Biomedical subjects
Publications and source records attributed to M Lynch.
Central metatarsal fractures are unique, secondary to biomechanical function, anatomy, and position within the foot. This article reviews the current and historical literature and the classic textbooks on fracture management to give a thorough understanding of the anatomy, biomechanics, incidence, mechanism of injury, classification, diagnosis, and treatment of the various presentations of this type of fracture.
Repeated activation of neural pathways by kindling induces brief seizures, permanent increases in seizure susceptibility, neuronal loss in the hippocampus, and mossy fiber sprouting in the dentate gyrus. Because kindling induces permanent cellular alterations in hippocampal pathways that have been implicated in memory, it was of interest to determine if kindling also induces long-lasting impairments in a spatial memory task in rats. In this study, the effects of kindling on memory were investigated by assessing kindled rats in a radial arm maze behavior that is impaired by hippocampal damage. Kindled rats studied at 1 month after the last of 30-134 evoked generalized tonic-clonic seizures acquired competence in the performance of the radial arm maze task at a rate that was indistinguishable from age-matched normal controls, but demonstrated a deficit in the ability to repeat the task on consecutive days. The repetition deficit was not observed in rats that experienced three afterdischarges or three generalized tonic-clonic seizures, and the severity of the deficit varied directly with the number of evoked kindled seizures. Repeated brief seizures evoked by kindling induced a long-lasting deficit in a radial arm maze task that is a rodent model of memory. The observation of a long-lasting deficit in radial arm maze performance in kindled rats suggests that the cellular alterations induced in the hippocampus by seizures could contribute to the memory dysfunction in human epilepsy.
Two membrane-photosensitizing dyes were used to investigate whether selected sites in the plasma membrane vary in their sensitivity to damage by singlet oxygen (1O2*) and, if so, what factors are responsible for the variation. The relative ability of Rose bengal (RB) and merocyanine 540 (MC540), both of which localize in the plasma membrane and produce 1O2*, to photosensitize five plasma membrane functions in P388D1 cells was evaluated. The five membrane functions assessed were: plasma membrane potential, proline transport, facilitated glucose diffusion, 5'-nucleotidase activity, and dye exclusion. Photosensitization efficiency by RB varied by a factor of 188 for these membrane functions, whereas for MC540 a range of only 24 was found. RB was a more efficient photosensitizer than MC540 but the relative efficiencies varied with the membrane function. The wide range of P50 values for RB suggests that it binds selectively to membrane sites where it causes damage with high efficiency; possibly a non-1O2* mechanism is involved. In contrast, MC540 photosensitized the three membrane functions involving integral membrane proteins about equally suggesting that differences are due to small variations in the distribution of MC540 in the plasma membrane and/or variations in the inherent reactivity of the membrane targets with 1O2*. The results indicate that the lability of membrane sites to photosensitization depends both on their inherent reactivity with 1O2* and the relative location of specific protein and dye molecules.
The aims of this study were (1) to assess the possibility of predicting allergic reactions to streptokinase (SK) by measuring pretreatment antibody titers and by intradermal skin testing, and (2) to determine if SK is associated with subclinical changes in renal function. Specific anti-SK immunoglobulin G (IgG) and subclass IgG1 were assessed by enzyme-linked immunosorbent sorbent assays, and renal function was assessed by measurement of serum urea and creatinine in 204 patients with acute myocardial infarction. Twenty-six patients had 24-hour proteinuria loss and creatinine clearance assessed at presentation. Median IgG titer at presentation was 6 (range 0 to 10,000), and increased to 60 (range 0 to 18,000; p < 0.0001) on day 6. Fifteen of 180 patients (8.3%) had minor allergic reactions to SK; the median titer on admission for these patients was 5 (range 0 to 60), identical to those who tolerated SK uneventfully. No change was seen in serum urea or creatinine; for those treated with SK, the median value for proteinuria loss at day 0 was 0.45 g/liter (range 0.1 to 2), and decreased by day 5 to 0.1 g/liter (range 0.1 to 0.8; p = 0.0027). No significant proteinuria was seen in those who did not receive SK. The reactions to SK were minor, and could not be predicted on the basis of IgG titers at presentation. Significant proteinuria was found in the first 24 hours in SK-treated patients, but not in those who did not receive SK, and it resolved by day 5.
