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Biomedical subjects

S Johnson

Publications and source records attributed to S Johnson.

At least 37 records · Page 2Linked to original sources
PubMed2003

Do mitochondria regulate cellular iron homeostasis through citric acid and haem production? Implications for cancer and other diseases.

Citric acid is produced industrially by depriving Aspergillus niger of iron. The lack of Fe deactivates mitochondrial aconitase and interrupts the krebs cycle, causing the mitochondria to release citric acid as a siderophore (an Fe getter). When the mitochondrion has plenty of Fe and the cell has enough ATP, aerobic phosphorylation stops and fatty acid or haem synthesis take place, when the cell has plenty of haem, haem synthesis stops. Since most of the Fe activity in the cell is related to the mitochondria, I hypothesise that in the animal cell when the mitochondria are low in Fe, citric acid acts as a signal that triggers the production of transferrin receptor messenger RNA (TrR mRNA) in the nucleus, which in the absence of Fe causes the expression of transferrin receptor. When the cell has plenty of Fe, cytosolic aconitase detaches itself from the transferrin receptor and ferritin mRNA stopping expression of the former and initiating expression of the latter. The detached cytosolic aconitase transforms the citric acid, blocking the production of the transferrin receptor mRNA.

Blood Platelets↗
PubMed2003

An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole.

It was previously shown that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in patients with breast cancer. The objective of this study was to compare letrozole (2.5 mg per day) and anastrozole (1 mg per day) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-oestrogen. This randomised, multicentre and multinational open-label phase IIIb/IV study enrolled 713 patients. Treatment was for advanced breast cancer that had progressed either during anti-oestrogen therapy or within 12 months of completing that therapy. Patients had tumours that were either positive for oestrogen and/or progesterone receptors (48%) or of unknown receptor status (52%). The primary efficacy endpoint was time to progression (TTP). Secondary endpoints included objective response, duration of response, rate and duration of overall clinical benefit (responses and long-term stable disease), time to treatment failure, and overall survival, as well as general safety. There was no difference between the treatment arms in TTP; median times were the same for both treatments. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) (19.1% versus 12.3%, P=0.013), including in predefined subgroups (receptor status-unknown, and soft-tissue- and viscera-dominant site of disease). There were no significant differences between the treatment arms in the rate of clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure or overall survival. Both agents were well tolerated and there were no significant differences in safety. These results support previous data documenting the greater aromatase-inhibiting activity of letrozole and indicate that advanced breast cancer is more responsive to letrozole than to anastrozole as second-line endocrine therapy.

Adult↗
PubMed2003

Toxoplasmosis in Indo-Pacific humpbacked dolphins (Sousa chinensis), from Queensland.

OBJECTIVE: To describe the clinical signs, gross pathology, serology, bacteriology, histopathology, electron microscopy and immunohistochemistry findings associated with toxoplasmosis in four Indo-Pacific humpbacked dolphins (Sousa chinensis) that stranded in Queensland in 2000 and 2001. DESIGN: Clinical assessment, gross necropsy, and laboratory examinations. PROCEDURE: Necropsies were performed on four S. chinensis to determine cause of death. Laboratory tests including serology, bacteriology, histopathology and transmission electron microscopy were done on the four dolphins. Immunohistochemistry was done on the brain, heart, liver, lung, spleen and adrenal gland from various dolphins to detect Toxoplasma gondii antigens. RESULTS: Necropsies showed all of four S. chinensis that stranded in Queensland in 2000 and 2001 had evidence of predatory shark attack and three were extremely emaciated. Histopathological examinations showed all four dolphins had toxoplasmosis with tissue cysts resembling T. gondii in the brain. Tachyzoite stages of T. gondii were detected in the lungs, heart, liver, spleen and adrenal gland, variously of all four dolphins. Electron microscopy studies and immunohistochemistry confirmed the tissues cysts were those of T. gondii. All four dolphins also had intercurrent disease including pneumonia, three had peritonitis and one had pancreatitis. CONCLUSION: Four S. chinensis necropsied in Queensland in 2000 and 2001 were found to be infected with toxoplasmosis. It is uncertain how these dolphins became infected and further studies are needed to determine how S. chinensis acquire toxoplasmosis. All four dolphins stranded after periods of heavy rainfall, and coastal freshwater runoff may be a risk factor for T. gondii infection in S. chinensis. This disease should be of concern to wildlife managers since S. chinensis is a rare species and its numbers appear to be declining.

Animals↗
PubMed2003

Genetic linkage analysis of a novel syndrome comprising North Carolina-like macular dystrophy and progressive sensorineural hearing loss.

