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Biomedical subjects

H Stewart

Publications and source records attributed to H Stewart.

At least 19 recordsLinked to original sources
PubMed2004

A prognostic index for operable, node-negative breast cancer.

Clinical data and samples from patients diagnosed, more than 10 years previously, with operable node-negative breast cancer (participants in the Scottish Adjuvant Tamoxifen trial), were revisited. Cases with two distinct categories of outcome were selected; more than 10 years disease-free survival ('good outcome') or distant relapse within 6 years of diagnosis ('poor outcome'). An initial set of cases was analysed for a range of putative prognostic markers and a prognostic index, distinguishing the two outcome categories, was calculated. This index was then validated by testing its predictive power on a second, independent set of cases. A combination of histological grade plus immunochemical staining for BCL-2, p27 and Cyclin D1, generated a useful prognostic index for tamoxifen-treated patients but not for those treated by surgery alone. The value of the index was confirmed in a second set of tamoxifen-treated, early stage breast cancers. Overall, it correctly predicted good and poor outcome in 79 and 74% of cases, respectively (odds ratio 11.0). Other markers assessed added little to prediction of outcome. In the case of molecular assays, sensitivity and reliability were compromised by the age of the tissue specimens and the variability of fixation protocols. In selecting patients for adjuvant systemic chemotherapy, the proposed index improves considerably on current international guidelines and matches the performance reported for 'gene-expression signature' analysis.

Biomarkers, Tumor↗
PubMed2003

Successful radioiodine treatment in a 3 year old child with Graves' disease following antithyroid medication induced neutropenia.

A 3 year old child with Graves' disease and mitral valve prolapse became neutropenic on carbimazole therapy. She was switched to propylthiouracil but the neutropenia recurred. She was treated with radioiodine but required two doses of 113 MBq and then 198 MBq five months later before becoming hypothyroid. The mitral valve prolapse resolved when she was euthyroid on thyroxine replacement. Antithyroid drugs, surgery, and radioiodine all have a place in the management of the thyrotoxic child.

Antithyroid Agents↗
PubMed2003

The familial contribution to non-syndromic ocular coloboma in south India.

AIMS: To identify the proportion of familial cases of isolated ocular colobomatous malformations in a case series from south India. METHODS: Children with ocular coloboma without systemic features were recruited from multiple sources in Andhra Pradesh, India. Their families were traced, pedigrees drawn, and family members examined. RESULTS: 56 probands, 25 females (44.6%) and 31 males (57.4%) with a colobomatous malformation were identified. In 12 cases (21.4%) another family member was affected. The risk to siblings was 3.8%. The parents were consanguineous in 25 cases (44.6%). CONCLUSIONS: 21.4% of cases of isolated ocular coloboma in this highly consanguineous population of south India were familial, with both autosomal dominant and autosomal recessive mechanisms likely in different families.

Adolescent↗
PubMed2002

Responses of ankle extensor and flexor motoneurons to transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) of the motor cortex excites limb muscles of the contralateral side of the body. Reports of poorly defined, or a complete lack of systematic excitatory responses of soleus motoneurons compared with those of tibialis anterior (TA) motoneurons has led to the proposal that while all ankle flexor motoneurons receive strong corticomotoneuronal connections, very few soleus motoneurons do. In addition, the connections to these few motoneurons are weak. The nature of corticomotoneuronal connections onto these two motoneuron pools was re-evaluated in the following experiments. The leg area of the left motor cortex was stimulated with a large double-cone coil using Magstim 200, while surface electromyographic (EMG) and single motor unit (SMU) responses were recorded from soleus and TA muscles of healthy adult subjects. Under resting conditions, the onset (25-30 ms) and duration of concomitantly recorded short latency motor evoked potentials (MEPs) in surface EMG from both muscles were similar. The input-output relationships of the simultaneously recorded soleus and TA EMG responses showed much greater increases in TA MEPs compared with soleus MEPs with identical increases in stimulus intensity. Under resting and nonisometric conditions, a later peak with onset latency of approximately 100 ms was observed in soleus. During isometric conditions or with vibration of the TA tendon, the second soleus peak was abolished indicating reflex origin of this peak. Recordings from 42 soleus and 39 TA motor units showed clear response peaks in the peristimulus time histograms (PSTHs) of every unit. Two statistical tests were done to determine the onset and duration of response peaks in the PSTHs. With chi(2) test, the duration was 6.9 +/- 4.2 ms (mean +/- SD) for soleus and 5.1 +/- 2.1 ms for TA. Using the criterion of discerning a peak by bin counts being three SDs above background, the duration was 10.0 +/- 4.4 ms for soleus and 7.8 +/- 2.6 ms for TA. Results of these experiments do not suggest a lack of systematic corticomotoneuronal connections on soleus motoneurons when compared with those on TA, though some differences in the strengths of corticomotoneuronal connections onto the two pools do exist.