Establishing regulatory mechanisms that mediate proliferation of osteoblasts while restricting expression of genes associated with mature bone cell phenotypic properties to post-proliferative cells is fundamental to understanding skeletal development. To gain insight into relationships between growth control and the developmental expression of genes during osteoblast differentiation, we have examined expression of three classes of genes during the cell cycle of normal diploid rat calvarial-derived osteoblasts and rat osteosarcoma cells (ROS 17/2.8): cell cycle and growth-related genes (e.g., histone), genes that encode major structural proteins (e.g., actin and vimentin), and genes related to the biosynthesis, organization, and mineralization of the bone extracellular matrix (e.g., alkaline phosphatase, collagen I, osteocalcin, and osteopontin). In normal diploid osteoblasts as well as in osteosarcoma cells we found that histone genes, required for cell progression, are selectively expressed during S phase. All other genes studied were constitutively expressed both at the transcriptional and posttranscriptional levels. Alkaline phosphatase, an integral membrane protein in both osteoblasts and osteosarcoma cells, exhibited only minimal changes in activity during the osteoblast and osteosarcoma cell cycles. Our findings clearly indicate that despite the loss of normal proliferation-differentiation interrelationships in osteosarcoma cells, cell cycle regulation or constitutive expression of growth and phenotypic genes is maintained.
There is increasing clinical interest focused on ex vivo manipulation and expansion of hematopoietic cells. In this study, we demonstrate that a simple combination of growth factors can expand progenitors to yield functional myeloid cells. Furthermore, this system can produce mature, functionally competent cells in the absence of fetal bovine serum (FBS), which will enhance the clinical utility of this approach. Hematopoietic progenitor cells obtained from normal bone marrow and from leukapheresis products were studied. The mononuclear fraction was enriched for CD34 cells using the Ceprate CD34 biotin kit (CellPro #LC34-1 or LC34-2). The selected cells were expanded for two weeks in Iscove's medium supplemented with 20% FBS and various combinations of interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF) and interleukin -6 (IL-6) added either simultaneously or sequentially. The optimal combination of these factors identified for myeloid expansion was simultaneous addition of IL-3, SCF and G-CSF (at 50 ng/ml each), resulting in an average 773 +/- 133-fold expansion of nucleated cells (n = 5). When corrected for the purity of CD34 cells in the starting population, the mean fold expansion with IL-3, SCF and G-CSF was 2,265 +/- 729. A mean of 74.7 +/- 10.5% (n = 3) of the expanded cells was positive for CD11b; 86-91% (n = 2) of the cells were promyelocytes or more mature granulocytes. Functional assays demonstrated normal phagocytosis and intracellular killing of Staphylococcus aureus (S. aureus) by the expanded cell population. Studies performed using cells expanded in defined serum-free media demonstrated that fold expansion was decreased and that the cells produced were less mature and functionally less competent than cells expanded with FBS. The decreased expansion could be partially reversed, and the functionality almost completely restored by the addition of autologous plasma.
The efficiency of mapping and diagnosis of X-linked disorders by linkage depends upon the existence of a high-density genetic map of polymerase chain reaction (PCR)-based markers. DXS1120, DXS1122, DXS1123, DXS1124, DXS1125, DXS1126, and DXS1153 were randomly isolated from a flow-sorted lambda bacteriophage library of the human X chromosome. The CCN (N = A or G) repeat within the androgen receptor was also found to be polymorphic and primers were designed for genotyping the CCN polymorphism in addition to the AGC polymorphism. The above markers, together with microsatellite polymorphisms at DXS237 (GMGX9), 5'DYS-II and 3'DYS MS (within the dystrophin locus), DXS538 (XL27B), PGK1P1, DXS300 (VK29AC), DXS294 (VK17AC), and DXS102 (cX38.1AC), were genotyped in the 40 CEPH reference families. One marker, DXS1153, was found to include cryptic alleles that amplify only in homozygotes and hemizygotes but not heterozygotes. A PCR-based linkage map was constructed using all of the above markers plus PCR-based markers from the CEPH database and those PCR-based markers previously typed in our laboratory: ALAS2, DXS292 (VK14AC), DXS297 (VK23AC), FRAXAC1, and FRAXAC2. The genetic map of the X chromosome incorporates 62 PCR-based marker loci, integrates the Weissenbach markers, and extends from XG near Xpter to DXS52 near Xqter, a distance of 236 cM.
Trichiasis/Entropion are the severe consequences of chronic trachoma during early life. Blindness and vision loss is preventable with timely lid surgery to correct trichiasis. In a trachoma hyperendemic region of Central Tanzania, a two year follow-up survey was conducted among 205 women with trichiasis to determine the proportion who had had surgery and the barriers to having surgery. Only 18% of the women had undergone surgery by the 2 year follow-up. Those who had surgery tended to report more eye problems at baseline and have more corneal opacities at baseline. Barriers preventing women from going to surgery were costs, problem of children left at home alone, and difficulties in identifying someone to accompany them to the health center. Over 2/3 of those who had surgery reported a significant decrease in pain, improvement of vision, and improved ability to carry out activities of daily life. Ways to improve compliance with recommendations for trichiasis surgery need to be developed.