AIM: To characterise the phenotype and identify the underlying genetic defect in a family with deafness segregating with a North Carolina-like macular dystrophy (NCMD). METHODS: Details of the family were obtained from the Moorfields Eye Hospital genetic clinic database and comprised eight affected, four unaffected members, and two spouses. Pedigree data were collated and leucocyte DNA extracted from venous blood. Positional candidate gene and genetic linkage strategies utilising polymerase chain reaction (PCR) based microsatellite marker genotyping were performed to identify the disease locus. RESULTS: The non-progressive ocular phenotype shared similarities with North Carolina macular dystrophy. Electro-oculography and full field electroretinography were normal. Progressive sensorineural deafness was also present in all affected individuals over the age of 20 years. Hearing was normal in all unaffected relatives. Haplotype analysis indicated that this family is unrelated to previously reported families with NCMD. Genotyping excluded linkage to the MCDR1 locus and suggested a potential novel disease locus on chromosome 14q (Z=2.92 at theta=0 for marker D14S261). CONCLUSION: The combination of anomalies segregating in this family represents a novel phenotype. This molecular analysis indicates the disease is genetically distinct from NCMD.

Adolescent↗
PubMed2002

High-frequency ultrasound imaging of the intervertebral disc.

In vitro investigation of the detailed structure of the intervertebral disc has been reliant upon microdissection and histological techniques. However, these techniques are laborious and destructive; the latter aspect is important because it precludes repetitive testing of the disc during in vitro experimentation. The aim of the present study was to investigate the potential of using scanning acoustic microscopy (SAM) to image the detailed structure of the intact disc. A mechanically scanned 46-MHz transducer operating in pulse-echo mode was used to obtain images of porcine coccygeal and lumbar discs; scanned regions-of-interest (ROIs) were marked using permanent dye and small surface cuts, respectively. SAM images were compared with corresponding images obtained using conventional histological techniques. The annulus fibrosus was characterised by alternate light and dark bands; the former represent the boundary between adjacent lamellae. Lamellar discontinuities and pathologic abnormalities were observed in specimens. SAM is a novel, nondestructive method for detailed visualisation of the internal structure of the disc in vitro.

Acoustics↗
PubMed2002

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Chorea↗
PubMed2002

Communicating mild and borderline abnormal cervical smear results: how and what are women told?

The way in which women are informed about borderline or mild smear results can have a significant psychological impact. By means of a questionnaire survey of general practices in Nottingham, England, this study audited the means by which abnormal smear results were normally communicated to subjects and analysed the content of these communications. Transmitting abnormal smear results, either by letter or by telephone call, was typically the responsibility of the practice nurse, and communications varied widely in informational content. We conclude that the method and content of communications imparting mild or borderline smear results differs between general practices, even within a small geographical area.

Female↗
PubMed2002

Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2).

OBJECTIVE: To determine the molecular basis for achromatopsia using autozygosity mapping and positional candidate gene analysis. DESIGN AND METHODS: A large consanguineous Pakistani family containing six subjects with autosomal recessive complete achromatopsia was ascertained. After excluding linkage to the two known achromatopsia genes (CNGA3 and CNGB3), a genome wide linkage screen was undertaken. RESULTS: Significant linkage was detected to a 12 cM autozygous segment between markers D1S485 and D1S2881 on chromosome 1p13. Direct sequence analysis of the candidate gene GNAT2 located within this interval identified a frameshift mutation in exon 7 (c842_843insTCAG; M280fsX291) that segregated with the disease. CONCLUSIONS: The GNAT2 gene codes for cone alpha-transducin, the G protein that couples the cone pigments to cGMP-phosphodiesterase in phototransduction. Although cone alpha-transducin has a fundamental role in cone phototransduction, mutations in GNAT2 have not been described previously. Since mutations in the CNGA3 gene may cause a variety of retinal dystrophies (complete and incomplete achromatopsia and progressive cone dystrophy), GNAT2 mutations may also prove to be implicated in other forms of retinal dystrophy with cone dysfunction.

Amino Acid Sequence↗
PubMed2001

Quinupristin-dalfopristin-resistant Enterococcus faecium on chicken and in human stool specimens.

BACKGROUND: The combination of the streptogramins quinupristin and dalfopristin was approved in the United States in late 1999 for the treatment of vancomycin-resistant Enterococcus faecium infections. Since 1974, another streptogramin, virginiamycin, has been used at subtherapeutic concentrations to promote the growth of farm animals, including chickens. METHODS: To determine the frequency of quinupristin-dalfopristin-resistant E. faecium, we used selective medium to culture samples from chickens purchased in supermarkets in Georgia, Maryland, Minnesota, and Oregon and stool samples from outpatients. RESULTS: Between July 1998 and June 1999, samples from 407 chickens from 26 stores in four states were cultured, as were 334 stool samples from outpatients. Quinupristin-dalfopristin-resistant E. faecium was isolated from 237 chicken carcasses and 3 stool specimens. The resistant isolates from stool had low-level resistance (minimal inhibitory concentration [MIC], 4 microg per milliliter; resistance was defined as a MIC of at least 4 microg per milliliter). The resistant isolates from chickens in general had higher levels of resistance (MICs ranging from 4 to 32 microg per milliliter; MIC required to inhibit 50 percent of isolates, 8 microg per milliliter). CONCLUSIONS: Quinupristin-dalfopristin-resistant E. faecium contaminates a large proportion of chickens sold in U.S. supermarkets. However, the low prevalence and low level of resistance of these strains in human stool specimens suggest that the use of virginiamycin in animals has not yet had a substantial influence. Foodborne dissemination of resistance may increase, however, as the clinical use of quinupristin-dalfopristin increases.

