown in selenium-rich soil has antioxidant activity and has other direct effects on tumor cells. Higher lThe Selenium and Vitamin E Cancer Prevention Trial (SELECT) was started to evaluate the role of vitamin E and selenium supplementation in preventing prostate cancer. This proVariation in the degree of exposure to sunlight affects the blood levels of vitamin D and calcium in the population. Studies have shown that men with higher levels of serum calcium have a four to fivefold elevated risk of metastatic prostate cancer.40 The acSummary: Food rich in lycopenes , omega 3 fatty acids (fish oils), isoflavonoids (soybeans), polyphenols (green tea), α-tocopherol , selenium , vitamin D and fiber can significantly reduce the risk of developing prostate cancer or even reduce the mortality due to the disease.Non-steroidal anti-inflammatory drugs act to prevent the synthesis of endogenous prostaglandins by inhibition of the cyclo-oxygenase (COX) enzyme. Expression of the COX-2 isoenzyme is three to five times greater in patients with prostate cancer than in those with benign prostatic hyperplasia and is responsible for increased angiogenesis, tumorigenesis and prostate cancer growth.44 Non-stSummary: Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, sulindac and ibuprofen are reported to have prostate cancer chemopreventive activity.Interest in SERMs as preventive agents is stimulated by an apparent role of estrogens in the pathogenesis of prostate cancer through promotion of cell growth. FurthermSummary: Phytoestrogens and SERMs are found to have prostate cancer prevention potential in experimental studies.In vitro studies also showed that the growth of previously established prostate cancer lines were inhibited by 5-alpha-reductase inhibition.[It is well known that dihydrotestosterone is the principal androgen responsible for normal and hyperplastic growth of prostate and is 10 times more potent than testosterone. 5-alpha-reductase inhibitors prevent the conversion of testosterone to dihydrotestosterone. Of the two isoenzymes of 5-alpha-reductase, Type 2 is present in normal and hypertrophic prostate tissue, whereas Type 1 is the predominant form in prostate cancer cells and is over-expressed in some prostate cancers. Because androgens are required for the development of prostate cancer and men hibition.50 Out ofhibition. In the Phibition. The poteA Phase II, double-blind, placebo-controlled, dose-ranging comparative trial clearly demonstrated that serum dihydrotestosterone suppression was significantly greater with the dual (Type 1 and 2) 5-alpha-reductase inhibitor dutasteride 0.5 mg/day than with finasteride 5 mg/day in men with benign prostatic hyperplasia. The ReduHowever, other androgen blockers like flutamide, bicalutamide and nilutamide are associated with too many side-effects to be of practical use in the asymptomatic healthy population, unlike finasteride.Summary: 5-alpha-reductase inhibitors such as finasteride and dutasteride have been recommended as chemotherapeutic agents for prevention of prostate cancer.1, vitamin B2, niacin, zinc, protein and carbohydrates with prostate cancer. However, other drugs like nonclassic antioxidant agents including the polyphenols, the isothiocyanates, difluromethylornithine, oltipraz and N-acetyl cysteine have been proposed as potential chemopreventive agents.[Studies by Giovannucci and Clinton have shoe agents.57in vitro and in vivo preclinical models.[Many chemotherapeutic agents including Silibinin, Inositol hexaphosphate, Hecursin, Apigenin, Acacetin and Epigallocatechin-3 gallate have been identified in laboratory studies to be of use in the management of prostate cancers. The extrl models. Similarll models. Grape sePhytochemicals are nonnutritive components of plants that are currently being studied in chemoprevention of various diseases for their pleiotropic effects and non-toxicity. Various studies–63 have Sanguinaria canadensis has been shown to possess anti-microbial, anti-inflammatory and antioxidant properties. It has been shown that sanguinarine can cause cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin dependent kinase machinery.[Sanguinarine, an alkaloid derived from the bloodroot plant achinery. The growEncouragingly, it was recently proposed that the consumption of red wine might be protective against prostate cancer. Every adEating at least five servings a week of cruciferous vegetables such as broccoli and cauliflower can significantly decrease the risk of developing prostate cancer. SulforapRosmarinus officianalis), turmeric (Curcuma longa), ginger , basil (Ocimum basilicum), green tea (Camellia sinensis), Japanese knotweed (Polygonum cuspidatum), Chinese goldthread (Soptis spp), barberry (Berberis spp), Oregano (Origanum vulgare) and Chinese or Baikal skullcap .Zyflamend, a unique herbal preparation with non-selective COX-inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. ZyflamenSummary: Nonclassic antioxidant agents like polyphenols, isothiocyanates, difluromethylornithine, oltipraz and N-acetyl cysteine and chemotherapeutic agents including Silibinin, Inositol hexaphosphate, Hecursin, Apigenin, Acacetin and Epigallocatechin-3 gallate have all been proposed to have antineoplastic properties. The extracts of pomegranate and grape seed, curcumin, sanguinarine, an alkaloid derived from the bloodroot plant Sanguinaria canadensis, resveratrol in red wine and sulforaphane in cruciferous vegetables can also significantly decrease the risk of developing prostate cancer.Vaccines for prostate cancer, which for several years have been shown to generate immunological responses, are beginning to show significant clinical promise. DendritiSummary: Trials on vaccines offer great promise for prevention of prostate cancer in the near future.Identifying pharmacologic and nutritional preventive strategies for prostate cancer remains a challenge for physicians and researchers. Though prevention of prostate cancer seems to be novel approach, it is yet to be understood who would benefit from these drugs. It is logical to understand that people with genetic predisposition are less likely to benefit than men at risk for sporadic cancer. The efficacy of the drugs will also have to be proved by large randomized clinical trials of long duration. Biomarkers of carcinogenesis, tailored to the agent under investigation are essential in the clinical development of chemopreventive agents. Prostatic intraepithelial neoplasia (PIN) is an intraluminal proliferation of secretory cells of the prostate duct-acinar system. Common get al.,[Androgen receptor (AR) plays a key role as a transcriptional factor in prostate development and carcinogenesis. Identification of androgen-regulated genes is essential to elucidate the AR pathophysiology in prostate cancer. By combining chromatin immunoprecipitation (ChIP) with tiling microarrays (ChIP-chips), the androgen target genes that are directly regulated by AR in LNCaP cells have been identified. This wilet al., showed tet al., has sugget al., providesFor the common man, the bottom line of prostate cancer prevention would be to consume a variety of fruits and vegetables, reduce the intake of white bread, meats and saturated fat, reduce or eliminate smoking, reduce stress, sleep well, exercise, avoid unnecessary hormone use, particularly androgens, eat more fiber and fish oil. However, it is worthwhile for the treating physician to understand the various agents useful in primary prevention which includes the period prior to the diagnosis of prostate cancer and in secondary prevention which may involve the prevention of recurrence or progression of micrometastatic disease. An ounce of prevention is worth a pound of cure.


