Biomedical subjects
Publications and source records attributed to A Graham.
Although the development of the inner ear has been a favorite subject for biologists to study, it is not yet clear exactly which molecules are involved in the induction of the otic placode, the plug of embryonic ectoderm that will become the inner ear. In his Perspective, Graham takes us on an inner ear odyssey, explaining how the signaling molecules FGF-19 and Wnt-8c cooperate to induce formation of the otic placode (Ladher et al.).
A recent study has shown that the T-box gene eomesodermin, which was first identified in Xenopus, not only plays a conserved role in vertebrates directing gastrulation, but interestingly in mammals has acquired a new function in the development of the trophoblast.
The synthesis and structural characterisation of a series of cobalt and nickel cages are reported. Eight of these structures contain a [M10(mu3-OH)6(eta2, mu3-xhp),(eta2, mu2-O2CR)6]2+ core (where M = Co or Ni; xhp = 6-chloro- or 6-methyl-2-pyridonate: R = Me, Ph, CHMe2, CH2Cl, CHPh2 or CMe3), where the ten metal atoms describe a centred-tricapped-trigonal prism (ttp). The cage contains six hydroxide ligands around the central metal, and the exterior is coated with pyridonate and carboxylate ligands. For four of the cages additional metal centres are found attached to the upper and/or lower triangular faces of the trigonal prism, generating dodeca- and undecanuclear cages. Three further cages are reported that contain a metal core based on an incomplete centred-tetraicosahedron. These cages involve trimethylacetate as a ligand in company with either 6-methyl-2-pyridonate or 6-chloro-2-pyridonate. Comparison of these latter structures with the trigonal prisms reveal that they can be described as a pentacapped-trigonal prism missing one edge. Magnetic studies of three of the nickel cages with trigonal prismatic cores show spin ground states of S = 8, 4 and 2 for Ni12, Ni11 and Ni10 cages, respectively.
Our view of how-many phyla relate to each other is being radically revised by molecular phylogenetics. For example, arthropods and annelids are no longer placed together, but are now considered to be in separate clades. The new tree has important ramifications for developmental biology and genomics.
Apolipoprotein E (ApoE) plays an important role in cholesterol and triglyceride metabolism, being one of the major structural components of chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE functions as a ligand in the receptor-mediated uptake of these remnants from the blood by the liver. A variant form of ApoE, apolipoprotein E*3-Leiden, shows reduced affinity for the low density lipoprotein (LDL) receptor, and results in the dominant expression of type III hyperlipoproteinemia. Two-dimensional electrophoresis (2-DE) has been used to characterise protein expression in serum samples from control and transgenic mice expressing the human ApoE*3-Leiden mutation, fed a cholesterol-rich diet, and transgenic mice fed a normal diet. For the identification of proteins, single silver-stained spots were excised from the 2-DE gels and subjected to in-gel enzymatic digestion. Extracted peptides were analysed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). This proteomic approach has enabled the ApoE*3-Leiden variant to be positioned in a 2-DE separation of serum proteins, and has identified changes in the expression of haptoglobin, indicating that this protein may provide a marker for the potential onset of atherosclerosis.
The functional IL-5 receptor is a heteromeric complex consisting of an alpha and beta subunit. The cloning, sequencing and expression of guinea-pig IL-5Ralpha and beta subunits is described. The guinea-pig IL-5Ralpha subunit cDNA encodes a protein of M(r)47 kDa, which is 72 and 66% homologous to the human and murine orthologs, respectively. Three guinea-pig IL-5Rbeta subunit cDNA clones were isolated, which differ in the N-terminus and are 56-64% homologous to the human and murine IL-5Rbeta subunits. Expressing human IL-5Ralphabeta and guinea-pig IL-5Ralphabeta(1)in the baculovirus-insect cell system resulted in recombinant receptors which bound hIL-5 with high affinity (K(d)=0.19 and 0.11 nM, respectively). Expressing just gpIL-5Ralpha was not sufficient to demonstrate binding. This contrasts with the human receptor, where hIL-5Ralpha alone can bind hIL-5 with high affinity. gpIL-5Ralphabeta(1)bound both hIL-5 and mIL-5 with comparable affinity (K(i)=0.10 and 0.06 nM), similar to that seen with hIL-5Ralphabeta. Thus, both the heteromeric hIL-5R and gpIL-5Ralphabeta(1)can bind multiple IL-5 orthologs with high affinity whereas the murine IL-5R is selective for the murine ligand.