Adult↗
PubMed2001

Electromyography of respiratory muscles in amyotrophic lateral sclerosis.

We reviewed the records of 52 amyotrophic lateral sclerosis (ALS) patients examined between 1995 and 2000 who had needle electromyography (EMG) of their respiratory muscles, including the diaphragm, at or near the time of their diagnosis. With respiratory function testing, patients with abnormal diaphragmatic EMG at diagnosis (Group 1, n=23) had significantly lower forced vital capacity (FVC), lower daytime arterial PO(2) and higher PCO(2) measurements (p<0.05) than patients with normal diaphragmatic EMG (Group 2, n=29). Twenty-eight percent of the patients without symptoms or signs of respiratory insufficiency at the time they were examined had an abnormal diaphragm EMG. Mean survival of Groups 1 and 2 were similar. However, sub-analysis of patients within each group, comparing those treated with non-invasive positive pressure ventilation (NIPPV) with those not treated, showed that treated patients in Group 1 (abnormal diaphragm EMG) survived significantly longer (p<0.05) than untreated patients. They also started NIPPV earlier than treated patients in Group 2. We conclude that respiratory muscle EMG was simply and safely performed on ALS patients at or around the time of diagnosis. The procedure can detect sub-clinical respiratory muscle dysfunction. The technique used for EMG of the respiratory muscles, its pitfalls and contraindications are also reviewed.

Aged↗
PubMed2001

De novo deletion of chromosome 18q in a baby with harlequin ichthyosis.

Harlequin ichthyosis, (MIM 242500), is a rare, autosomal recessive skin disorder due to an inborn error of epidermal keratinization. The gene for this condition has not been localized. We present a case of HI in which there was a de novo deletion of chromosome 18q: the karyotype was 46, XY, del(18)(q21.3). We postulate that the gene for HI may lie at, or distal to 18q21.3 and that the deletion observed in this case may have unmasked this autosomal recessive disorder.

Chromosome Banding↗
PubMed2001

The safe use of syringe drivers for palliative care: an action research project.

A palliative care team in north Scotland identified serious drug errors occurring in the local health-care trust. These were connected with the use of variable rate syringe drivers (IVAC P100) to deliver pain and symptom management rather than the more suitable Graseby MS26. An action research approach was taken to effecting change. An educational workshop was set up which 23 nurses attended. Clinical support was provided and 3 months later an evaluation was carried out. Of the 13 nurses who had used an MS26, most were able to correctly follow the process of setting up the driver and had made appropriate observations, but drug calculations were a problem. Change was stated to have taken place in seven clinical areas but the degree of change was variable. Facilitators and obstacles to the change process are identified and recommendations made for the next round in the action research cycle.

Equipment Design↗
PubMed2000

The split hand in ALS has a cortical basis.

Loss of highly fractionated movement involving the thumb and index finger is an early characteristic of hand dysfunction in many ALS patients. These movements are largely subserved by the 'thenar complex' including the first dorsal interosseus muscle (FDI), whereas the 'hypothenar complex', innervated by the same myotome, has less ability to fractionate and is relatively spared. This suggests that in ALS, hand dysfunction and wasting is related to corticomotoneuronal representation and input. To determine whether corticomotoneuronal input to the thenar spinal pool is preferentially impaired compared to the hypothenar spinal pool in ALS, we studied 18 ALS patients and 11 normal subjects. Compound muscle action potentials (CMAPs) and motor evoked potentials (MEPs) of the thenar and hypothenar complexes were evoked by peripheral nerve stimulation and transcranial magnetic stimulation. In healthy control subjects the cortical/peripheral (MEP/CMAP) ratios were significantly larger for the thenar complex suggesting a stronger corticomotoneuronal input to this muscle complex (P<0.005). This was not the case in ALS patients. Comparing the ratios between control subjects and patients revealed a significant reduction for the thenar complex (P<0.02) in ALS patients but not for the hypothenar complex. We conclude that corticomotoneuronal input to the thenar complex is preferentially affected in ALS and that corticomotoneuronal disease may be the prime determinant of hand dysfunction and wasting.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium.

Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-kappaB essential modulator)/IKKgamma (IkappaB kinase-gamma) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-kappaB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-kappaB activation is defective in IP cells.

Exons↗
PubMed2000

Is tourniquet use necessary for knee arthroscopy?