Image-guided focussed ultrasound (FUS) ablation is a non-invasive procedure that has been used for treatment of benign or malignant breast tumours. Image-guidance during ablation is achieved either by using real-time ultrasound (US) or magnetic resonance imaging (MRI). The past decade phase I studies have proven MRI-guided and US-guided FUS ablation of breast cancer to be technically feasible and safe. We provide an overview of studies assessing the efficacy of FUS for breast tumour ablation as measured by percentages of complete tumour necrosis. Successful ablation ranged from 20% to 100%, depending on FUS system type, imaging technique, ablation protocol, and patient selection. Specific issues related to FUS ablation of breast cancer, such as increased treatment time for larger tumours, size of ablation margins, methods used for margin assessment and residual tumour detection after FUS ablation, and impact of FUS ablation on sentinel node procedure are presented. Finally, potential future applications of FUS for breast cancer treatment such as FUS-induced anti-tumour immune response, FUS-mediated gene transfer, and enhanced drug delivery are discussed. Currently, breast-conserving surgery remains the gold standard for breast cancer treatment. Breast cancer is the most frequently occurring malignant disease and leading cause of cancer-related death in women in the Western world. The number of new cases and deaths from breast cancer for women in the US in 2007 was estimated to be 178,480 and 40,460, respectively , 4. AfteTechnological advances over the last decade have fuelled interest in even less invasive treatment of patients with localized breast cancer. Currently available minimally invasive image-guided tumour ablation techniques include radiofrequency ablation, cryoablation, laser ablation, microwave ablation, and focussed ultrasound (FUS) ablation . DiffereUltrasound beams are generated by a piezoelectric ultrasound transducer and propagate through tissue as a high-frequency pressure wave. By focussing the ultrasound beams to a focal spot at a certain distance from its source, acoustic energy is converted to heat, and a sharp circumscribed lesion caused by thermal coagulation will be produced . The skiThe potential application of FUS ablation for thermal tumour destruction was demonstrated as early as 1942. Lynn et al. reported focal lesions after FUS ablation in mammalian brain tissue . HoweverDiagnostic ultrasound can also be used to guide the FUS ablation procedure . With USThis first experience of MRI-guided FUS for treatment of benign breast tumours was reported by Hynynen et al. in 2001 . They deIn the study performed by Khiat et al. the effect of post-treatment delay for evaluation of MR images on the presence of residual cancer was assessed in 25 patients with 26 tumours . HistopaThe first study on MRI-guided FUS ablation of breast cancer as an adjunct to a preexisting tamoxifen citrate chemotherapeutic regimen for treatment of elderly, high-risk surgical patients was reported by Gianfelice et al. in 2003 . Since nExperience with ultrasound (US)-guided FUS ablation of breast cancer is limited and has only been reported by Wu et al. They reported three studies on the accuracy of US-guided FUS ablation for breast cancer treatment , 33, 36.In the past decades, screening programmes and development in breast imaging techniques have led to an increase in the detection of early stage breast cancer . Breast-To be equivalent to surgical removal, the effect of FUS ablation should be to achieve total (100%) tumour necrosis. Results of studies on FUS breast cancer ablation to date have been variable, with histopathologic analysis demonstrating complete tumour necrosis in 20% to 100% of patients treated , 40–47. Several studies have examined the importance of tumour-free surgical margins after breast-conserving therapy . IdeallyIf FUS is to be implemented in clinical breast cancer treatment as an alternative to conventional surgery in the future, a reliable method for tumour margin assessment and detection of residual tumour after FUS ablation must be available. Since FUS treatment would lack a surgically excised pathological specimen, the tumour margin status could not be assessed by histopathological analysis. To date, most protocols have been treat-and-resect protocols, i.e., FUS ablation followed by surgery, which allows histopathological tissue examination to evaluate the therapeutic effect of FUS. In the few FUS ablation studies where treated tumour tissue was left in situ after ablation, different strategies have been used to assess outcome. Furusawa et al. used clinical follow-up by MRI and US every 3 months . If one Another important issue for successful FUS ablation is appropriate patient selection. Some breast cancer patients cannot be scheduled for FUS ablation for technical reasons. For FUS treatment a distance of at least 1 cm between the tumour and the skin (to avoid skin burn) and tumour and chest wall (to prevent heat accumulation in the underlying ribs and lung) is required . For MRIWhen FUS ablation is applied for local tumour control in non-surgical candidates with locally advanced breast cancer or metastatic breast disease, the two issues of tumour size and extensive intradutcal tumour component are less important . In thesFor breast cancer patients, information about the presence of metastases in regional axillary lymph nodes is an important prognostic factor. Sentinel lymph node biopsy (SLNB) is a validated minimally invasive diagnostic procedure used to determine the status of regional lymph nodes for staging purposes –61. TheoAlthough most of the FUS research focusses on thermal ablation for localized thermal treatment of breast cancer, it has been reported that thermal and mechanical damage of a primary tumour by FUS may trigger systemic biological responses in vivo as well. FUS tumour ablation creates a large amount of tumour antigens in the form of necrotic cells and damaged tumour cells, which may trigger dendritic cell activation. This mechanism may play a critical role in FUS-induced anti-tumour immune response. This hypothesis was recently tested in mice implanted with adenocarcinomas and treated with thermal and mechanical FUS ablation in order to assess FUS-induced effects on the mice’s immunological response, as expressed by in vivo dendritic cell activity . The resAnother potential therapeutic application is FUS-mediated gene transfer . One of FUS hyperthermia has also been studied in animal models for targeted chemotherapy to solid tumours. Since conventional chemotherapeutic regimens cause systemic toxicity, developing strategies for improved targeted chemotherapeutic delivery is of great clinical interest. One method used for targeted chemotherapy is the use of heat-sensitive liposomes. In this method the chemotherapeutic drug is encapsulated in the liposome, which results in prolonged intra-vascular circulation time. Because malignant tumours are associated with neo-angiogenesis resulting in leaky vessels, liposomes will preferentially accumulate in the interstitium surrounding the tumour . FUS-indFUS ablation has the potential to become an important modality for non-invasive image-guided treatment of localized breast cancer. Multiple phase I studies have proven MRI-guided and US-guided FUS ablation of breast cancer to be technically feasible and safe. The reported efficacy of FUS ablation as measured by percentages of complete tumour necrosis ranged from 20% to 100%. The difference in outcome between FUS ablation studies can be explained by differences in patient selection, imaging techniques, and tumour ablation protocols used. Although the results of US-guided and MRI-guided FUS ablation are promising, the data are too scant to justify a randomized controlled trial that compares FUS ablation with breast-conserving surgery for treatment of localized breast cancer. To date, MRI-guided treatment protocols of breast tumours offer the most accurate imaging technique for breast tumour targeting, breast tumour delineation, treatment monitoring (including temperature mapping), and detection of residual disease after treatment. The next step towards clinical implementation of FUS for breast tumour ablation would be a large prospective treat-and-resect study that assesses the therapeutic efficacy of MRI-guided FUS ablation in patients with small (<2 cm) solitary breast cancers and provides data that can be used for technique standardization and guideline formulation. In addition, FUS for anti-tumour immune response induction, controlled transgene expression, and targeted drugs delivery in breast cancer patients should be explored. Currently, breast-conserving surgery remains the gold standard for breast cancer treatment.


Case-control studies in diverse populations around the world have reported a lower risk of breast cancer in association with higher intake of dietary fibre and complex carbohydrates. Although this has not been confirmed in prospective studies in the USA, the observations have prompted the hypothesis that prolonged use of dietary fibre supplements might reduce breast cancer risk in high-incidence populations. Several possible mechanisms of action have been suggested, all involving a reduction of bioactive oestrogen levels in the blood. The various mechanisms are not necessarily mutually exclusive. First, a high-fibre diet might reduce circulating oestrogen levels by reducing the enterohepatic recirculation of oestrogen. Second, many plants and vegetables contain isoflavones and lignans capable of conversion in the bowel into weak oestrogens that may compete with oestradiol for target binding-sites. Third, a high-fibre diet is less often associated with obesity, which tends to increase availability of the biologically active 16-alpha metabolites of oestrone. Fourth, a high-fibre diet usually has a lower content of fat and a higher content of antioxidant vitamins, which may protect against breast cancer risk. Finally, diets rich in fibre and complex carbohydrates have been shown to improve insulin sensitivity, with an associated reduction in circulating oestrogen levels. Synergism between these effects offers a possible mechanism by which a high fibre intake might suppress breast cancer growth in women.


