Studies of cerebral palsy in the childhood population of Edinburgh

This thesis is the result of an investigation of the prevalence, clinical findings and aetiology of cerebral palsy in the childhood population of Edinburgh which was carried out during 1952 and 1953, whilst the author held a George Guthrie Research Fellowship from the University of Edinburgh. The aims of the investigation were, firstly to establish the prevalence of cerebral palsy in the childhood population of the city; secondly to study the clinical features of cerebral palsy and their effects on the patient's way of life; to define some of the important aetiological factors in cerebral palsy in a representative group of children in the community. During the investigation it became increasingly apparent that the currently defined categories included in "Cerebral 'Palsy" did not allow for an accurate classification of cases by neurological findings. Eventually a new classification on the basis of neurological syndromes was evolved. This classification will be described and compared to previous classifications in Section 3. It was possible to establish figures for the prevalence of cerebral palsy in the childhood population of Edinburgh, though a complete ascertainment of all patients was not made. The clinical features of cerebral palsy in the childhood ;community were studied and are described in Section 4. During the survey it became increasingly apparent that "Cerebral Palsy" was no clinical entity. Rather it comprised a number of neurological disorders in which the only common factor appeared to be that there was motor dysfunction due to abnormality of the brain which was present in early life. The clinical features varied widely from category to category. The ways in which patients were handicapped and the extent to which they were printed from taking part in everyday activities were very different. A detailed study was made of the clinical findings and handicaps of patients and they were compared to those described by previous authors. Thus, some idea of the importance of cerebral palsy in the community was obtained, (Section 5). Aetiological factors which were important in one form of cerebral palsy were found to be much less important in others. Many different "causes" of cerebral palsy were found which varied from developmental malformation to traumatic head injury, and from abnormal parturition to the complications of infectious diseases in early life. The multiplicity of aetiological factors in single categories and even single patients was impressive. For example, within the category of "Ataxic Diplegia" patients were found whose disorder appeared to be genetically determined, and patients who were suffering from the effects of birth injury, parainfectious encephalomylitis or meningitis. To take account of the multiplicity of aetiological factors it was necessary to study the heredity and social backgrounds of patients as well as their individual' birth and later histories. The current concept of cerebral palsy as being due predominantly to the effects of birth injury is a misleading simplification of the true position. In the same way as there are many different causes of stillbirth and infant death, !so there are many causes of cerebral palsy in children who survive. The later sections of this thesis are concerned with demonstrating that the aetiological factors in cerebral palsy are as complex as those involved in infant mortality. Social, genetic, obstetric and many unknown factors play a .part. An attempt has been made to define the importance of some of them in Sections 5 and 6

Elucidation of the RamA Regulon in Klebsiella pneumoniae Reveals a Role in LPS Regulation

Klebsiella pneumoniae is a significant human pathogen, in part due to high rates of multidrug resistance. RamA is an intrinsic regulator in K. pneumoniae established to be important for the bacterial response to antimicrobial challenge; however, little is known about its possible wider regulatory role in this organism during infection. In this work, we demonstrate that RamA is a global transcriptional regulator that significantly perturbs the transcriptional landscape of K. pneumoniae, resulting in altered microbe-drug or microbe-host response. This is largely due to the direct regulation of 68 genes associated with a myriad of cellular functions. Importantly, RamA directly binds and activates the lpxC, lpxL-2 and lpxO genes associated with lipid A biosynthesis, thus resulting in modifications within the lipid A moiety of the lipopolysaccharide. RamA-mediated alterations decrease susceptibility to colistin E, polymyxin B and human cationic antimicrobial peptide LL-37. Increased RamA levels reduce K. pneumoniae adhesion and uptake into macrophages, which is supported by in vivo infection studies, that demonstrate increased systemic dissemination of ramA overexpressing K. pneumoniae. These data establish that RamA-mediated regulation directly perturbs microbial surface properties, including lipid A biosynthesis, which facilitate evasion from the innate host response. This highlights RamA as a global regulator that confers pathoadaptive phenotypes with implications for our understanding of the pathogenesis of Enterobacter, Salmonella and Citrobacter spp. that express orthologous RamA proteins

On the eigenvalues of Cayley graphs on the symmetric group generated by a complete multipartite set of transpositions

Given a finite simple graph \cG with $n$ vertices, we can construct the Cayley graph on the symmetric group $S_n$ generated by the edges of \cG, interpreted as transpositions. We show that, if \cG is complete multipartite, the eigenvalues of the Laplacian of \Cay(\cG) have a simple expression in terms of the irreducible characters of transpositions, and of the Littlewood-Richardson coefficients. As a consequence we can prove that the Laplacians of \cG and of \Cay(\cG) have the same first nontrivial eigenvalue. This is equivalent to saying that Aldous's conjecture, asserting that the random walk and the interchange process have the same spectral gap, holds for complete multipartite graphs.Comment: 29 pages. Includes modification which appear on the published version in J. Algebraic Combi

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development