PURPOSE: With several studies identifying the tourniquet as a factor for increased risk of complications in knee arthroscopy, we wished to identify whether its use is necessary. TYPE OF STUDY: We performed a prospective randomized trial on 109 patients undergoing knee arthroscopy. MATERIALS AND METHODS: All patients had a tourniquet placed on the thigh and were assigned to either have it inflated or not inflated. Personal information, operative details, postoperative pain scores, analgesic requirements, and complications were recorded. RESULTS: The 2 groups were comparable. There was no significant difference between the 2 groups with respect to operative view, duration of operation, pain scores, analgesic requirements, or complications. The tourniquet required intraoperative inflation in 4 patients assigned not to have it inflated; in 1 patient, the tourniquet made no difference to the operative view. CONCLUSIONS: Many orthopaedic units continue to use a tourniquet routinely for knee arthroscopy, probably in the belief that a clear operative view can only be achieved with one. However, the findings in our trial indicate that knee arthroscopy may be performed adequately without the use of a tourniquet. Therefore, we recommend that its routine use for this procedure is discontinued.

Adolescent↗
PubMed2000

Ultrastructural and molecular analysis of Bowman's layer corneal dystrophies: an epithelial origin?

PURPOSE: Two mutations (R555Q and R124L) in the BIGH3 gene have been described in anterior or Bowman's layer dystrophies (CDB). The clinical, molecular, and ultrastructural findings of five families with CDB was reviewed to determine whether there is a consistent genotype:phenotype correlation. METHODS: Keratoplasty tissue from each patient was examined by light and electron microscopy (LM and EM). DNA was obtained, and exons 4 and 12 of BIGH3 were analyzed by polymerase chain reaction and single-stranded conformation polymorphism/heteroduplex analysis. Abnormally migrating products were analyzed by direct sequencing. RESULTS: In two families with type I CDB (CDBI), the R124L mutation was defined. There were light and ultrastructural features of superficial granular dystrophy and atypical banding of the "rod-shaped bodies" ultrastructurally. Patients from three families with "honeycomb" dystrophy were found to carry the R555Q mutation and had characteristic features of Bowman's dystrophy type II (CDBII). CONCLUSIONS: There is a strong genotype:phenotype correlation among CBDI (R124L) and CDBII (R555Q). LM and EM findings suggest that epithelial abnormalities may underlie the pathology of both conditions. The findings clarify the confusion over classification of the Bowman's layer dystrophies.

Adult↗
PubMed1999

Motor system abnormalities in heterozygous relatives of a D90A homozygous CuZn-SOD ALS patient of finnish extraction.

Presently, 64 mutations in the gene encoding the enzyme CuZn-superoxide dismutase have been found in a small fraction of amyotrophic lateral sclerosis patients worldwide. All but one of these mutations show autosomal dominant inheritance. In Scandinavia, the D90A mutation is inherited as an autosomal recessive trait and patients have an easily recognizable characteristic phenotype with little variation among patients, even amongst different families. Importantly, all D90A heterozygous relatives of Scandinavian D90A homozygous patients have been reported as clinically unaffected. We have investigated a Canadian family of Finnish extraction in which the D90A homozygous proband developed ALS with the characteristic phenotype. Remarkably, two D90A heterozygous relatives show slight symptoms and signs of motor system involvement, suggesting that the final phenotype of an individual with a CuZn-superoxide dismutase mutation is shaped by the combination of the particular CuZn-SOD mutation, other polymorphic modifying genes elsewhere in the genome, stochastics and possible environmental factors.

Aged↗
PubMed1999

The "CMT rat": peripheral neuropathy and dysmyelination caused by transgenic overexpression of PMP22.

We have generated a transgenic rat model of Charcot-Marie-Tooth disease type 1A (CMT1A) providing formal proof that this neuropathy can be caused by increased expression of peripheral myelin protein-22 (PMP22). Heterozygous PMP22-transgenic rats develop muscle weakness and gait abnormalities as well as reduced nerve conduction velocities and EMG abnormalities, which closely resemble recordings in patients with CMT1A. Dys- and demyelination, Schwann cell hypertrophy, and "onion bulb" formation are also similar to findings in humans. When bred to homozygosity, transgenic rats completely fail to elaborate myelin, but all myelin-forming Schwann cells segregate with axons in the normal one-to-one ratio. Although arrested at this "promyelin" stage, differentiation proceeds in homozygous rats at the molecular level, as demonstrated by high-level expression of myelin structural genes. Intracellular trafficking of the wild-type protein is not visibly impaired, even when strongly overexpressed, suggesting that PMP22 blocks myelin assembly in a late Golgi/cell membrane compartment of the affected Schwann cell.