Fusarium mycotoxins directly accumulated in grains during the infection of wheat and other cereal crops by Fusarium head blight (FHB) pathogens are detrimental to humans and domesticated animals. Prevention of the mycotoxins via the development of FHB-resistant varieties has been a challenge due to the scarcity of natural resistance against FHB pathogens. Various antibodies specific to Fusarium fungi and mycotoxins are widely used in immunoassays and antibody-mediated resistance in planta against Fusarium pathogens has been demonstrated. Antibodies fused to antifungal proteins have been shown to confer a very significantly enhanced Fusarium resistance in transgenic plants. Thus, antibody fusions hold great promise as an effective tool for the prevention of mycotoxin contaminations in cereal grains. This review highlights the utilization of protective antibodies derived from phage display to increase endogenous resistance of wheat to FHB pathogens and consequently to reduce mycotoxins in field. The role played by Fusarium-specific antibody in the resistance is also discussed. Aspergillus, Fusarium and Penicillium [Fusarium head blight (FHB) pathogens takes place mainly during the flowering period of small grain cereal crops in field and consequently mycotoxins produced during the infection directly accumulate in grains, and thus enter food/feed chains. Fusarium mycotoxins are among the main fungal mycotoxin contaminations in food and livestock in China, and some human diseases, such as Kashi-Neck diseases and esophageal cancer, have been epidemiologically associated with consumption of trichothecence mycotoxins [Fusarium mycotoxin-producing pathogens under high disease pressure [Mycotoxins are secondary metabolites that are produced by many different genera of fungi including icillium , 2. Infecotoxins . To prevpressure , 5 and tpressure , 7. Currpressure –11.Fusarium mycotoxins and pathogens have been generated. Fungus-specific antibodies have been shown to reduce fungal growth in vitro [Fusarium mycotoxins in filed, with emphasis on application of antibody fusion proteins in cereal crops.Antibodies, or immunoglobulins, are defense molecules synthesized by all vertebrates in response to the presence of a foreign substance, called an antigen. They display defined specificity and affinity for the antigens that elicited their synthesis. Antibodies recognize and bind substance-specific antigens and thus help to eliminate substances from the body. Various antibodies specific for in vitro  and to pin vitro . Monocloin vitro –19 and iin vitro , 21 in ain vitro . ExpressFusarium mycotoxins and mycotoxin-producing fungi are isolated and widely used in immunoassays [in vitro from libraries containing diverse repertoires of antibodies V-genes, which bypasses hybridoma technology altogether and generates single-chain antibodies with specificity and affinity similar to monoclonal antibodies. This is based on the fact that the difference in antigen-binding specificities between antibodies lies entirely within their variable regions that are directly involved in the interaction with antigens. Therefore, it is necessary only to isolate genes encoding for the variable domains, which can then be jointed to constant regions by recombinant techniques [Fusarium mycotoxin-producing pathogens in cereals.With the invention of hybridoma technology , monoclonoassays –28. Howenoassays , 30. By chniques , 32. TheE. coli. Phages isolated from the bacteria are used for the next round of panning on the antigens. Solution phase panning can be carried out by incubating the phage library with biotinylated antigens and capturing the complex on streptavidin coated paramagnetic beads. Eluted phages are subjected to bacterial infection as described for the solid phase panning. A total of three rounds of panning is usually performed. Phage displayed antibodies are screened for binding to the antigens by enzyme-linked immunosorbent assay (ELISA). After BstNI fingerprinting of ELISA-positive clones, the nucleotide sequences encoding for scFv antibodies can be determined. scFv antibody genes can be manipulated genetically with ease for the construction and expression of new recombinant proteins, such as AFP -scFv fusions described in Fusarium cell surface. Western blot analyses and immunofluorescence labelings confirm that these antibodies react strongly with cell wall-bound proteins and bind to the surface components of F. asiaticum, a predominant FHB species in China [Fusarium pathogens and for the construction of antibody fusion proteins [In phage display, each phage displays a single antibody fragment comprising the variable regions of the heavy and light chains that form the Fv domains of natural antibodies, which is called a single-chain variable fragment (scFv). The scFv gene contained in the phagemid encodes for the scFv antibody displayed on the surface of a phage particle, and thus phage display directly links phenotype (scFv antibody) and genotype (scFv gene) . Specifiin China . One of proteins , 42.Antibody expression in plants was pioneered by Hiatt and colleagues  and DüriFusarium-specific single-chain antibody in planta has been shown to confer Fusarium resistance in transgenic Arabidopsis plants similar to that of expressing an antifungal protein [Expression of antibodies and their proper assembly and transport in plants have resulted in an increasing awareness that this strategy could be utilized for neutralizing and blocking plant pathogens, and thus for generating resistant plants. Cytosolic expression of a single-chain antibody against artichoke mottled crinkle virus in transgenic tobacco has been shown to reduce viral infection and delay the progression of disease symptoms . Also, s protein . These rAgrobacterium cells into intact leaf tissue, where the antibody gene is expressed. The leaf tissue is used only for transient protein production and no selection to identify transformed cells is required. The transferred T-DNA does not get integrated into plant chromosome but is present in the nucleus, where it is transcribed, and this leads to transient expression of the antibody. Expression levels observed in the transient assay are very consistent with those obtained with transgenic approach. We routinely use this system to test expression of antibodies or genes of interest, and to study their functions before moving to generating transgenic plants [Antibodies can be expressed either transiently in plant leaves or stably in transgenic plants, depending on applications required. Both expression systems in plants have been well established and widely exploited to produce antibodies for basic research and the pharmaceutical, agricultural and biotechnological industries , 53, 54.c plants , 55.Agrobacterium tumefaciens or projectile bombardment, including wheat, barley, maize, oat and rice that are frequently infected by FHB pathogens. Transgenic cereal crops without any genes or sequences encoding for antibiotics or herbicides can be generated [Fusarium mycotoxin-producing pathogens during storage for a long period of time.Stable expression in plants involves generating transgenic plants where the antibody gene is stably integrated into the plant genome and expressed throughout different generations. With the advances of biotechnology, many crops have been successfully transformed via enerated , 57. Difenerated . Endoplaenerated . Antibodenerated . Thus stFusarium mycotoxins are produced by Fusarium species that cause an economically devastating disease, called Fusarium head blight, on wheat and other small grain cereal crops worldwide [orldwide . In Chinorldwide . FHB hasorldwide , 60, 61,orldwide , 62–64 aorldwide , 55, 65.et al. [Fusarium asiaticum, the predominant Fusarium species in wheat FHB epidemic regions in China [Fusarium-specific antibodies that target AFPs to the site of infection by binding to surface components of the invading fungus in plants in order to directly interfere with fungal growth and development. Thus, Fusarium cell wall-bound proteins are selected as the target for the protective antibodies, since these proteins are displayed on the pathogen surface during infection. A chicken-derived phage display scFv antibody with a high-affinity is identified that reacts strongly with cell wall-bound proteins from Fusarium pathogens [To evaluate the potential of antibody-mediated FHB resistance in plants, Peschen et al.  generatein China , 66 and in China . This stathogens .Arabidopsis thaliana plants upon infection with Fusarium pathogens 14 days post inoculation (dpi). More importantly, when the coding sequence of this antibody is genetically fused to any of three AFPs, the resulting AFP-scFv fusion proteins display strong inhibitory activity on the growth of Fusarium spp. in vitro, whereas under the same conditions no inhibitory activity is observed in the mixtures of antibodies and AFPs that are separately expressed. In transgenic Arabidopsis thaliana plants 21 dpi, a very significantly enhanced resistance to the pathogens is seen only for plants expressing these scFv-AFP fusions but not for the plants expressing the fusions containing a non-Fusarium-specific scFv antibody and the same AFPs. Therefore, the presence of a Fusarium-specific antibody is essential for the inhibitory activity and the enhanced resistance. Furthermore, no difference between the transgenic plants and nontransgenic controls after inoculation with a non-Fusarium fungal species, Sclerotinia sclerotiorum indicates that this resistance is Fusarium-specific [This antibody confers a significantly enhanced resistance in transgenic specific . These rF. asiaticum [Fusarium spreading (i.e. type II resistance). Also at 21 dpi after spray inoculation, T3 transgenic wheat plants show a significant disease reduction of up to 41% in area under the disease progress curve (AUDPC) compared with the nontransgenic wheat, suggesting an enhanced resistance of wheat plants to initial infection by Fusarium pathogens (i.e. type I resistance). Thus, the antibody fusion conferred both type I and type II resistance in wheat plants. Moreover, some transgenic wheat lines display a higher level of type I resistance than Sumai3, the best natural FHB-resistant wheat cultivar