Biomedical subjects
Publications and source records attributed to M Harris.
In 1989 the uprising against the Ceausescu regime blew the lid off the hidden horrors of Romania's mental hospitals. Aid poured in from western agencies and charities. Eight years on, with attention switched elsewhere, how much has changed?
The human genome is thought to harbor 50,000 to 100,000 genes, of which about half have been sampled to date in the form of expressed sequence tags. An international consortium was organized to develop and map gene-based sequence tagged site markers on a set of two radiation hybrid panels and a yeast artificial chromosome library. More than 16,000 human genes have been mapped relative to a framework map that contains about 1000 polymorphic genetic markers. The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease. The integrated resource is available through a site on the World Wide Web at http://www.ncbi.nlm.nih.gov/SCIENCE96/.
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The nef gene is unique to the primate lentiviruses and encodes a cytoplasmic membrane-associated protein that affects T-cell signaling and is essential for both maintenance of a high virus load in vivo and for disease progression. Here we investigated the perturbation of cell signaling by Nef in T-cells and found that Nef interacts with the T-cell restricted Lek tyrosine kinase both in vitro and in vivo. The molecular basis for this interaction was analyzed. We show that cell-derived Nef is precipitated in a synergistic manner by the recombinant Src homology 2 (SH2) and SH3 domains from Lck. A functional proline-rich motif and the tyrosine phosphorylation of Nef were evidenced as likely participants in this interaction. The precipitation of Nef by the Lck recombinant proteins was specific, since neither Fyn, Csk, p85 phosphatidylinositol 3-kinase nor phospholipase Cgamma SH2 domains coprecipitated Nef from T-cells. Finally, depressed Lck kinase activity resulted from the presence of Nef, both in vitro and in intact cells, and nef expression resulted in impairment of both proximal and distal Lck-mediated signaling events. These results provide a molecular basis for the Nef-induced T-cell signaling defect and its role in AIDS pathogenesis.
The importance of angiogenesis, assessed by tumour microvessel density, as a marker of survival was examined in 160 patients with infiltrating lobular carcinoma of the breast (ILC). The median follow-up was 5.1 years. Of these patients, 46 were node-negative, 59 were node-positive, and in 55 the pathological lymph node status was not known. Tumour sections were immunohistochemically stained with Factor VIII-related antibody. Microvessels were identified using previously recommended methodology and counted in three separate fields, selected from areas of highest vascularity, at x 200 magnification (field area = 0.785 mm2). Only the highest count was considered in the analysis. No association was found between microvessel density and age, menopausal status, tumour size, histological subtype, peritumoural vessel invasion, and lymph node involvement at presentation. There was no association between microvessel density and overall survival or relapse-free survival. These results suggest that microvessel density assessment, using currently recommended methods, is unlikely to be of prognostic value in ILC.
Women who are diagnosed with a major mental illness, who have a history of drug or alcohol abuse, and who have been episodically homeless are also likely to have been the victims of sexual or physical abuse. Treatment for these women needs to incorporate an active program of trauma recovery. A program of trauma-based treatment that includes supportive group therapy, cognitive reframing, and social skills training is discussed along with clinical examples.
Odontogenic cysts arise from tooth-forming epithelial residues. The stimulus for the formation of radicular cysts is thought to be endotoxin released from the infected necrotic tooth pulp. However, in keratocysts and follicular cysts, such a stimulus is not present. In order to investigate what drives the cyst epithelium to proliferate, explant media and fluids from 16 radicular cysts, eight keratocysts and seven follicular cysts and explant media from four specimens of non-inflamed gingival tissue were examined for the presence of endotoxin and cytokines. Cyst fluids were also cultured for 72 h in anaerobic and aerobic conditions to detect micro-organisms. Endotoxin from three different bacteria, cytokines [interleukin-(IL) 1 alpha, IL-1 beta and IL-6] as well as prostaglandin E2 (PGE2) were tested in an epithelial cell-proliferation assay. As the cyst epithelium is supported by a connective tissue capsule, the effect of fibroblast culture media on epithelial cell proliferation was also investigated. The results showed significantly higher concentrations of endotoxin in radicular cyst fluid than in the keratocyst or the follicular cyst. None of the cyst fluids contained micro-organisms. Immunoassays demonstrated the presence of IL-1 alpha and -6 in all fluids and explants tested; IL-1 beta was only found in the inflammatory radicular cysts. However, reverse transcriptase-polymerase chain reaction showed that mRNAs for IL-1 alpha, -1 beta and -6 were present in all cyst types. Proliferation studies indicated that endotoxin and the cytokines had a mitogenic effect on epithelia at low concentrations; PGE2 had very little effect at low concentrations, and had an inhibitory effect at high concentrations. Cyst fibroblast culture media had a mitogenic effect on the epithelia that was enhanced by the presence of endotoxin.
