No description available.

No description available.

The induction of phenylketonuria in mice through the use of excess dietary phenylalanine is an area in which limited research has been done. This study intends to pursue further work in this area, more specifically, to study the effects of excess dietary phenylalanine and the phenylalanine analogue A.P.B.A. (2-amino-3-phenyl butanoic acid) (7) on brain serotonin and brain norepinephrine. In addition, the effects of these two compounds on the incidence of audiogenic seizures will be explored.

This thesis is about the experience of Muslim British Pakistani families coping with thalassaemia (a chronic, inherited blood disorder) and the implications for service delivery. Its central concern is to illustrate that simplistic and culturally-biased assumptions are an unsatisfactory base on which to devise health service delivery for minority populations, and that with careful study it is possible to deliver culturally sensitive and appropriate services. The thesis is written in four parts. The first part contains the research methods and the clinical aspects of thalassaemia. It also provides an introduction to the families in the study. The British Pakistani population is considered in the context of migration to Britain, which has created a plural society requiring adaptations to services to meet the diverse health needs of the different ethnic minorities. The second part deals with the socio-economic and cultural background of British Pakistanis in Pakistan: this (is) crucial to an understanding of their present situation. Family dynamics, marriage patterns and decision-making processes are explored, as is the central role of religion and kinship networks in the lives of British Pakistanis. It also examines their settlement process and present living conditions and illustrates how the social structures prevalent in Pakistan have been re-established in England, albeit in a modified form. The third part documents, using case studies, the experiences of British Pakistani families with thalassaemic children. These are analysed to highlight deficiencies in health service delivery and areas where cultural misconceptions exist. These areas require attention to provide an effective genetic counselling service for this population. The final part examines the social and clinical implications of consanguineous marriage. It gives the results of a study showing increased frequency of consanguineous marriage among British Pakistanis than among Pakistanis in Pakistan. It then illustrates how kinship networks within communities practising this marriage pattern provide an opportunity to offer a genetic counselling service in a unique way, by making positive use of the practice. This proposed approach applies not only to thalassaemia but also to other inherited diseases.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv. / Härtill 5 uppsatser.

No description available.

<p>Hemophilia A and B are X-linked recessive bleeding disorders caused by the deficiency of coagulation factor VIII (FVIII) and Factor IX (FIX), respectively. Current treatment involves life-long protein replacement therapy which is invasive, expensive and inaccessible to the majority of hemophiliacs worldwide. Treatment is further compromised by the development of neutralizing antibodies. Thus, the development of an alternative treatment that is safer, cost effective and non-invasive that circumvents immune response induction is desirable.</p> <p>To this end, a chitosan-mediated gene therapy strategy delivered orally was developed to provide clinically relevant plasma expression of FVIII or FIX. Hemophilia A mice that ingested chitosan nanoparticles containing FVIII DNA transiently expressed canine FVIII reaching >100 mU one day post treatment, together with partial phenotypic correction. Residual FVIII activity was detected for several days. Repeated administration of nanoparticles restored FVIII expression for 4 weeks and reduced clotting time in treated mice. Interestingly, inhibitors and non-neutralizing antibodies were not detectable throughout the experiment.</p> <p>The immunomodulatory effects of chitosan-mediated oral gene delivery was investigated in naive hemophilia A mice and mice with pre-existing inhibitors. Administration of nanoparticles containing human FVIII DNA in naive mice suppressed systemic antibody responses and provided long-term tolerance to rhFVIII protein immunizations for at least 8 weeks. This tolerance was transferable to naive mice, suggesting development of regulatory T cells. In contrast, repeated oral nanoparticle administration was unable to suppress FVIII-specific antibody responses in hemophilia A mice with pre-existing inhibitors.</p> <p>Treatment of hemophilia B is challenged by a 25-50 fold higher therapeutic threshold. Nevertheless, hemophilia B mice fed chitosan nanoparticles containing CpG-FIXi plasmid transiently expressed therapeutically relevant human FIX >14mU/mL plasma.</p> <p>Chitosan nanoparticle formulation was optimized <em>in vitro</em> for improved transfection efficiency. Nanoparticles formulated at a chitosan:DNA charge ratio of >2:1 (N:P) provided DNA protection against proton and enzymatic degradation that mimic conditions of the stomach and intestine, respectively. The inclusion of 25 mM sodium acetate-acetic acid decreased transfection of HEK 293 cells 4-fold, while 50 mM sodium sulphate increased uptake by ~40%. Optimal transfection was achieved with chitosan chloride (CL 213) formulated at a charge ratio of 3:1 in 50 mM sodium sulphate.</p> <p>These findings suggest chitosan nanoparticles can provide clinically relevant FVIII and FIX transgene expression, which is amenable to a one-tablet-a-day dosing strategy. Taken together, chitosan-mediate gene therapy delivered orally is proposed as a potential non-invasive alternative strategy for hemophilia treatment and without inducing neutralizing and non-neutralizing antibody production.</p> / Doctor of Philosophy (PhD)

Cancer is one of the leading causes of death across the globe which needs appropriate and cost-effective treatment. Several recent studies have suggested that dietary intake of various flavonoids such as myricetin have a protective effect against different types of cancers and cardiovascular diseases. The present study was conducted to investigate the genoprotective and genotoxic effects of myricetin nano and bulk forms on the lymphocytes from pre-cancerous and multiple myeloma cancer patients compared to those from healthy individuals. Also, to investigate the protective potential of myricetin bulk and nano against the oxidative stress produced in vitro by 2- amino-1-methyl-6 phenylimidazo [4, 5-b] pyridine and reactive oxygen species- induced DNA damage using the Comet assay, micronucleus assay, cellular reactive oxygen species and glutathione detection assay, Western blotting, real-time polymerase chain reaction and immunofluorescence. Lymphocytes from the patient groups showed significantly higher levels of basal DNA damage compared to the lymphocytes from healthy individuals which was observed throughout the in vitro treatment. Myricetin in both forms has not induced any significant DNA damage in all of the investigative groups at selective lower concentrations; in fact, the results demonstrate a reduction in DNA damage upon treating with myricetin nano in lymphocytes from pre-cancerous patients demonstrated by significant reduction in micronuclei formation in mononucleated cells. DNA repair capacity of myricetin bulk and nano was determined by co-treating the drugs with hydrogen peroxide. Myricetin significantly reduced the oxidative stress related damage caused by hydrogen peroxide, where myricetin nano seemed to be more effective employing the Comet assay. In the presence of myricetin bulk and nano, the damaging effects of 2- amino-1-methyl-6 phenylimidazo [4,5-b] pyridine were considerably decreased, where myricetin nano was more effective. This could be because nanoparticles have a larger surface area which could improve their reactivity and also the reduction in size of the particles could improve the anti-cancer properties of this compound. Myricetin has shown genoprotective and anti-oxidant effects by demonstrating the potential to reduce DNA damage caused by over-production of reactive oxygen species and oxidative stress. It has also shown anti-cancer potential in the lymphocytes from multiple myeloma patients by regulating the apoptosis related proteins, dependent on oxidative stress. Therefore, this study suggests that myricetin supplementation in our regular diet with enhanced bioavailability could have potential health beneficial effects and possibly protect against various diseases including cancer.