Recent hypotheses and findings indicate that measurements of interactions between cerebrospinal fluid (CSF) biogenic amine systems, rather than measurement of CSF biogenic amine metabolites, better correlate with clinically important findings in schizophrenia. To test hypotheses, we used a recent technological advance in high performance liquid chromatography with electrochemical detection and combined it with multivariate statistical analyses to study biogenic amine concentrations in CSF in schizophrenia. This approach enabled the study of the interactions of several metabolites of each of the three major neurotransmitter pathways (dopaminergic, noradrenergic, and serotonergic) to test existing hypotheses regarding the neurobiochemical basis of schizophrenia. Twenty biogenic amines, their metabolites, and other compounds from 24 medication-free schizophrenic patients and 12 normal control subjects were simultaneously measured using a recently developed technique of gradient high performance liquid chromatography coupled with a 16-channel electrochemical array detector. After covariation for storage time, results of a stepwise discriminant function analysis comparing the control and patient groups identified tryptophan, tryptophol, and epinephrine as discriminating variables. Hotelling's paired T2 test from a subgroup of schizophrenic patients studied while they were and were not receiving neuroleptic treatment did not yield any significant differences between subgroups. A discussion of the findings and a comparison with previous studies of CSF biogenic amines in schizophrenia are presented.
Ten women with recurrent vulvovaginal candidiasis (RVVC) due to Candida albicans were followed for a mean of 35.3 months, and 81 vaginal isolates were evaluated by pulsed-field gel electrophoresis for strain delineation. The initial strain of C. albicans isolated was unique to each patient; in addition, in 8 women, only 1 strain type of C. albicans was identified throughout follow-up. In 1 patient, 3 strains of C. albicans were identified over a 27-month period and in another, 2 strains were recovered over a 30-month period. Two pairs of women shared identical strains of C. albicans. These results confirm the enormous diversity of strain types of C. albicans and demonstrate the persistence of colonization with the same strain over prolonged periods despite therapy. Results also support the concept of recurrent vaginitis being due to vaginal relapse or endogenous reinfection with the identical strain.
Factors affecting mobilization and engraftment were analysed in 54 patients undergoing transplant using autologous PBSCs mobilized with high-dose recombinant granulocyte stimulating factor (rhG-CSF). Patients received 5-7 d of rhG-CSF, 16 micrograms/kg/d, administered subcutaneously. PBSCs were harvested by leukapheresis using automated continuous-flow blood cell separators beginning on day 4 of rhG-CSF, processing 10 litres of whole blood, for 2-6 consecutive days. Transplants were performed for the following diseases: breast cancer (n = 22), non-Hodgkin's lymphoma (n = 18), multiple myeloma (n = 7) and other (n = 7). Engraftment was rapid with patients reaching a neutrophil count of 1 x 10(9)/l a median of 12 d (range 9-22) after transplant. Platelets > 20 x 10(9)/l independent of transfusion support were achieved a median of day 10 (range 7-60) after infusion. Multiple factors potentially influencing engraftment were examined using a Cox regression model. The number of CD34+ cells per kg was highly correlated with the time to achievement of granulocyte and platelet recovery (P < 0.012, 0.0001). The use of a post-infusion growth factor and a radiation preparative regimen was important for neutrophil recovery, and a diagnosis of breast cancer was important for platelet recovery. In an analysis by linear regression of the logarithm of CD34+ cells collected, lower age, marrow without disease, no prior radiation, and lower number of prior chemotherapy regimens, were important factors influencing larger numbers of CD34+ cells in collections.
Antibodies to streptokinase (SK) are widespread in the population, but reports of their effect on the action of SK are conflicting. Specific anti-SK IgG was purified from the sera of 10 patients, five with low titres of anti-SK IgG and five with high titres. The effect of increasing specific anti-SK IgG antibodies on the action of SK was evaluated in vitro using a fluorimetric assay for plasmin and by a fibrin plate lysis assay. The inhibition of SK by whole plasma from a further group of patients was also assessed by the fibrin plate assay. There was a positive correlation between the serum antibody concentration and the quantity of specific anti-SK eluted (r = 0.797; P < 0.005). The addition of specific anti-SK IgG caused a dose-related decrease in SK activity (fluorimetric assay r = -0.93; P = 0.02; fibrin plate assay r = -0.98; P < 0.001). The addition of patient plasma to the fibrin plate assay also resulted in decreased lysis, which was dependent upon antibody titre (r = -0.95; P < 0.0001). Significant in vitro reduction of the activity of SK by specific antibody was demonstrated, and this was similar with plasma containing comparable amounts of antibody. The findings suggest that treatment with SK would be unlikely to induce an effective thrombolytic state when antibody titres are high (such as those seen within 2 years of an initial dose of SK).