Prognostic factors predicting for breast recurrence following breast conserving surgery and radiotherapy have been identified in a prospective randomised trial comparing two different radiotherapy techniques. The first used megavoltage radiation to encompass the whole breast and regional nodes (WF group). The second used an electron field directed to the tumour bed only (LF group). With a median follow up of 8 years survival in both groups was the same (72%). There was an increased rate of breast recurrence in the LF group: 25%, compared to the WF group: 13% (P = 0.00008), expressed in actuarial terms at 8 years. In a multivariate analysis of factors predicting for breast recurrence, once the difference in treatment technique is allowed for, only two factors were found to be significant: histological grade (P = 0.013) and lymphovascular invasion in the histological specimen (P = 0.037).
Thirty-nine mammographically detected, (M-detected) small invasive carcinomas of the breast (< or = 5 mm) were compared with 78 consecutive clinical cancers (> or = 10 mm) for a variety of morphological and biological markers of prognostic importance. There were more tubular carcinomas in the M-detected group (12.8% v 3.8%), but this did not reach statistical significance. Incidences of other histological types were similar. The types of associated in situ component were similar in the two groups. M-detected cancers were of lower overall grade (P < .001), lower architectural and nuclear grades (P = .0164 and P < .0001 respectively), and had fewer mitotic cells (P < .0001). None showed positive lymph nodes (P < .0001). Estrogen and progesterone receptor expression was similar in both groups. M-detected cancers expressed p53 nuclear protein less frequently than clinical cancers (P = .0398), had lower levels of microvessel density (P = .0001), and were more often diploid (P = .0131). S-phase of diploid tumors in the two groups was similar, but S-phase of aneuploid tumors was lower in the M-detected group (P = .0057). Ki67 expression was lower in M-detected cancers (P < .0001). In conclusion, M-detected small breast cancers, although invasive, represent an evolutionary phase of breast cancer that generally lacks morphological and biologic markers of aggressive behavior. The presence or absence of these markers, collectively, may explain the influence of tumor size on survival in patients with breast cancer.
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The development of an anterior open bite in four patients with facial arthromyalgia is described. There were radiological signs of condylar erosion in three of these cases. It is proposed that the pre-senile destructive arthropathy of the temporomandibular joint, seen in a small proportion of patients with facial arthromyalgia, results from lysis of articular cartilage and bone, secondary to an inflammatory process initiated by the local release of neuropeptides. Occlusal changes, including anterior open bite, may occur if the destructive arthropathy is severe and outstrips dentoalveolar compensation.
AIMS: it is now recommended that cord blood acid-base measurement is performed routinely at time of delivery in the UK as a measure of fetal response to labour. However, there remains some uncertainty about the value of this procedure. In this paper our experience of cord blood analysis is described and the literature is reviewed to: (1) provide an overview of the physiological basis of cord blood acid-base assessment; (2) describe the appropriate methodology and identify issues which have contributed to confusion and undermined the value of cord blood sampling; and (3) address the practical issues of cord blood sampling. CONCLUSIONS: cord blood acid-base measurement has a sound physiological basis. It provides objective information which is a useful adjunct to subjective methods of newborn assessment, enables babies at risk of neonatal morbidity to be identified, can be helpful in litigation cases and is a prerequisite for clinical audit. However, to be of benefit the information must be correct and correctly interpreted.
