Biomedical subjects
Publications and source records attributed to J Black.
An in vitro study of the activity of 10 oral agents against 153 pediatric isolates of Streptococcus pneumoniae identified moxifloxacin and levofloxacin as the most active agents regardless of penicillin or macrolide susceptibility. Moxifloxacin inhibited all strains at 0.25 microg/ml and was 8- to 16-fold more potent than levofloxacin.
OBJECTIVE: Investigation of the role of sleep states on the respiratory effort of controls and subjects with upper airway resistance syndrome (UARS) using nasal cannula/pressure transducer system and esophageal manometry. PATIENTS AND METHODS: One night's monitoring of sleep and breathing, including the determination of peak end inspiratory esophageal pressure (respiratory effort) with esophageal manometry and flow limitation with nasal cannula. Analysis of the data, breath-by-breath, using visual inspection and a computerized program. Setting - a university sleep laboratory. Patients were nine men with UARS and nine control men matched for age, ethnicity, and body mass index. RESULTS: A modulation of respiratory effort by sleep state and stages is seen in all subjects, the lowest noted during REM sleep and the highest associated with Slow Wave Sleep. When total nocturnal breaths are investigated, a significant difference between peak end inspiratory esophageal pressure [(Pes)-considered as an index of respiratory effort] is noted between normal subjects and UARS. Two specific breathing patterns, seen primarily in UARS patients, are NREM sleep stage dependent. Crescendos (defined as more negative peak end inspiratory Pes with each successive abnormal breath) occur mostly during stages 1-2 NREM sleep, while segments consisting of regular and continuous, breath-after-breath, high respiratory efforts are associated with Slow Wave Sleep. Depending on sleep stage, visually scored arousal response displays differences in Pes negativity. The termination of the abnormal breathing pattern, always well defined with Pes, is not necessarily associated with a pattern of 'flow limitation' at the nasal cannula tracing, even when a visually scored EEG arousal is present. CONCLUSIONS: UARS patients have significantly more breaths, with more negative peak end inspiratory Pes, than do control subjects. The modulation of peak end inspiratory Pes (an index of respiratory effort) by sleep stage and state differs in UARS patients and control subjects. The nasal cannula/pressure transducer system may not detect all abnormal breathing pattern during sleep. As indicated by the visual sleep scoring, repetitive arousals may lead to more or less severe sleep fragmentation.
Narcolepsy is a syndrome of unknown aetiology characterised by excessive daytime sleepiness (often severe) usually in association with cataplexy (brief episodes of partial or complete muscle paralysis) and often with other uncommon symptoms. Due to limited disease-specific knowledge, medication treatment for this condition has focussed on specific symptom amelioration rather than improving or eliminating underlying disease mechanisms. Such treatment generally consists of stimulants for daytime sleepiness and anticataplectic medication for cataplexy; hence, both types of agents are reviewed in this article. Recent discoveries, including the finding that canine familial narcolepsy is caused by a single gene defect in the hypocretin receptor, coupled with the findings in human narcoleptics of undetectable hypocretin levels in the CSF and of severe hypocretin-containing neuronal atrophy in brains of deceased narcoleptics, have shifted the focus of narcolepsy treatment research to the hypocretin system. The hope is that a single agent can be developed to provide effective treatment for all symptoms of narcolepsy. While the mechanism of action in narcolepsy is unknown, gamma-hydroxybutyrate (GHB) is proving to be such an agent. Interestingly, GHB is not known to impact hypocretin pathways in the brain, yet specific research exploring this possible interaction has not been performed. The market for medications limited to use by narcoleptics is small because of the relatively low prevalence of narcolepsy; however, the prevalence of clinically important daytime sleepiness and/or fatigue is surprisingly high. New agents that effectively manage the sleepiness of narcolepsy thus have a much larger potential for appropriate use in treating sleepiness and fatigue in the general population. This fact has recently been demonstrated by the tremendous success of modafinil, a drug introduced to the market a little over 2 years ago, which was developed to treat sleepiness in narcolepsy but now is used in a much larger patient population.
OBJECTIVE: To classify the causes of death in Maputo City, Mozambique, using the methods of the Global Burden of Disease study, in order to provide information for health policy-makers and to obtain a baseline for future studies in Maputo City and provincial capitals. METHODS: Data were taken from the Maputo City death register and autopsy records for 1994. FINDINGS: A total of 9011 deaths were recorded in the death register, representing a coverage of approximately 86%. Of these, 8114 deaths (92%) were classified by cause. Communicable, maternal, perinatal, and nutritional disorders accounted for 5319 deaths; noncommunicable diseases for 1834; and injuries for 961. The 10 leading causes of registered deaths were perinatal disorders (1643 deaths); malaria (928); diarrhoeal diseases (814); tuberculosis (456); lower respiratory infections (416); road-traffic accidents (371); anaemia (269); cerebrovascular diseases (269); homicide (188); and bacterial meningitis (178). CONCLUSIONS: Infectious diseases of all types, injuries, and cerebrovascular disease ranked as leading causes of death, according to both the autopsy records and the city death register. AIDS-related deaths were underreported. With HIV infection increasing rapidly, AIDS will add to the already high burden of infectious diseases and premature mortality in Maputo City. The results of the study indicate that cause of death is a useful outcome indicator for disease control programmes.