Animals↗
PubMed1999

A mutation within exon 14 of the TGFBI (BIGH3) gene on chromosome 5q31 causes an asymmetric, late-onset form of lattice corneal dystrophy.

PURPOSE: Two forms of autosomal-dominant lattice corneal dystrophy (LCD), types I and IIIA, have previously been shown to be caused by different mutations within the transforming growth factor, beta-induced (TGFBI) gene. A clinical and molecular analysis of three unrelated kindreds with a clinically distinct late-onset LCD was undertaken to determine whether this phenotype is also caused by mutations within the TGFBI gene. DESIGN: Experimental study. PARTICIPANTS: Thirty-two members of three kindreds with corneal dystrophy. DNA from 100 normal control subjects was used as a control population. METHODS: Members of three kindreds with LCD were examined clinically, and blood samples were taken for DNA analysis. Mutation analysis was undertaken on all individuals for the coding region of the TGFBI gene by means of polymerase chain reaction (PCR) followed by single-stranded conformation polymorphism/heteroduplex analysis, subcloning, and sequencing. MAIN OUTCOME MEASURES: Detection of mutations within the TGFBI gene. RESULTS: Clinical examination revealed a form of LCD that was bilateral in all but one case, with onset around the fourth to fifth decade. The majority of cases showed significant asymmetry, and in one case there was evidence of onset directly after minor superficial corneal trauma. Molecular analysis in all families demonstrated sequence changes within exon 14 of the TGFBI gene on chromosome 5q31, at codon 622 in family 3, and at codon 626 in families 1 and 2, which are presumed to be responsible for the disease. CONCLUSIONS: Previously, a late-onset form of LCD, termed IIIA, was shown to be caused by a P501T mutation in exon 11 of TGFBI. The authors present the first description of mutations in exon 14 of TGFBI causing an LCD, also of late onset. Although the condition presented is morphologically and histopathologically typical of an isolated lattice dystrophy, the age of onset and clinical course is not typical of type I, III, or IIIA lattice dystrophy. This, in conjunction with recent developments in our understanding of the molecular genetics of these disorders, calls into question the usefulness and validity of the current classification of the isolated lattice dystrophies.

Adult↗
PubMed1999

X-inactivation and marker studies in three families with incontinentia pigmenti: implications for counselling and gene localisation.

Familial incontinentia pigmenti (IP) is an X-linked dominant disorder with an extremely variable clinical presentation. Ambiguous diagnosis can complicate genetic counselling and attempts to refine the gene location in Xq28. Marked skewing of X-inactivation patterns is a hallmark of IP and provides a means for investigating uncertain cases. We have conducted X-inactivation studies in three families where Xq28 marker studies were at odds with the original clinical assessment. The results indicate that no recombination between the disease locus and Xq28 loci has occurred and suggest that mosaicism is responsible for the discrepancy in one family.

Chromosome Mapping↗
PubMed1999

Mutants of Escherichia coli heat-labile toxin act as effective mucosal adjuvants for nasal delivery of an acellular pertussis vaccine: differential effects of the nontoxic AB complex and enzyme activity on Th1 and Th2 cells.

Mucosal delivery of vaccines is dependent on the identification of safe and effective adjuvants that can enhance the immunogenicity of protein antigens administered by nasal or oral routes. In this study we demonstrate that two mutants of Escherichia coli heat-labile toxin (LT), LTK63, which lacks ADP-ribosylating activity, and LTR72, which has partial enzyme activity, act as potent mucosal adjuvants for the nasal delivery of an acellular pertussis (Pa) vaccine. Both LTK63 and LTR72 enhanced antigen-specific serum immunoglobulin G (IgG), secretory IgA, and local and systemic T-cell responses. Furthermore, using the murine respiratory challenge model for infection with Bordetella pertussis, we demonstrated that a nasally delivered diphtheria, tetanus, and acellular pertussis (DTPa) combination vaccine formulated with LTK63 as an adjuvant conferred a high level of protection, equivalent to that generated with a parenterally delivered DTPa vaccine formulated with alum. This study also provides significant new information on the roles of the binding and enzyme components of LT in the modulation of Th1 and Th2 responses. LTK63, which lacks enzyme activity, promoted T-cell responses with a mixed Th1-Th2 profile, but LTR72, which retains partial enzyme activity, and the wild-type toxin, especially at low dose, induced a more polarized Th2-type response and very high IgA and IgG antibody titers. Our findings suggest that the nontoxic AB complex has broad adjuvant activity for T-cell responses and that the ADP-ribosyltransferase activity of the A subunit also appears to modulate cytokine production, but its effect on T-cell subtypes, as well as enhancing, may be selectively suppressive.

Adjuvants, Immunologic↗