available [Recently, further analyses of transgenic wheat plants reveal highly significantly enhanced resistance for plants expressing an AFP-scFv fusion after single-floret injection and spraying inoculation with siaticum . Up to 8vailable , 68. Anavailable .Fusarium-specific antibody in the enhanced resistance in transgenic plants. The antibody derived from chicken was isolated by phage display with the mycelium cell wall-bound proteins [F. asiaticum that was originally isolated from a scabby wheat spike in Wuhan, a frequent FHB epidemic region in China [F. asiaticum mycelium or infection structures. The antibody fusion shows a high binding specificity and affinity towards Fusarium species and strongly inhibits the fungal growth by damaging the mycelium cell walls in vitro [Fusarium-specific antibody within the fusion protein actively targets the fusion into the fungal infection structures in plant tissues whereby the antibody directly interacts with the fungal antigens and the antifungal peptide damages the mycelium membranes to interfere the fungal development [in planta regulated by the maize ubiquitin promoter would provide a continual supply of the antibody fusion proteins that are secreted into apoplast and/or accumulated surrounding the fungal infection structures in plant tissues, resulting in an effective restriction of the fungal infection and growth. Controlling fungal spreading and development on wheat spikes in field is a key step at fountainhead point to reduce or eliminate Fusarium mycotoxins in cereal grains. Fusarium-specific antibodies fused to antifungal peptides are ideal molecules for constitutive expression in cereal crops that grow in field.We hypothesize a vital role played by the proteins  from a hin China , 66. Immin vitro . It is lelopment , 69, 70.Fusarium mycotoxin-producing fungi bind specifically to the fungal cell walls. scFv antibodies are genetically manipulated with ease to create scFv-AFP fusion proteins that display synergistic, bi-functional activity specific to Fusarium pathogens in vitro and in planta. Various forms of antibodies have been expressed in plants and plant-expressed antibodies are functionally similar to their counterparts that are derived from mammalian cells. Transgenic expression of antibodies protects plants from pathogens and a Fusarium-specific scFv antibody confers a significant enhancement of resistance to Fusarium pathogens. A more significantly enhanced resistance to Fusarium pathogens is obtained in transgenic plants expressing a Fusarium-specific antibody fused to an antifungal protein. Fusarium-specific antibody is essential for the enhanced resistance in plants. This is the first demonstration for fungal resistance by exploiting fungus-specific scFv antibody fusions and more efforts are required to obtain antibody-mediated resistance to other fungal pathogens. Methods for generation of transgenic cereal plants without any antibiotics or herbicide marker genes are established. Combined with the advances of plant biotechnology, antibody-mediated resistance to initial infection and spreading of Fusarium head blight pathogens on wheat spikes provides new opportunities for the development of environmentally friendly mycotoxin control strategies for cereals in field and during storage.Antibodies show high specificity and affinity towards antigens. Recombinant scFv antibodies and their corresponding genes can be isolated simultaneously by phage display. Antibodies generated against the mycelium surface antigens of


The purpose of this study was to determine the prevalence of barriers to healthcare utilization in persons with fatiguing illness and describe its association with socio-demographics, the number of health conditions, and frequency of healthcare utilization. Furthermore, we sought to identify what types of barriers interfered with healthcare utilization and why they occurred.In a cross-sectional population-based survey, 780 subjects, 112 of them with chronic fatigue syndrome (CFS), completed a healthcare utilization questionnaire. Text analysis was used to create the emerging themes from verbatim responses regarding barriers to healthcare utilization. Multiple logistic regression was performed to examine the association between barriers to healthcare utilization and other factors.Forty percent of subjects reported at least one barrier to healthcare utilization. Of 112 subjects with CFS, 55% reported at least one barrier to healthcare utilization. Fatiguing status, reported duration of fatigue, insurance, and BMI were significant risk factors for barriers to healthcare utilization. After adjusting for socio-demographics, medication use, the number of health problems, and frequency of healthcare utilization, fatiguing status remained significantly associated with barriers to healthcare utilization. Subjects with CFS were nearly 4 times more likely to forego needed healthcare during the preceding year than non-fatigued subjects while those with insufficient fatigue (ISF) were nearly 3 times more likely.Three domains emerged from text analysis on barriers to healthcare utilization: 1) accessibility; 2) knowledge-attitudes-beliefs (KABs); and, 3) healthcare system. CFS and reported duration of fatigue were significantly associated with each of these domains. Persons with CFS reported high levels of healthcare utilization barriers for each domain: accessibility (34%), healthcare system (25%), and KABs (19%). In further examination of barrier domains to healthcare utilization, compared to non-fatigued persons adjusted ORs for CFS having "accessibility", "KAB" and "Healthcare System" barrier domains decreased by 40%, 30%, and 19%, respectively.Barriers to healthcare utilization pose a significant problem in persons with fatiguing illnesses. Study results suggested two-fold implications: a symptom-targeted model focusing on symptoms associated with fatigue; and an interactive model requiring efforts from patients and providers to improve interactions between them by reducing barriers in accessibility, KABs, and healthcare system. Chronic fatigue syndrome (CFS) comprises a complex problem for health care providers and patients. The illness is defined based on symptoms and ruling-out medical and psychiatric conditions with similar clinical characteristics ,2. ThereBarriers to healthcare utilization are particularly important. Minorities, the uninsured, and persons living in rural areas are at greater risk of not seeking needed healthcare. For example, blacks and Hispanics are less likely to seek medical care for depression than whites, although healthcare providers recommend treatment at equal rates . CompareThere are at least three reasons as to why people with CFS have not been diagnosed: 1) barriers within the medical community ; 2) lack of access to healthcare ; and 3) barriers to healthcare utilization  . In a ChThere has been limited effort to estimate the occurrence of barriers to healthcare utilization among persons with fatiguing illness including CFS. This article addresses these needs by evaluating: 1) the prevalence of barriers to healthcare utilization in persons with fatiguing illness identified from a large stratified random population sample in the state of Georgia; 2) nature (domains) of the barriers; and 3) associations between these barriers and fatiguing status, socio-demographic, the number of health conditions, and frequency of healthcare utilization. This knowledge is necessary to devise strategies for reducing barriers to healthcare utilization.The study adhered to the human experimental guidelines of the US Department of Health and Human Services and the Helsinki Declaration. The Human Subjects Committee of the Centers for Disease Control and Prevention approved the study protocol, and all subjects gave informed consent.The data derive from a large cross-sectional population-based study of CFS and chronic unwellness in Georgia, investigating the prevalence of CFS between September 2004 and July 2005 [In Phase 1, a random sample of 10,837 households  was included in a cross-sectional, screening survey that utilized Computer Assisted Telephone Interviews (CATI). Based on the household screening survey, 8,862 adults were selected for detailed telephone interviews; 5,630 individuals completed the detailed telephone interview; 1874 refused to participate, 134 were ineligible, and 1272 were excluded due to physical/mental impairment, unable to contact, language barriers, and deceased – an overall response rate of 75%.Phase 2 comprised a one-day clinical assessment that included a standard medical and psychiatric evaluation and healthcare utilization questionnaire ,2,4. BasTwo hundred sixty-eight randomly selected chronically unwell telephone interview respondents completed the clinical evaluation. Finally, 223 individuals classified as well on telephone interview, who were matched to the CFS-like based on residence , sex, race/ethnicity and age (within 3 years) completed clinic evaluations. The matching of the source study was done for the investigation of the prevalence of CFS.Based on their clinical evaluation, subjects were identified with medical comorbid conditions such as previously undiagnosed thyroid disease , anemia 18%), uncontrolled diabetes (14%), autoimmune disease (11%), inflammatory disease (8%), heart disease (7%), arthritis (3%) and pulmonary disease (3%); and psychiatric comorbid conditions encompassed previously undiagnosed alcohol or substance abuse (43%), melancholic depression (26%), bipolar disorder (19%), psychosis (7%), and anorexia/bulimia (5%). To examine the impact of co-existing health conditions with fatiguing illness on healthcare utilization, the fatiguing status of subjects were identified as: 1) CFS, 2) CFS, but for an exclusionary diagnosis (subjects who fulfill empiric criteria for CFS but who have an exclusionary diagnosis), 3) insufficient fatigue (ISF) , 4) ISF with otherwise exclusionary conditions, or 5) non-fatigued (NF). CFS was diagnosed as specified in the 1994 international research case definition [8%, unconWe defined healthcare utilization by responses to the question "During the past year, did you see, talk to, or consult with a healthcare professional about your personal