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Mooted changes to the Declaration on the agenda of the World Medical Association have sparked a vigorous debate on international research issues. The medical, research and ethics communities in Australia need to participate more broadly in this debate.
A novel spermatogenesis associated factor (SPAF) was found to be aberrantly expressed at the malignant conversion stage in a clonal epidermal model of chemical carcinogenesis. Sequence analysis revealed two ATPase modules, classifying this gene as a new member of the AAA-protein family (ATPase associated with diverse activities). Immunohistochemical staining of mouse testis sections with SPAF antibody localized expression to spermatogonia and early spermatocytes in the basal compartment of the seminiferous tubules. Northern and Western analysis of SPAF expression in testes of mice at different developmental stages confirmed its expression at early stages of spermatogenesis. In view of a mitochondrial-localization-like signal, sequence similarities to membrane-associated proteins, ATP binding properties, and intracellular expression patterns in testis, we speculate that SPAF protein may be involved in morphological and functional mitochondrial transformations during spermatogenesis. Ectopic expression of the SPAF gene in malignant epidermal cells may signify adoption of an early germ cell-like phenotype advantageous in malignant conversion.
The distribution of titanium [Ti] and chromium [Cr] in serum protein fractions of patients with and without total joint replacements containing Cr and Ti was studied. Three groups were evaluated: 10 patients with cobalt-chromium [CoCr] alloy prostheses and known elevated levels of Cr; 10 patients with Ti containing implants and known elevated levels of Ti; and 10 age matched controls without prostheses. Metal-protein binding was also examined by adding various concentrations of Cr(+3) (CrCl(3)) to control serum. Cr and Ti were bound to serum proteins within specific molecular weight ranges in both patient groups. Two molecular weight ranges were found to bind Cr (at approximately 70 and approximately 180 kDa) in patients with CoCr alloy prostheses, whereas a single molecular weight range (at approximately 70 kDa) was found to bind Ti in patients with Ti alloy implants. This metal-protein binding was reproduced in vitro by adding CrCl(3) at concentrations of approximately 100 and 1000 ppb Cr, which is orders of magnitude higher than that contained in the serum of patients with CoCr alloy implants ( approximately 3 ppb Cr). This suggests that protein binding is initiated in the periprosthetic space where metal concentrations are typically 2-3 orders of magnitude higher than that observed systemically in the serum. In vitro, high molecular weight proteins including immunoglobulins demonstrated the highest affinity to Cr. Determination of specific protein carriers of metal degradation products is an essential component in the assessment of the long-term biological affects of total joint replacement devices.
Rosetting, the binding of parasitized erythrocytes to 2 or more uninfected erythrocytes, is an in vitro correlate of disease severity in Plasmodium falciparum malaria. Although cell ligands and receptors have been identified and a role for immunoglobulin M has been suggested, the molecular mechanisms of rosette formation are unknown. The authors demonstrate unequivocally that rosette formation by P falciparum-infected erythrocytes is specifically dependent on human serum, and they propose that serum components act as bridging molecules between the cell populations. Using heparin treatment and Percoll density gradient centrifugation, they have developed an assay in which parasitized erythrocytes grown in serum-containing medium and optimally forming rosettes are stripped of serum components. These infected cells were no longer able to form rosettes when mixed with erythrocytes and incubated in serum-free medium. Rosette formation was restored by the addition of serum or certain serum fractions obtained by concanavalin A (conA) affinity, anti-IgM affinity, anion exchange, and gel filtration chromatography. The authors clearly demonstrate that multiple serum components-IgM and at least 2 others-are involved in rosette formation. Those others consist of 1 or more acidic components of high-molecular mass that binds to conA (but that is not thrombospondin, fibronectin, or von Willebrand's factor) and of at least 1 more basic, smaller component that does not bind to conA. Data on the size and number of rosettes formed support the authors' hypothesis that multiple bridges are involved in this complex cellular interaction. These findings have important implications for the understanding of pathogenic adhesive interactions of P falciparum and host susceptibility to severe malaria. (Blood. 2000;95:674-682)
Metal hypersensitivity is a well-established phenomenon occurring in a variety of domestic and workplace settings. Degradation products of metallic biomaterials may mediate metal hypersensitivity. However, little is known about the short- and long-term pharmacodynamics and bioavailability of circulating metal degradation products in vivo. Mechanisms by which in vivo metal sensitivity reactions occur have not been well characterized and the degree to which metal sensitivity may be a predisposing factor for eliciting an overaggressive immune response remains clinically unpredictable. In vitro leukocyte migration inhibition assays have been used for investigating cell-mediated hypersensitivity reactions to biomaterial and biomaterial degradation products. This review provides a historical and technical summary of four in vitro techniques used for determination of leukocyte migration activity: (1) membrane migration or Boyden chamber, (2) capillary tube, (3) leukocyte migration using agarose technique, and (4) collagen gels. It is difficult to determine which, if any, of these techniques is singularly best suited for the investigation of suspected biomaterial-related symptoms in patients. However, Boyden chamber membrane migration testing is recommended for clinical investigations, principally because a high degree of standardized investigator independent materials and methodologies is necessary for compiling and comparing the results of patients tested at various times over the length of an extended study. Ultimately, in vitro migration inhibition testing has the potential to provide a reliable means for predicting some complications and thus enhancing the outcome for patients receiving metallic implants. Continuing improvements in migration inhibition testing methods, used alone or in combination with other immunologic assays, will likely improve assessment of patients susceptible to biomaterial antigen-induced delayed-type hypersensitivity responses.