OBJECTIVE: To examine the incidence, radiographic and histologic findings of medial femoral neck buttressing in a consecutive group of patients undergoing total hip arthroplasty. DESIGN: Biomechanical parameters were evaluated on standard anteroposterior pelvic radiographs of 113 patients prior to hip replacement surgery. Demographic information on all patients was reviewed and histologic evaluation was performed on specimens obtained at the time of surgery. RESULTS: The incidence of medial femoral neck buttressing was found to be 50% in a consecutive series of patients undergoing total hip arthroplasty. The incidence was slightly higher in women (56% vs. 41%). Patients with buttressing had increased neck-shaft angles and smaller femoral neck diameters than were seen in patients without buttressing. Histologic evaluation demonstrated that the buttress resulted from deposition bone by the periosteum on the femoral neck in the absence of any evidence of femoral neck fracture. CONCLUSION: It would appear that femoral neck buttressing occurs in response to increased joint reactive forces seen at the hip being transmitted through the femoral neck. The increased joint reactive force can be related to the increased neck shaft angle seen in patients with buttressing.
Neurogenic placodes are specialized regions of the embryonic ectoderm that are central to the development of the cranial sensory systems of vertebrates. These structures generate many of the sensory neurones of the head and also, in some instances, the associated sensory receptor cells. The neurogenic placodes have often been thought to share common pathways of development and to have evolved together. However, recent work has shown that this is not the case. The term 'neurogenic placodes' no longer seems to describe a cohesive group. Rather, the neurogenic placodes fall into a number of categories, and it is within each of these that the members share a common development and evolution.
Brain nicotinic acetylcholine receptors (nAChR) are a class of ligand-gated channels composed of alpha and beta subunits with specific structural, functional and pharmacological properties. They participate in the physiological and behavioural effects of acetylcholine and mediate responses to nicotine. They are associated with numerous transmitter systems and their expression is altered during development and ageing as well as in diseases such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and Lewy body dementia. Nicotinic receptors containing a number of different subunits are highly expressed during early human development. Disorders believed to be associated with abnormal brain maturation involve deficits in both alpha4beta2, in the case of autism, and alpha7 possibly in addition to alpha4beta2 nAChRs in the case of schizophrenia. In ageing and age-related neurodegenerative disorders nAChR deficits are predominantly associated with alpha4-containing receptors, although some studies also indicate the involvement of alpha3 and alpha7 subunits. Whilst ageing appears to be associated with reductions in subunit mRNA as well as protein expression, in Alzheimer's disease only protein loss is apparent. Nicotinic therapy may be of benefit in a number of neurological conditions, however studies evaluating further both the distribution of specific subunit involvement and the correlation of nAChR deficits with clinical symptoms are required to inform therapeutic strategy.
In the past year, studies on protochordates have provided evidence that many features that we take to be indicative of the vertebrates were evident early in chordate evolution. Furthermore, many of the important developmental regulatory genes have also been identified in these invertebrates. Finally, we are also gaining a better insight into how the vertebrate genome itself evolved.
Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology.