The relative reproducibility of two widely used arbitrary face-bow transfer systems, the Denar Slidematic and the Dentatus type AEB, was assessed for use in orthognathic surgery planning. A novel method was also developed to determine any variation in three-dimensional spatial position and orientation of the maxillary cast. This envelope of movement enabled realistic comparisons to be made for each face-bow system, operator, and skeletal type. The overall face-bow/articulator procedure showed poor reproducibility. However, the Denar Slidematic face-bow was better (P < 0.001) than the Dentatus type AEB standard face-bow, and the errors were higher in the anteroposterior and lateral directions than the vertical direction. There was no significant difference between operators for each system.
Since its histologic recognition by the World Health Organization in 1990, polymorphous low-grade adenocarcinoma (PLGA) is now regarded as the second most common salivary gland tumour after mucoepidermoid carcinoma. Distinguishing it from high-grade tumours such as adenoid cystic carcinoma or carcinoma arising within a pre-existing pleomorphic adenoma is important, as PLGA may usually be treated by local excision alone. Any evidence of incomplete marginal clearance, perineural and perivascular spread, and lymph-node involvement is treated with a course of radiotherapy. Follow-up should be for life, and as reported in this series, long-term survival rates are very good, one of our patients surviving for 11 years. The importance of reporting these cases is emphasized.
We describe the clinicopathological features of gastrointestinal autonomic nerve tumours in nine patients where the diagnosis was confirmed by electronmicroscopy. Most patients presented with abdominal pain. At laparotomy, large intra-abdominal tumour masses were found which tended to be cystic and haemorrhagic. The predominant histological patterns were nests, sheets and fascicles of spindle and epithelioid cells. Immunohistochemistry showed positive staining for neuron specific enolase (9/9), PGP 9.5 (9/9), NKI/C3 (7/9), vimentin (7/9), alpha-smooth muscle actin (5/9), vasoactive intestinal peptide (3/9) and CD34/QBend10 (2/9). Grimelius staining was positive in two of nine cases. All tumours were negative for CAM 5.2, chromogranin, synaptophysin, Leu 7, neurofilament protein, muscle-specific actin (HHF-35) and desmin (D33). Ultrastructural examination showed cellular processes and dense-core granules in all cases. Three tumours had microtubules and/or intermediate filaments, particularly in cell processes. Skeinoid fibres were seen in three cases. No convincing synapses or small (synaptic-type) vesicles were identified. There was no evidence of epithelial, smooth muscle or nerve sheath differentiation. Two patients died due to tumour, two died of unknown causes and the remainder are alive 2-44 months after presentation. Four of the five survivors have recurrent/residual intra-abdominal tumour. So-called gastrointestinal autonomic nerve tumours are apparently slow-growing malignant tumours showing neuronal differentiation. Four cases arose in the mesentery/retroperitoneum or omentum rather than bowel wall and therefore a more appropriate nomenclature might be intra-abdominal stromal tumour with neuronal differentiation.
One hundred thirty-two recipients of blood components that retrospectively tested positive for antibody to human immunodeficiency virus type 1 (anti-HIV-1) were identified. Fourteen (11%) remained seronegative throughout follow-up. Donor and recipient characteristics that could have influenced transmission were examined. Attributes did not differ for infected and uninfected recipients. Peripheral blood mononuclear cells (PBMC) from uninfected recipients were HIV-1-negative by DNA amplification and culture but were susceptible to in vitro infection. Transmitting and nontransmitting donors at donation differed only for HIV-1 RNA positivity. By immunocapture reverse transcriptase-polymerase chain reaction, 6 of 11 transmitters and 0 of 11 nontransmitters tested RNA-positive (P = .02). A more sensitive quantitative RNA assay detected RNA in all donation sera, but median levels were higher in transmitting than nontransmitting sera (P = .01). Median CD4 cell counts were lower for transmitting than nontransmitting donors at enrollment (P = .02). Level of viremia is an important determinant of HIV infection by blood transfusion.
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