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Biomedical subjects

J MacFarlane

Publications and source records attributed to J MacFarlane.

At least 19 recordsLinked to original sources
PubMed2004

A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis.

Juvenile hemochromatosis (JH) is an autosomal recessive condition that leads to significant morbidity due to early onset systemic iron overload. The majority of families with JH link to chromosome 1q and were recently found to have mutations in the HFE2 gene encoding hemojuvelin; however, several JH families have been reported to have mutations in the HAMP gene encoding hepcidin. Here, we report a multiply consanguineous family with a father and daughter showing iron overload consistent with JH. Sequence analysis of HAMP revealed homozygosity for amino acid substitution C78T due to a c.233G > A mutation. This mutation disrupts one of eight highly conserved cysteines that are believed to be critical for the function of the active enzyme. This finding adds support to the importance of the role of these conserved cysteines in the activity of hepcidin.

Adult↗
PubMed2001

Family support by lay workers: a health visiting initiative.

There has been considerable research on the effectiveness of intensive professional home visiting schemes in improving parenting; lay visiting schemes, however, although often popular with clients, are under-researched. This article focuses on a lay visiting scheme set up and supported by health visitors in a deprived inner city area of Sheffield between 1998 and 2000. Although this scheme was designed to run for 2 years, an interim evaluation has taken place to track its effectiveness. This mainly qualitative evaluation has not only shown benefits to clients but also identified a number of issues for safe practice. The scheme has now been awarded core funding. It illuminates the kind of relationships that can develop between lay workers and clients, and enables a discussion of the benefits of this project and the challenge such schemes can present to both policy and practice.

Adolescent↗
PubMed1999

Pathological missense mutations of neural cell adhesion molecule L1 affect homophilic and heterophilic binding activities.

Mutations in the gene for neural cell adhesion molecule L1 (L1CAM) result in a debilitating X-linked congenital disorder of brain development. At the neuronal cell surface L1 may interact with a variety of different molecules including itself and two other CAMs of the immunoglobulin superfamily, axonin-1 and F11. However, whether all of these interactions are relevant to normal or abnormal development has not been determined. Over one-third of patient mutations are single amino acid changes distributed across 10 extracellular L1 domains. We have studied the effects of 12 missense mutations on binding to L1, axonin-1 and F11 and shown for the first time that whereas many mutations affect all three interactions, others affect homophilic or heterophilic binding alone. Patient pathology is therefore due to different types of L1 malfunction. The nature and functional consequence of mutation is also reflected in the severity of the resultant phenotype with structural mutations likely to affect more than one binding activity and result in early mortality. Moreover, the data indicate that several extracellular domains of L1 are required for homophilic and heterophilic interactions.

Animals↗
PubMed1999

In vitro studies with purified components reveal signal recognition particle (SRP) and SecA/SecB as constituents of two independent protein-targeting pathways of Escherichia coli.

The molecular requirements for the translocation of secretory proteins across, and the integration of membrane proteins into, the plasma membrane of Escherichia coli were compared. This was achieved in a novel cell-free system from E. coli which, by extensive subfractionation, was simultaneously rendered deficient in SecA/SecB and the signal recognition particle (SRP) components, Ffh (P48), 4. 5S RNA, and FtsY. The integration of two membrane proteins into inside-out plasma membrane vesicles of E. coli required all three SRP components and could not be driven by SecA, SecB, and DeltamicroH+. In contrast, these were the only components required for the translocation of secretory proteins into membrane vesicles, a process in which the SRP components were completely inactive. Our results, while confirming previous in vivo studies, provide the first in vitro evidence for the dependence of the integration of polytopic inner membrane proteins on SRP in E. coli. Furthermore, they suggest that SRP and SecA/SecB have different substrate specificities resulting in two separate targeting mechanisms for membrane and secretory proteins in E. coli. Both targeting pathways intersect at the translocation pore because they are equally affected by a blocked translocation channel.

Adenosine Triphosphatases↗
PubMed1996

Outline structure of the human L1 cell adhesion molecule and the sites where mutations cause neurological disorders.

The L1 cell adhesion molecule has six domains homologous to members of the immunoglobulin superfamily and five homologous to fibronectin type III domains. We determined the outline structure of the L1 domains by showing that they have, at the key sites that determine conformation, residues similar to those in proteins of known structure. The outline structure describes the relative positions of residues, the major secondary structures and residue solvent accessibility. We use the outline structure to investigate the likely effects of 22 mutations that cause neurological diseases. The mutations are not randomly distributed but cluster in a few regions of the structure. They can be divided into those that act mainly by changing conformation or denaturing their domain and those that alter its surface properties.