health?" and then "During the past year, how many times did you see, talk to, or consult with a healthcare professional about your personal health." Respondents were asked about frequencies of consulting with a healthcare professional because of problems with four CFS defining symptoms: fatigue, sleep, memory or concentration, and pain. Respondents who reported foregoing healthcare were asked to indicate reasons for seeking healthcare, and why they did not seek healthcare. These responses were recorded as open-ended text. Subjects selected for the clinical evaluation completed the Healthcare Utilization Questionnaire at home prior to their clinic visit. At the clinic, study coordinator reviewed the responses to assure the understanding of questions and logic of skip pattern and worked with subjects to rectify omissions and errors if necessary.The primary outcome was a binary indicator of the occurrence of barriers to healthcare utilization. If a respondent reported foregoing healthcare , then he or she was identified as having barriers to healthcare utilization. The secondary outcome variables included three barrier domains to healthcare utilization that emerged as theme categories from the text (verbatim) responses in open-ended questions regarding reasons for not seeking needed healthcare. If a respondent reported having at least one barrier type in a domain, then the presence of a barrier was established. An aggregated variable for the count of the number of barrier types was also created and ranged from 0 (no barrier) to 11 (maximum).We identified the following as correlates to barriers to healthcare utilization: 1) Socio-demographic characteristics – sex, age, race, residential areas , marital status, parental status (children under 18 vs. no children under 18), work status, income, education, and insurance; 2) Health history – history of CFS diagnosis , reported duration of fatigue, current CFS diagnosis (met 1994 CFS case definition at the clinic visit), use of over-the-counter (OTC) pain relievers; and 3) Health status – Body Mass Index (BMI), Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, and the number of health problems . PCS and MCS scores are indicators of health status with PCS measuring wellness or illness and MCS for mental health status . The PCS and MCS scores were derived from the 8 dimensions of the Medical Outcomes Survey Short Form (SF-36). PCS and MCS are a linear combination of 8 SF-36 scales; PCS is predominantly based on the scales Physical Functioning, Role Physical, Bodily Pain and General Health Perceptions while MCS is predominantly based on the scales Mental Health, Role Emotional, Social Functioning and Vitality)  .In this study, fatiguing status is the exposure variable of interest and confounding variables include socio-demographics, the number of health conditions, and frequency of healthcare utilization.We analyzed all text (verbatim) responses with SPSS Text Analysis for surveys 2.0  . In SPSSAn exact 95% confidence interval for a binomial proportion was reported for the estimated prevalence of barriers to healthcare utilization. Univariate logistic regression was performed to examine the bivariate association between barrier status and factors such as fatiguing status, socio-demographic characteristics, the number of health conditions, and frequency of healthcare utilization. Multivariate analyses were conducted using separate logistic regression models for each outcome: the presence of barriers to healthcare utilization, and the presences of three domains, with fatiguing status as the main independent variable adjusted for covariates. All tests of significance were two-tailed with the alpha level set at 0.05.The median age of 780 subjects was 45 years . The majority were women (76%), white (71%), and racial diversity of the sample reflects the Georgia population [In the text analysis, nine themes emerged from reasons for barriers to healthcare utilization and these themes were classified into three domains: accessibility, knowledge-attitudes-beliefs (KABs), and healthcare system.The accessibility domain includes physical constraints such as family and work responsibilities that interfered with seeking help, geographical location (not enough providers in an area), difficulty obtaining transportation to the provider's office, difficulty obtaining a timely appointment to see a provider, and inconvenient office hours. This domain also included financial concerns about cost, insurance company co-payment, and that insurance would not cover the care received.The primary knowledge barrier consisted of both those with the illness and healthcare professionals overlooking a fatiguing illness due to lack of knowledge about such illnesses. Attitudinal barriers included subjects' thinking that the problem was "no big deal" or would "get better on its own," and that individuals needed an excuse or a better reason to see a healthcare professional. Personal barriers (minimization of illness and lack of family support) and fear (fear of stigmatization and confronting the problem) were additional beliefs held by study subjects.The third domain, healthcare systems, comprised themes of trust and confidence, structural or system barriers, and self-diagnosis/self-treatment. Subjects indicated that trust and confidence in healthcare professionals impacted their decision not to seek healthcare consultation: a doctor may not do enough to find out what is making them sick; the treatment did not make them feel better; a healthcare professional will require more tests without reviewing previous test results; belief that doctors did not believe in the diagnosis of CFS; and subjects felt dejected by healthcare professionals or that healthcare professionals might minimize their illness.Structural/system barriers in this category included lack of referral system and insensitivity to patient needs. In terms of self-diagnosis and self-treatment barriers, subjects sometimes self-diagnosed their symptoms or illness and considered them as consequences of lack of exercise, overweight, aging, hormone imbalance, depression, pre-menopause, menopause and intermittent pain. As a consequence of foregoing healthcare and self-diagnosis, subjects self-treated themselves. One of the commonly used self-treatments of their symptoms or illness was using over-the-counter medications to treat their "comes and goes" pain.The top seven themes among all barrier domains consisted of attitudes (9.7%), self-diagnosis (9.6%), finance (9.5%), time constraint (8.3%), healthcare coverage (7.3%), fear (5.9%), and lack of trust and confidence in their health professionals (5%).Overall, 40% of subjects reported at least one barrier to healthcare utilization Table . Of 112 Table Table Subjects with CFS were nearly 4 times more likely to forego needed healthcare during the preceding year than non-fatigued persons  while subjects with ISF were nearly 3 times more likely . Subjects with fatigue lasting 6 months or longer were almost twice as likely as those who never had fatigue symptom before to forego needed healthcare . Of the 112 participants classified as CFS, the sixteen who reported having been diagnosed as CFS by a physician had worse physical health outcome and better mental health outcome than those without a prior formal CFS diagnosis .In general, overweight subjects were about 30% more likely to forego needed healthcare than under/normal weight subjects . When considering number of health problems, every health problem increases 9% of the likelihood of forgoing needed healthcare . We did not find any significant association between barriers and frequency of healthcare utilization in fatigue, sleep, cognition, and pain.Table Forty percent of all subjects in our population-based study of fatiguing illnesses reported barriers to healthcare utilization. Only 14% of non-fatigued subjects reported a barrier, while 55% of those with CFS and 43% of those classified as ISF reported at least one barrier.Age, race, place of residence, marital status, income, and education were not significant factors in barriers to healthcare utilization. Women were more likely than men to report barriers to healthcare utilization regardless of women's higher frequencies of healthcare utilization in terms of general health and on several somatic symptoms: fatigue, sleep, and pain. A noteworthy finding as other studies shows that CFS is more prevalent in women than men. The higher barriers in seeking healthcare within women may be explained by the severity of their symptoms and their recognition of healthcare. Race and ethnicity alone also do not appear as significant barriers in seeking healthcare for fatiguing illnesses, a finding that differs from other chronic illnesses such as depression .High-deductible health plans can be a good fit for relatively healthy people, but such health plans may also lead to people foregoing healthcare because they cannot afford the deductibles for unforeseen health conditions or illness. The uninsured impact is much bigger in people with fatiguing illness and concurrent psychiatric conditions, and may lead this group to forego healthcare frequently. However, foregoing healthcare when needed may lead to more serious and more expensive health problems in the future, and prove more costly to the individual in missing work, in reduced family responsibility, and health-related quality of life.Six percent of the sample reported being diagnosed with CFS by healthcare professionals in the past. Nevertheless, 13 of 50 26%) subjects with CFS history did not fulfill the CDC published diagnostic research criteria for CFS at the time of the clinical assessment in this study. The study showed that in seeking healthcare consultation, respondents with the history of CFS diagnosis were not significantly statistically different from those without the history of CFS diagnosis. Yet, respondents who fulfilled CDC published diagnostic research criteria for CFS at clinical assessment were more likely than non-fatigued respondents not to pursue needed healthcare consultation during the preceding year. These data lend support to previous research that found less than 20% of persons with CFS have been diagnosed [% subjectOver half of CFS subjects