Recent advances in the application of the polymerase chain reaction make it possible to score individuals at a large number of loci. The RAPD (random amplified polymorphic DNA) method is one such technique that has attracted widespread interest. The analysis of population structure with RAPD data is hampered by the lack of complete genotypic information resulting from dominance, since this enhances the sampling variance associated with single loci as well as induces bias in parameter estimation. We present estimators for several population-genetic parameters (gene and genotype frequencies, within- and between-population heterozygosities, degree of inbreeding and population subdivision, and degree of individual relatedness) along with expressions for their sampling variances. Although completely unbiased estimators do not appear to be possible with RAPDs, several steps are suggested that will insure that the bias in parameter estimates is negligible. To achieve the same degree of statistical power, on the order of 2 to 10 times more individuals need to be sampled per locus when dominant markers are relied upon, as compared to codominant (RFLP, isozyme) markers. Moreover, to avoid bias in parameter estimation, the marker alleles for most of these loci should be in relatively low frequency. Due to the need for pruning loci with low-frequency null alleles, more loci also need to be sampled with RAPDs than with more conventional markers, and some problems of bias cannot be completely eliminated.
To examine the benefits of thrombolytic therapy in diabetic patients with acute myocardial infarction a retrospective study of all diabetic and non-diabetic patients with acute myocardial infarction admitted to the coronary care unit of the General Hospital, Birmingham between January 1984 and December 1987 was made and findings compared to corresponding groups admitted between January 1990 and May 1992 when thrombolytic therapy was routine. In-hospital mortality and morbidity were assessed in 208 diabetic and 1029 non-diabetic patients with acute myocardial infarction admitted 1984 and 1987 and in 115 diabetic and 501 non-diabetic patients with myocardial infarction between January 1990 and May 1992. Following the introduction of thrombolytic therapy, there was a reduction in mortality among non-diabetic patients from 17% to 8.5%; p < 0.001 (observed reduction: 49%; 95% CI: 30-70%) and in the incidence of left ventricular failure (from 22% to 8%, p < 0.1 (observed reduction: 52%; 95% CI: 40-85.5%). Diabetic patients showed a reduction in mortality from 30% to 17%; p = 0.02 (observed reduction: 42%; 95% CI: 9.4-73.8%) and in the incidence of left ventricular failure from 39% to 21%; p < 0.01 (observed reduction: 45%; 95% CI: 20.3-72.5%). Thrombolytic therapy confers a major benefit on diabetic patients with acute myocardial infarction, although this group remains at a prognostic disadvantage compared to non-diabetic patients.
OBJECTIVES: To assess the prevalence of typical clinical features and need for treatment of small intestinal bacterial overgrowth (SIBO) in the elderly. DESIGN: Random selection of patients, regardless of their nutritional status. SETTING: Acute admissions ward in the Dept. of Medicine for the Elderly. PATIENTS: Thirty elderly patients between 68 and 90 years of age. MEASUREMENTS: Active clinical problems, including the presence of recent weight loss and diarrhea, were recorded. Routine blood tests, including serum vitamin B12, red cell folate, albumin and calcium, and qualitative small bowel bacteriology results, were analyzed. The effect of age on all variables was studied. RESULTS: Twenty of the 30 small bowel aspirates had proven SIBO, and strict anaerobes were isolated in 15. The mean blood test values did not differ significantly between culture-positive and culture-negative patients. There was no significant correlation between those variables and the total bacterial counts. Of the 20 proven SIBO cases, eight had anemia, five had hypoalbuminemia, five had diarrhea, four complained of recent weight loss, and none had B12 deficiency. Alternative causes other than SIBO were identified for many of these abnormalities. Advancing age correlated significantly with rising counts of small bowel strict anaerobes. CONCLUSIONS: These data suggest that age may be a predisposing factor in the development of anaerobic overgrowth but that SIBO is a benign entity in the elderly. Contrary to previous recommendations, treatment of this condition is not routinely indicated.
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