Amino Acid Sequence↗
PubMed1994

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

Aphasia↗
PubMed1993

A group approach for the management of insomnia.

To date, the management of insomnia has primarily consisted of pharmacological and behavioral approaches for individual patients. This paper documents the authors' work in formulating a group intervention for patients suffering from insomnia. The treatment rationales are discussed and include group theory, cognitive-behavioral and educational frames of reference. A description of the techniques used and the structure and process of the group model used is provided.

Behavior Therapy↗
PubMed1993

Liver Biopsies Following Ileogastrostomy.

Patients who have had ileogastrostomy for the treatment of morbid obesity require close, long-term follow-up. One concern in patients undergoing any form of intestinal bypass surgery is that of possible liver damage. To assess for possible liver damage in morbidly obese patients undergoing ileogastrostomy, we undertook a prospective study of liver biopsies in 12 consecutive patients. Preoperative and 2-year postoperative biopsies of the liver were planned. There were six liver biopsies available for comparison both pre- and post-operatively. The biopsies showed changes of fatty infiltration both pro- and post-operatively. There were no differences in the degree of fatty infiltration, or of other histological parameters which we measured. There were no cases of cirrhosis of the liver recorded.

Journal Article↗
PubMed1993

[Splenectomy by celioscopy. Experience of 20 cases].

We describe the clinical course of 20 patients considered for laparoscopic splenectomy. One patient was excluded on the basis of preoperative angiography findings and two (10.5%) were converted to open surgery. The first patient in the series was converted for a hemorrhagic incident and the eight patient, who had a 34 cm spleen, for dissection difficulties. In the remaining 17 patients who successfully underwent laparoscopic splenectomy, no mortality was reported and there were four postoperative complications (23.5%). Mean operating time was 3 h 40 min (135-300 min). After a mean postoperative stay of four days, all patients, except two, were back to normal activities within 2 weeks of hospital discharge. Preoperative splenic artery embolization was begun with the third patient and was found to significantly reduce operative blood loss and make the procedure easier to perform. Laparoscopic splenectomy has become our procedure of choice for elective removal of normal-sized or moderately enlarged spleens.

Adolescent↗
PubMed1992

Mapping of a visceral leishmaniasis-specific immunodominant B-cell epitope of Leishmania donovani Hsp70.

We have shown that a member of the 70-kDa heat shock protein (Hsp70) family is a major target of the humoral immune response during Leishmania donovani infection. A recombinant fusion protein was recognized by sera from 92% (35 of 38) of patients with visceral leishmaniasis, including representatives from each of the major regions where it is endemic. Serological analysis of recombinant Hsp70, expressed by a series of deletion constructs, identified the carboxy-terminal region as the immunodominant site. This region, which is the most evolutionarily divergent part of the molecule, was recognized by all sera from patients with visceral leishmaniasis which exhibited an anti-Hsp70 response. Purified recombinant L. donovani Hsp70 was not recognized by sera from patients with cutaneous leishmaniasis, Chagas' disease, leprosy, malaria, or schistosomiasis. To determine the regions involved in antibody recognition, a series of overlapping peptides were synthesized on polyethylene pins by the Pepscan method, and a hexamer, EADDRA, was identified by the visceral leishmaniasis serum samples as an immunodominant B-cell epitope.

Amino Acid Sequence↗
PubMed1990

Identification and characterisation of a Leishmania donovani antigen belonging to the 70-kDa heat-shock protein family.

A Leishmania donovani promastigote cDNA library was screened with serum obtained from a patient infected with visceral leishmaniasis. Sequence analysis of a clone obtained from this library revealed that the 600-bp insert corresponded to the carboxy-terminal region of an antigen related to the 70-kDa heat-shock protein family. The full-length sequence of the corresponding gene (1959 nucleotides) was determined after isolation of genomic clones. Genes encoding the antigen are present on a single chromosome as a series of approximately twelve 3.7-kb direct tandem repeats. The antigen can be identified as a 70-kDa heat-shock cognate protein by virtue of its molecular mass, sequence and constitutive expression during heat shock. It is expressed at all stages of the parasite life-cycle. Antibodies against the lambda gt11 fusion protein were detected in more than 50% of serum samples obtained from patients with visceral leishmaniasis, but were not detected in sera from patients with cutaneous leishmaniasis or Chagas' disease.

Amino Acid Sequence↗