reported delayed help-seeking behavior. Although there was no statistically significant association between CFS history and healthcare under-utilization, regardless of the current CFS status, respondents with CFS history had higher utilization of healthcare consultation in symptoms associated with CFS – fatigue, sleep, cognitive dysfunction, and pain – than those who have not been diagnosed with CFS in the past. This suggests that higher healthcare utilization for CFS associated symptoms may be occurring for treatment and management issues even after a CFS diagnosis was given.Subjects previously diagnosed as CFS by their physician had significantly worse physical health status (lower PCS score) than those without a formal diagnosis of CFS in the past. However, the previously diagnosed CFS subjects had significantly better mental health status (higher MCS score) compared to those without a previous diagnosis. This paradox suggests that receiving a CFS diagnosis may encourage seeking professional medical help and may also alleviate potential mental anxiety and stress about the origins of their illness. However, the cross-sectional data do not allow us to examine their health-related quality of life (measured by PCS and MCS) before or after receipt of the diagnosis of CFS by a physician, what treatment they received, and what information they received to help them for self-management of the illness. Further studies to explore this association are needed. Finally, co-existing medical or psychiatric conditions and obesity increased the chance of not pursuing healthcare consultation when needed. This result may be a confounder with socio-demographic factors such as uninsured, underinsured, and responsibilities of child care. The uninsured were more likely not to have sought healthcare services than were those who reported two or more forms of healthcare coverage.The study qualitatively examined types of healthcare utilization barriers and found seven reoccurring barriers: attitudes, self-diagnosis, finance, time constraints, healthcare coverage, fear, and lack of trust and confidence in health professionals. Each of these types was listed as to reasons why subjects did not seek healthcare when needed. Results show that barriers as a whole were a significant issue for persons classified as CFS or "CFS but an exclusionary diagnosis". While not significant, a trend in barrier status is evident with non-fatigued subjects reporting the least barriers compared to those with some type of physical or mental health problems. When barriers were further classified into three domains – accessibility, KAB, and healthcare system – analyses indicate that for the CFS group, accessibility and healthcare system were the greatest barriers in seeking healthcare.Lack of healthcare coverage is a known barrier to healthcare utilization and this study now supports this result in a population of fatiguing illnesses. Fifty-three percent (60) of uninsured study subjects reported barriers to healthcare utilization compared to 38% (255) of insured subjects . Furthermore, 10% of study subjects reported foregoing healthcare because of financial barriers, which was nearly two-fold as that in the 2005 National Health Interview Survey (5%) .Mistrust of healthcare professionals was significant among subjects classified with CFS. CFS subjects were less likely to seek healthcare and reported more barriers to healthcare utilization than other study groups. Mistrust stems from lack of confidence not only in healthcare professionals making a diagnosis but also in the structural barriers in the healthcare system such as the referral systems or perceived perceptions around a CFS diagnosis. As a consequence, subjects in the "healthcare system" domain were more likely to report making self-diagnosis and treating themselves with OTC medications further delaying seeking healthcare.The study's strengths include a rigorous study design with a random sample from a cross-sectional population-based study in fatiguing illness, which allows for a more generalizable inference of what can be achieved by identifying barriers to healthcare utilization and ways to eliminate or reduce barriers. This study employed both quantitative and qualitative research methods. Quantitative methods enabled the calculations of the prevalence of barriers to healthcare utilization, while qualitative methods allowed for in-depth analyses as to why subjects delayed health seeking behaviors.One limitation of this study is that the sample was screened via random-digit-dial, computer-assisted phone screening in English and therefore excluded Spanish or other non-English speaking individuals. Other studies have shown that Hispanics or Latinos have at least as high prevalence of CFS as whites and yet they may not be represented in this analysis. The use of medications was documented for medications used in the two weeks prior to the clinic visit and makes it difficult to correlate to healthcare utilization in the preceding year. However, it is important to examine the association since the use of OTC pain relievers is the primary method in which study subjects self-treated pain symptoms. Another limitation is the possibility of recall bias on self-reported healthcare utilization data. This may be difficult to remedy and complex because recall bias may have affected the reporting of symptom occurrence, healthcare utilization and healthcare foregoing. These should be further explored in other studies.We acknowledge that some of the findings from the current study may be attributed to socio-political and cultural contexts in the United States and those healthcare systems differ by country. In a cross-national study on perceived barriers to mental health, a cross-national effect was found in structural barriers and financial barriers; many more U.S. respondents  reporting financial barriers than respondents in Ontario, Canada or the Netherlands . HoweverThis study shows that barriers to healthcare utilization pose a significant problem in persons with fatiguing illnesses. Health status, accessibility, and the healthcare system were barriers with the biggest impact on utilization. Results from the text analysis suggest that subjects may forgo needed medical care because they tend to self-diagnose their symptoms such as muscle and joint pains, headache, sleeping problems, etc. As a consequence of self-diagnosis, they self-treated their symptoms with over-the-counter medications. This approach may lead to more serious health problems later. Considering all of these, we suggest a two-fold model approach for future interventions: a symptom-targeted model and an interactive model. The symptom-targeted model would focus on symptoms associated with fatigue, such as fatigue, sleep, and pain, and encourage people experiencing these symptoms to seek healthcare promptly. Simultaneously it would recommend to healthcare professionals that patients seeking healthcare with these symptoms may need continued monitoring for potential CFS, chronic fatigue or other chronic conditions.The interactive model would target patients and healthcare professionals with the goal of improving interactions between these two groups in terms of fatiguing illness. This model would emphasize the accurate diagnosis of underlying diseases thereby decreasing misdiagnosis and increasing CFS diagnosis in order to provide targeted therapy. Furthermore, it would encourage continued dialog between patients and healthcare professionals in terms of illness of management. These goals will be accomplished through education efforts aimed at health care practitioners enabling them to recognize the criteria for CFS diagnosis and management. Intervention for CFS should also address perceived stigma and trust for persons seeking healthcare in the area of CFS. Examples include reducing health professionals' barriers by increasing knowledge about CFS, increasing diagnostic self-efficacy and skills, and facilitating understanding of the patient's needs to reduce mistrust. This proposed model would also focus on improving individual perceptions of seeking healthcare consultation among persons with fatiguing illnesses with the goal to decrease unconstructive attitudes and beliefs that may act as barriers.The authors declare that they have no competing interests.JSL contributed to the conception, had primary responsibility for qualitative and quantitative analysis, interpretation of the data, and drafted the manuscript. DJB contributed to intellectual input to data interpretation and the emerged text theme categories, and critically revising the manuscript. RB collaborated in preparing the medication use of pain relievers, interpretation of the data, and critically revising the manuscript. JJ collaborated with others in designing the Healthcare Utilization questionnaire for fatiguing illness, and critically revising the manuscript. WCR was Principal Investigator of the study, collaborated with others in designing the study, writing the protocol, supervising field work, interpretation of the data, and revising the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