UNLABELLED: Renal dysfunction is a common serious complication after cardiac surgery. Reports of proteinuria and hyperkalemia after cardiac surgery with epsilon-aminocaproic acid (EACA) have therefore raised concerns for renal safety. Since EACA renders these markers unreliable, we used perioperative change in creatinine clearance (DCrCl) to test the hypothesis that EACA is associated with greater reductions in creatinine clearance after heart surgery, particularly for patients with renal disease. We evaluated data from all elective primary coronary bypass patients during EACA introduction at our institution (July 1, 1991-December 31, 1992; 10 g iv bolus pre-cardiopulmonary bypass, then 1 g/h for 5 h). DCrCl was calculated using preoperative (CrPre) and postoperative peak serum creatinine values, using the Cockroft-Gault equation. Patients with CrPre > or = 133 micromol/L were also separately analyzed. Evaluated patients (n = 1502, +/-EACA; 581/905, 16 exclusions) included 233 with CrPre > or = 133 micromol/L (+/-EACA; 98/135). Multivariate analyses confirmed several known risk factors, but no association between DCrCl and EACA in all patients (P: = 0.66), and the subgroup with CrPre > or = 133 micromol/L (P: = 0.42). IMPLICATIONS: In a large population of primary Coronary Artery Bypass Graft including a subset with preoperative renal dysfunction, there were no postoperative reductions in creatinine clearance attributable to epsilon-aminocaproic (EACA) administration. This retrospective study suggests that moderate epsilon-aminocaproic acid dosing during cardiac surgery is safe for the kidney; however, this inference is based on a single marker of renal dysfunction and requires prospective confirmation using a variety of tests of renal function.
The problem of periprosthetic osteolysis is currently the major limiting factor in joint arthroplasty longevity. Because this process has been shown to be primarily a biologic response to wear particles, corrosion products, or both, efforts to reduce particle generation are being undertaken. These efforts include the development of modified polyethylene and alternative articulating surfaces. These alternate bearing surfaces currently include ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal. Although these alternate bearings diminish or eliminate the generation of polyethylene particles, ceramic and metal particles are produced. The purpose of the current review is to discuss the literature that addresses the biologic response to these particles, locally and systemically.
BACKGROUND: Celiac disease is an autoimmune disorder of the small intestine characterized by intolerance to gluten. Traditionally, diagnosis is made by intestinal biopsy. Testing for immunoglobulin (Ig) A endomysial antibodies in the serum also is used for diagnosis. Biopsy and serology revert to normal with adherence to a gluten-free diet. Often, after an index case is diagnosed, siblings with symptoms adhere to a gluten-free diet without biopsy or serologic confirmation. More than 90% of patients with celiac disease have the human leukocyte antigen (HLA) DQA1*0501-DQB1*0201 genotype. Non-HLA genes also have been implicated. METHODS: One hundred ninety-five individuals with confirmed or suspected celiac disease were identified in 73 families affected by the disease. IgA endomysial antibody testing was performed for all symptomatic family members who did not have biopsy-confirmed diagnoses. DNA samples were genotyped at D6S276 and the HLA class II loci DQA and DQB. RESULTS: At the time sampling was begun in families, 88 of 177 (49.7%) individuals were self-diagnosed and adhering to a gluten-free diet. Ninety percent (91/101) of confirmed cases (biopsy or serology) had at least 1 copy of the DQA1*0501-DQB1*0201 genotype, whereas only 67% (46/69) of cases self-diagnosed (adherence to gluten-free diet without confirmation) had at least 1 copy. Of confirmed cases, 61% carried two copies of DQB*0201. It is estimated that the HLA association and other unlinked genes contribute approximately equally to the sibling risk of celiac disease. CONCLUSIONS: A dosage effect of DQB1*0201 may be associated with an increased risk of celiac disease. Self-diagnosis of celiac disease is as common as confirmed diagnosis in families in the United States. Diagnosis of celiac disease on the basis of clinical response to gluten restriction is inaccurate. With long-term adherence to a gluten-free diet, serologic test results are likely to be negative. Based on HLA genotype, approximately one third of self-diagnosed individuals are unlikely to have celiac disease. However, it is not possible to determine which individuals consuming a gluten-free diet have the disease. Therefore, before starting a gluten-free diet, serologic screening and biopsy confirmation are necessary.
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