We have previously observed that melanocytes produce nitric oxide in response to ultraviolet radiation and lipopolysaccharide and in this study have examined how these responses are affected by alpha-melanocyte-stimulating hormone. Nitric oxide production by cultured cells was measured electrochemically in real time using an ISO-nitric oxide sensor probe. B16 mouse melanoma cells released nitric oxide in response to lipopolysaccharide and the effects were enhanced in cells that had been grown in the presence of 10-11-10-9 M alpha-melanocyte-stimulating hormone prior to stimulation. At concentrations in excess of 10-9 M alpha-melanocyte-stimulating hormone decreased nitric oxide production. Preincubation with lipopolysaccharide, a well-known inducer of inducible nitric oxide synthase, also increased nitric oxide production but this response was reduced by alpha-melanocyte-stimulating hormone. alpha-Melanocyte-stimulating hormone also increased the levels of nitric oxide produced in response to ultraviolet radiation (20-100 mJ per cm2) in B16 cells. The same effect was seen in human melanocytes and as this was inhibited by aminoguanidine would appear to involve an induction of inducible nitric oxide synthase. Reverse transcription-polymerase chain reaction showed that melanocytic cells express inducible nitric oxide synthase mRNA. Western blotting analysis and immunocytochemistry confirmed the presence of inducible nitric oxide synthase protein in B16 cells and FM55 human melanoma cells and that the levels were increased in response to alpha-melanocyte-stimulating hormone. alpha-Melanocyte-stimulating hormone, however, decreased inducible nitric oxide synthase protein expression, which occurred in response to lipopolysaccharide. These results suggest that alpha-melanocyte-stimulating hormone regulates nitric oxide production in melanocytic cells by modulating the induction of inducible nitric oxide synthase. Additional experiments showed that nitric oxide increased melanin production by B16 cells and human melanocytes. This is in keeping with a melanogenic role for nitric oxide but whether its production by melanocytes in response to alpha-melanocyte-stimulating hormone is associated with such a role or whether it has some other significance relating to melanocyte differentiation or in mediating immunomodulatory actions of alpha-melanocyte-stimulating hormone remains to be seen.
The purpose of this study was to describe the change in physical fitness of middle-aged adults with an intellectual disability over a period of 13 years. Participants were 32 adults who worked in a supported work environment in Montreal and had been participants in a physical fitness study in 1983. Using the Canadian Standardized Test of Fitness, the participants were evaluated for cardiovascular endurance, muscular strength, muscular endurance, flexibility, and body composition. A home visit prior to the testing session refamiliarized the participants with the test procedures. Two forms of analysis were used to describe the change in fitness over 13 years. First, a 2 x 2 (Group x Time) analysis of variance for each dependent variable assessed change over time. Second, effect sizes were calculated to measure the magnitude of change in fitness over the 13-year period in comparison to those without an intellectual disability. As expected, the physical fitness levels of the participants were low when compared to those without a disability and declined over the 13 years. In addition, the magnitude of change over the 13 years, as compared to those without a disability, was greater for male and female participants for body mass index and percentage of body fat and for female participants for cardiovascular endurance and sit-ups. It appears that adults with an intellectual disability may be particularly at risk for declining health associated with aging and low physical fitness.
PURPOSE: To evaluate the role of standard and ultrafast MR brain imaging and compare the information with CT. MATERIAL AND METHODS: This was a prospective study of 114 patients with acute neurological symptoms and signs. CT brain examinations consisted of axial non-enhanced images. MR imaging consisted of standard spin-echo/fast spin-echo sequences and a series of rapid techniques including echoplanar and single shot fast spin-echo sequences. RESULTS: Using standard MR methods, 41% of the patients had all five sequences of good technical quality, while using ultrafast methods 81% of the patients had good technical quality examinations in all five sequences. In 3% of the cases, ischaemic stroke was incorrectly reported on CT. In 24% of the cases, MR gave extra diagnostic information not reported on CT and in a further 8%, one neuroradiologist reported the abnormality in agreement with the MR, whilst the other neuroradiologist reported the CT as normal. In 2 cases, subarachnoid haemorrhage was missed on MR. Subarachnoid haemorrhage was not shown on the ultrafast sequences. CONCLUSION: MR can be used to image acute neurological admissions with a high success rate, particularly using ultrafast methods. In many cases, MR provided extra information of direct clinical relevance not shown on CT.