After traumatic brain injury (TBI), the most disabling problems are generally related to neuropsychiatric sequelae, including personality change and cognitive impairment, rather than neurophysical sequelae. Kluver-Bucy syndrome (KBS) is a rare neurobehavioral condition, first described in 1937 as an experimental neurobehavioral syndrome in monkeys with bitemporal brain lesions. The syndrome in man was subsequently observed to be transient or permanent in a variety of neurodegenerative disorders and after traumatic, nontraumatic and infectious brain injury. However, partial KBS may occur in the absence of the classic bilateral temporal lesion, though rare. Pharmacological treatment of post-TBI neuropsychiatric sequelae consists of symptomatic, functional and hypothetical approaches. Specific pharmacological treatment consists of antipsychotics, anti-kindling anticonvulsants or a combination thereof. A case of partial KBS presenting as delayed manifestation of traumatic brain injury that improved with carbamazapine and antipsychotics is presented. Recent evidence from clinical studies and animal models of brain injury suggests that neuronal and glial loss might progress after the initial insult in selectively vulnerable regions of the brain, such as the hippocampus .Traumatic brain injury (TBI) is a major public health issue. In the long term, after traumatic brain injury, the most disabling problems are generally related to neuropsychiatric sequelae, including personality change and cognitive impairment, rather than neurophysical sequelae . In some individuals, the TBI may cause decades-lasting vulnerability to psychiatric illnesses . However, partial KBS may occur in the absence of the classic bilateral temporal lesion, though rare . We present a case of partial KBS presenting as delayed manifestation of traumatic brain injury.Kluver-Bucy syndrome (KBS) is a rare neurobehavioral condition, first described in 1937 as an experimental neuro behaviour syndrome in monkeys with bitemporal brain lesions. The syndrome in man was subsequently observed to be transient or permanent in a variety of neurodegenerative disorders and after traumatic, nontraumatic and infectious brain injury . Mental status examination showed an ill-kempt unshaven individual; flattened affect; inability to recognize colleagues; intact sensorium; variable psychomotor activity, from complete withdrawal state to unprovoked aggression; no evidence of delusions or hallucinations; touching and rolling the objects in vicinity; irrelevant speech; lack of insight; and deranged biodrives. In the ward, he passed urine into a mug and washed his face. He was found to be putting inanimate articles into the mouth, and he even bit the escorts. He was noted to be fondling the genitals in public. No relevant past or family history could be obtained initially. Investigations including hemograms, urinalysis, blood sugar, blood urea were WNL. CT head showed “mild atrophy of right anterior temporal gyrus.” EEG was WNL. MRI confirmed CT findings and ruled out any other lesions.Behavioral control was achieved with neuroleptics quickly. The patient then gave past history of having met with a road traffic accident about a year back on a home visit while on leave and sustaining a closed head Injury. CT head then had revealed hemorrhagic contusions in the right frontoparietal region. He had been managed conservatively and he recovered. There was no other significant past or family history.He was diagnosed as a case of organic brain syndrome as a consequence of head injury. In the background of posttraumatic right-sided anterior temporal gyrus atrophy, increased oral activity, hypersexuality, features of hypermetamorphosis, loss of recognition of people, a diagnosis of partial Kluver-Bucy syndrome was entertained.He was treated with anti-kindling mood stabilizer carbamazapine and other supportive measures. He responded quickly and became asymptomatic within 3 weeks. Subsequent follow-up after convalescence leave did not reveal any residual neurobehavioral abnormality after gradual tapering off of the medication.Kluver and Bucy described a neurobehavioral syndrome following bitemporal lobectomy in monkeys in 1937, which was later named after them. Extrapolating any syndrome from monkey to man is fraught with controversy, but Aichner in 1984 after studying 53 patients with KBS described the phenomenology in detail . It includes the following symptoms: (a) Increased oral activity — a strong tendency to examine all objects orally, putting objects in mouth, licking, biting, chewing and touching with lips; (b) hypersexuality — hetero, homo or autosexual; (c) hypermetamorphosis — to touch everything in sight, to attend to every visual stimulus with grasping, hugging movements; (d) memory disorders; (e) placidity — flattened affect; (f) loss of recognition of people; and (g) bulimia. The KBS in man shows little etiologic specificity and has been seen with posttraumatic encephalopathy, encephalitis, anoxia and subarachnoid hemorrhage. Since the lesions in man are not as extensive and not as consistently localized as in animal experiments, it is not surprising that all abnormal behavioral deficits following bitemporal lobectomy have seldom been exactly reproduced in man. Hence the full syndrome is rarely seen; and to indicate a partial KBS in man, combinations of 3 or more different elements must be present.et al., 1997). It has been reported that even a single episode of closed head trauma induces long-lasting alterations in the hippocampus . KBS following unilateral temporal lobe injury has been reported by many . Though the exact mechanism has not been established, a transient functional bilateral temporal lobectomy has been postulated .Following a TBI, a chronically progressive degenerative process may be initiated . Carbamazapine has been used with good success by many . There is a need to follow up cases of head injury for a longer duration.Pharmacological treatment of post-TBI neuropsychiatric sequelae consists of symptomatic, functional and hypothetical approaches. Specific pharmacological treatment consists of antipsychotics, anti-kindling anticonvulsants or a combination thereof (Ahmed


Mutations in different types of fibroblastic growth factor receptors (FGFRs) have been associated with a variety of phenotype abnormalities, the common ones being Apert, Crouzon and Pfeiffer syndromes. In this study, we present two representative cases having the Apert and Pfeiffer syndromes, respectively, and discuss their clinical presentation, sequel and surgical implications. Fibroblastic growth factors (FGF) are a conglomerate of 22 known signal molecules that help in the regulation of self-proliferation, differentiation and migration pathways. Their action occurs through the FGF receptors (FGFRs) that consist of four tyrosine kinase receptors binding to the FGFR nonspecifically. Mutations in different types of FGFR receptors has been associated with a variety of phenotype abnormalities, e.g., FGFR1 mutation has been associated with the relatively milder form of Pfeiffer syndrome type 1 and mutations in FGFR2 and FGFR3 have been associated with the Apert, Crouzon and Pfeiffer syndromes.[In this study, we present two representative cases having the Apert and Pfeiffer syndromes respectively and discuss their clinical implications.This 4-month-old male child presented with bilateral proptosis, fusion and elevation of coronal suture, open anterior fontanelle and brachycephaly . He alsoThis 3-month-old female child presented with a clover leaf head with a bulging anterior fontanelle, bilateral temporal bulge, tense and prominent scalp veins, bilateral proptosis with adequate eye closure, midfacial hypoplasia and broad and short great toe and thumb Figure  and B. AThe characteristic skull shape in FGFR-related craniosynostosis syndromes is related to the growth of the skull in planes parallel to the prematurely closed sutures but not perpendicular to them. Coronal synostosis causes the skull to be brachycephalic (seen in our first patient) or turribrachycephalic (tower skull). A cloverleaf skull (kleeblatschadel) is due to coronal, lambdoidal, metopic and sagittal sutural synostosis, causing a trilobar skull deformity with the brain protruding through the open anterior and parietal fontanels (observed in our second patient). Lambdoidal or sagittal synostosis excludes a diagnosis of FGFR-related craniosynostosis even in the presence of hand and foot abnormalities. A metopic synostosis that results in trigonocephaly may occur as an isolated abnormality; its presence with other structure involvement, however, warrants exclusion of FGFR-related syndromes. The facial features common to all the syndromes include ocular hypertelorism, proptosis, midface hypoplasia, small beaked nose and mandibular prognathism.The specific clinical features in our first patient corresponded to the Apert syndrome. This syndrome has the highest risk of developmental delay and mental retardation . Turribrachycephalic skull with moderate to severe midface hypoplasia and soft tissue and bony (mitten glove) syndactyly of the fingers and toes and fused cervical vertebrae are the common findings. Hydrocephalus may occasionally be present.Pfeiffer syndrome has been divided into three types by Cohen in 1993, with types 2 and 3 being more common and severe than type 1.[The special clinical feature of Crouzon syndrome include a normal intellect and craniofacial abnormalities like significant proptosis, external strabismus and mandible prognathism, but with normal extremities. The risk of intracranial hypertension is the highest in Crouzon’s syndrome, and progressive hydrocephalus may occur. All thesBoth our patients had a normal intellect. Although both of them had marked orbital stenosis resulting in proptosis and midfacial protrusion, their eyelid closure was adequate. The foreshortened orbit may result in an antimongloid obliquity of the palpebral fissure, lid retraction, global prolapse and corneal scarring, with the risk of visual impairment. Tarsorraphy, canthal ligament release and levator lengthening may be the short-term procedures required for orbital proptosis. Progressive proptosis may ultimately warrant an orbital advancement and expansion. Facial hypoplasia  may result in malocclusion, upper airway obstruction and obstructive sleep apnea. Airway obstruction may occur at a higher level due to midfacial retrusion, or at a lower level due to cartilage sleeve abnormality affecting the trachea–bronchial tree. Chronic 3Vertebral anomalies and Chiari malformation are also commonly associated with these syndromes. The latter may be congenital or acquired. The usual causes of death in these patients include sleep apnea, upper respiratory tract infection, undiagnosed, uncontrolled hydrocephalus with secondary Chiari malformation and tracA summary of the commonly encountered bicoronal primary FGFR-related craniosynostosis syndromes and their differentiating features and sequel are presented. A cerebrospinal fluid diversion procedure to control the raised intracranial pressure, tarsorraphy and orbital expansion procedures to prevent visual loss, an aggressive airway management and treatment of Chiari malformation by posterior decompression significantly delays the incidence of early mortality in these patients.


Infected deer may pose a higher risk than elk for disease transmission. Chronic wasting disease (CWD) of deer and elk is a widespread health concern because its potential for cross-species transmission is undetermined. CWD prevalence in wild elk is much lower than its prevalence in wild deer, and whether CWD-infected deer and elk differ in ability to infect other species is unknown. Because lymphoid tissues are important in the pathogenesis of some transmissible spongiform encephalopathies such as sheep scrapie, we investigated whether CWD-affected elk and deer differ in distribution or quantity of disease-associated prion protein (PrPres) in lymphoid tissues. Immunoblot quantification of PrPres from tonsil and retropharyngeal lymph nodes showed much higher levels of PrPres in deer than in elk. This difference correlated with the natural prevalence of CWD in these species and suggested that CWD-infected deer may be more likely than elk to transmit the disease to other cervids and have a greater potential to transmit CWD to noncervids. Sc (d (Chronic wasting disease (CWD) is an emerging infectious disease first recognized in the 1960s. It is a member of the transmissible spongiform encephalopathy (TSE) disease group that includes sheep scrapie, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy, and several human diseases, including kuru, Creutzfeldt-Jakob disease (CJD), and variant CJD (vCJD). Several heritable but extremely rare forms of TSE are found, most notably, Gerstmann-Straussler-Schienker syndrome (GSS) and fatal familial insomnia. CWD, like other TSE diseases, is characterized by the accumulation in neural tissues of an abnormal disease-associated prion protein designated PrPres  have not shown differences between the 2 species that explain why CWD prevalence differs in natural settings . Elk were derived from game farms or research facilities where they became infected by contact with CWD-infected elk, a contaminated environment, or oral inoculation. All of the elk used in this study had definite clinical cases when they were euthanized. The deer used for PrPres quantification all had confirmed clinical cases and were from research facilities where they became infected by contact with infected animals. Three of the mule deer included in 2 by using either disposable Konex microcentrifuge tubes  and matched pestles (brain) or an omni tissue homogenizer ; 75%–90% of the total tissue mass of respective lymph nodes or tonsil was homogenized. Two-hundred–milligram aliquots of the total homogenate were processed further to concentrate PrPres by using ultracentifugation and proteinase K digestion as described . Reaction conditions were as recommended by the manufacturer except that denaturing of 1- to 30-mg tissue equivalents was done in a total volume of 20 μL sodium dodecyl sulfate–polyacrylamide gel electrophoresis sample buffer. Each sample was digested by using 2,500 U PNGaseF and incubated overnight at 37°C. Samples were frozen at −20°C until they were analyzed by immunoblotting.Tissues from 10 CWD-affected elk and 15 CWD-affected deer were analyzed in this study. All 10 of the elk had advanced clinical CWD when euthanized. The deer represented various stages of clinical disease. Detailed data showing PrPres glycoform profiles and quantification of PrPres are shown for 5 of the elk and 6 of the deer . Each ofDiagnosis of CWD is often based on detection of PrPres in tonsil tissue by using ELISA and IHC analysis. Therefore, we also analyzed tonsil tissue, but because we were interested in quantitative issues we used immunoblot technology.No PrPres was observed in tonsil from 2 of the elk , and onlPrPres quantities in RPLNs from elk were also low. RPLN from 1 elk was negative #4, , while wWe also sought to determine whether all of the nodes from individual deer contain similar levels of PrPres. Considerable variation was observed. In some deer, every node that was tested was PrPres positive, but more frequently only 1 or 2 nodes were positive. Furthermore, the intensity of the PrPres signals varied from node to node. In most deer, RPLN gave the strongest PrPres signal, but in other deer the prescapular or submandibular nodes were best . The mesThe spleen has been shown to influence disease pathogenesis in both sheep and mouse models of TSE disease  (blots nPrPres glycoform patterns have been used to define TSE strains and have been studied extensively in deer and elk brain . LikewisBecause PrPres band differences can be due both to differing glycosylation and different sites of proteinase cleavage, we treated samples of various tissues with PNGaseF to remove carbohydrates and thus show any differences due to proteolytic cleavages. Such differences in the PrPres structural core might provide evidence for the existence of different CWD strains as seen before in other TSE diseases . Thus, bWe found marked differences in the quantity of PrPres in tonsil and lymph nodes of CWD-infected elk versus deer by using immunoblot analysis. For example, PrPres was detected at high levels in deer, but not in elk, when 20-mg equivalents of tonsil or RPLN were analyzed. In contrast, brains from these deer and elk were all highly positive when the same immunoblot method was used. Both the quantitative PrPres difference  and the Our results suggest that fundamental differences may exist in the pathogenesis of CWD between deer and elk. In CWD-infected deer, as with scrapie in sheep, infectivity and PrPres are detectable in lymphoid tissues early after infection, well before they can be detected in brain tissue (In the TSE diseases in which lymphoid tissues are substantially involved, i.e., sheep scrapie and CWD in deer, horizontal transmission in natural situations is efficient. In contrast, when peripheral lymphoid tissues are not extensively involved, i.e., BSE in cattle . Thus, dSeveral other factors might also influence transmission within deer and elk populations. For example, differences in social interaction, the size of typical homeland range, preferred habitat, population densities, and so forth. The relative contribution of the possible factors is not known.Although CWD prevalence in elk is low in natural settings, it can be much higher in confinement situations. What differences increase transmission when animals are confined is not known. Apparently, high PrPres levels in lymphoid tissues are not essential for transmission in crowded conditions. However, at least 2 factors might have an additional impact on transmission in captive elk. First, restricting elk to small pastures, sheds, or corrals where infectious material has accumulated over time might facilitate increased transmission. Second, in confined settings, animal-to-animal contact would increase. This might involve exchange of infectivity through saliva, which has been found to be infectious in deer (Earlier studies have not shown any evidence for transmission of CWD to humans (


Despite significant improvements in tuberculosis (TB) management under the WHO directly observed treatment, short course (DOTS) strategy, childhood TB has been relatively neglected. Children are at high risk of severe disease, and reactivation of latent infection in adulthood perpetuates the epidemic. Almost a million cases of childhood TB are estimated to occur annually, but good-quality epidemiological data are scarce due to inherent difficulties diagnosing paediatric TB. There remains an urgent need both for better diagnostic tests and for robust regional data on the true burden of disease, otherwise childhood TB will remain an essentially ‘invisible’ and therefore neglected disease. Tuberculosis (TB) has been propelled to the forefront of the international health agenda in the wake of the HIV/AIDS epidemic and the evolution of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, stimulating a wide portfolio of research, and injecting new vigour into public health strategies to control the disease. Following the WHO declaration of a global TB emergency in 1993, the directly observed treatment, short course (DOTS) strategy was launched, underpinned by five key elements: sustained political commitment; improved case detection through quality assured bacteriology; standardized short course treatment; assured drug supply; and standardized monitoring and evaluation. Now implemented in nearly 200 countries, DOTS has already led to significant improvements in case detection and treatment outcomes.Childhood TB, however, has been relatively neglected. The emphasis placed by DOTS on detection of smear-positive cases (which are most infectious) does not address the situation in children, the vast majority of whom have smear-negative disease. In wealthier, low-burden countries, infected children are often identified by contact tracing and given chemoprophylaxis, but limited resources and a much higher disease incidence prohibit this in most high-burden settings. Until recently, most national tuberculosis programmes (NTPs) did not collect data on paediatric TB by age and clinical syndrome, reflecting its perceived lower priority.TB nevertheless remains an important and potentially preventable cause of childhood illness and death. Young children have a high risk of progression to disease following infection, and are much more likely to develop severe or disseminated TB. Children with latent tuberculosis infection (LTBI) become the reservoir of future disease in adulthood, perpetuating the epidemic. The HIV epidemic, which disproportionately affects young adults, many of whom are co-infected with TB, may also put their children at particularly high risk of infection. Observational data do suggest a disproportionately higher paediatric caseload where deteriorating socioeconomic conditions are accompanied by a higher overall incidence of TB, and children account for more than 20% of TB cases in some high-burden settings.Worldwide there were nearly a million estimated new cases of childhood TB in 2000 , but relMycobacterium tuberculosis still lack sensitivity; IFN-γ release assays appear to perform better than tuberculin skin testing, but do not differentiate active TB from LTBI (Despite the scale of the problem, progress developing better diagnostics has been slow. Serological assays have so far proved disappointing, and nucleic acid amplification tests for rom LTBI . All curBetter diagnostics are not the only challenge, however. Other priorities include the need for better, particularly shorter, treatment regimens; improved case management, contact tracing and delivery of chemoprophylaxis in low-resource settings; and the search for a new vaccine. Perhaps most importantly, there is a real need for prospective epidemiological studies to determine the true burden of TB among children in a wide spectrum of settings worldwide. Recent WHO guidance has already taken a significant step in this direction by recommending NTPs record childhood TB cases by age category and clinical syndrome . FurtherAJB is a Wellcome Trust Training Fellow in Clinical Tropical Medicine. BK is a Wellcome Trust Intermediate Fellow in Clinical Science.None declared.Not required.