In 1999 the incidence of multiple drug resistance (to four or more antimicrobials) in non-typhoidal salmonellas from humans in England and Wales fell in isolations of Salmonella enterica serotypes Typhimurium, Virchow, and Hadar. This fall has been most noticeable in S. Typhimurium, where 59% of isolates were multiresistant compared to 81% in 1996. The main reason for this has been a 75% decline in isolations of multiply-resistant S. Typhimurium definitive phage type (DT) 104 (MR DT104) since 1996. Nevertheless MR DT104 remains second to S. Enteritidis phage type 4 as the most common strain in cases of human salmonellosis in England and Wales. Multiple resistance has also remained high in S. Hadar, with 49% of isolates resistant to four drugs or more compared to 56% in 1996. Isolates with decreased sensitivity to ciprofloxacin (minimal inhibitory concentration: 0.25-1.0 mg/L) have increased in incidence in S. Enteritidis, S. Virchow, and S. Hadar; in S. Hadar 70% of isolates were resistant to ciprofloxacin at this level. It is hoped that Codes of Practice introduced by some pharmaceutical companies, governments, professional organisations, and others to combat the unnecessary prophylactic use of fluoroquinolones in animal husbandry will not result in a reduction in the incidence of resistance to ciprofloxacin in salmonella organisms causing infections in humans.
Surveillance of antibiotic resistance can be undertaken by compilation of routine data or by central testing of isolates. Routine results can be obtained cheaply and in sufficient quantities for correlation with population and prescribing denominators but there is concern about their quality. As one of a series of ongoing studies to assess this quality, we compared the proportions of resistance amongst Escherichia coli from patients with bacteraemia or meningitis between 1991 and 1997 (i) as recorded in routine data reported to the PHLS and (ii) as found in tests performed at the PHLS Laboratory of Enteric Pathogens (LEP). These two data sets both showed an overall upward trend in the proportion of isolates resistant to ampicillin, trimethoprim, gentamicin and ciprofloxacin. The average annual percentage increase in resistance was estimated in separate logistic regression models, and 95% confidence intervals (CI) were determined. The annual percentage increases in the proportions of isolates reported resistant were similar in the two data sets for trimethoprim, gentamicin and ciprofloxacin but differed for ampicillin. The upward trends were statistically significant except for gentamicin resistance in the LEP data set, where the 95% CI straddled zero. The proportions of resistant isolates for each antibiotic in the two data sets each year were in poorer agreement than the trends; however, the 95% CI of the difference of proportions resistant between the routine and LEP data sets straddled zero in 4 or 5 of the 7 years studied. Some discrepancies might be explained by geographical bias in the sampling or by differences in definitions of resistance. Thus (i) the proportion of resistant isolates tested at LEP almost always fell within the ranges bounded by the highest and lowest proportions for individual Regional Health Authorities, as recorded in the routine data, and (ii) the fact that LEP consistently recorded less gentamicin resistance but more ciprofloxacin resistance than the routine could be explained by breakpoint differences. We conclude that routine susceptibility data for ampicillin, ciprofloxacin, gentamicin and trimethoprim appear sound for E. coli and might be suitable for correlation with other data, e.g. for prescribing.
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We describe the effects of an absence of retinoic acid (RA) on the development of somites in the quail embryo. RA was removed by generating vitamin A deficient quail embryos whereupon the resulting defects in the embryos can be analysed. The effect on the somites is threefold. Firstly, they are half the size of normal, but the total number of somites is the same as normal. There has therefore been some global regulation event. Secondly, by TUNEL staining and TEM we show that the lateral halves of all of the somites undergo apoptosis between stages 11 and 14. This effect is confined to the sclerotome of the somites. Thirdly, some of the genes involved in somite differentiation are down-regulated such as fgf-4, fgf-8, engrailed and myogenin whereas others we examined such as cek-8, Delta, follistatin and myf5 are not affected. These studies reveal remarkably specific effects of RA on developmental gene pathways in the embryo.