Animal Feed↗
PubMed2001

Macrolide resistance among invasive Streptococcus pneumoniae isolates.

CONTEXT: Macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, are the mainstays of empirical pneumonia therapy. Macrolide resistance among Streptococcus pneumoniae, the most common cause of community-acquired pneumonia, is increasing in the United States. Whether resistance is a significant problem or whether macrolides remain useful for treatment of most resistant strains is unknown. OBJECTIVE: To examine the epidemiology of macrolide-resistant pneumococci in the United States. DESIGN AND SETTING: Analysis of 15 481 invasive isolates from 1995 to 1999 collected by the Centers for Disease Control and Prevention's Active Bacterial Core surveillance system in 8 states. MAIN OUTCOME MEASURES: Trends in macrolide use (1993-1999) and resistance and factors associated with resistance, including examination of 2 subtypes, the M phenotype, associated with moderate minimum inhibitory concentrations (MICs), and the MLS(B) phenotype, associated with high MICs and clindamycin resistance. RESULTS: From 1993 to 1999, macrolide use increased 13%; macrolide use increased 320% among children younger than 5 years. Macrolide resistance increased from 10.6% in 1995 to 20.4% in 1999. M phenotype isolates increased from 7.4% to 16.5% (P<.001), while the proportion with the MLS(B) phenotype was stable (3%-4%). The median erythromycin MIC (MIC(50)) of M phenotype isolates increased from 4 microg/mL to 8 microg/mL. In 1999, M phenotype strains were more often from children than persons 5 years or older (25.2% vs 12.6%; P<.001) and from whites than blacks (19.3% vs 11.2%; P<.001). CONCLUSIONS: In the setting of increasing macrolide use, pneumococcal resistance has become common. Most resistant strains have MICs in the range in which treatment failures have been reported. Further study and surveillance are critical to understanding the clinical implications of our findings.

Adolescent↗
PubMed2001

Fatal pseudomembranous colitis associated with a variant clostridium difficile strain not detected by toxin A immunoassay.

BACKGROUND: Many clinical laboratories use toxin A immunoassays to test for Clostridium difficile. OBJECTIVE: To describe the clinical course of a patient infected with a toxin variant strain of C. difficile that was not detected by toxin A immunoassay; to genetically characterize this strain; and to estimate the number of laboratories that use only toxin A immunoassays. DESIGN: Case report, molecular investigation, and laboratory survey. SETTING: Tertiary care hospital in Chicago, Illinois. PATIENT: An 86-year-old man. MEASUREMENTS: Restriction endonuclease analysis, polymerase chain reaction, and survey of regional clinical laboratories. RESULTS: An elderly hospitalized man died of advanced pseudomembranous colitis. Four stool specimens submitted over a 2-month period had tested negative on toxin A immunoassay, but a strain of C. difficile with a 1.8-kb deletion of the toxin A gene was recovered from each specimen. This strain, identified as restriction endonuclease analysis type CF4, is closely related to a widely disseminated variant, toxinotype VIII. Toxin A immunoassay was the only test being performed for detection of C. difficile at 31 of 67 (46%) regional clinical laboratories. CONCLUSIONS: Toxin A variant strains of C. difficile cause serious disease and are undetectable in clinical laboratories that use only toxin A immunoassays for C. difficile testing.

Aged↗
PubMed2001

Community-acquired methicillin-resistant Staphylococcus aureus in a rural American Indian community.

CONTEXT: Until recently, methicillin-resistant Staphylococcus aureus (MRSA) infections have been acquired primarily in nosocomial settings. Four recent deaths due to MRSA infection in previously healthy children in the Midwest suggest that serious MRSA infections can be acquired in the community in rural as well as urban locations. OBJECTIVES: To document the occurrence of community-acquired MRSA infections and evaluate risk factors for community-acquired MRSA infection compared with methicillin-susceptible S aureus (MSSA) infection. DESIGN: Retrospective cohort study with medical record review. SETTING: Indian Health Service facility in a rural midwestern American Indian community. PATIENTS: Patients whose medical records indicated laboratory-confirmed S aureus infection diagnosed during 1997. MAIN OUTCOME MEASURES: Proportion of MRSA infections classified as community acquired based on standardized criteria; risk factors for community-acquired MRSA infection compared with those for community-acquired MSSA infection; and relatedness of MRSA strains, determined by pulsed-field gel electrophoresis (PFGE). RESULTS: Of 112 S aureus isolates, 62 (55%) were MRSA and 50 (45%) were MSSA. Forty-six (74%) of the 62 MRSA infections were classified as community acquired. Risk factors for community-acquired MRSA infections were not significantly different from those for community-acquired MSSA. Pulsed-field gel electrophoresis subtyping indicated that 34 (89%) of 38 community-acquired MRSA isolates were clonally related and distinct from nosocomial MRSA isolates found in the region. CONCLUSIONS: Community-acquired MRSA may have replaced community-acquired MSSA as the dominant strain in this community. Antimicrobial susceptibility patterns and PFGE subtyping support the finding that MRSA is circulating beyond nosocomial settings in this and possibly other rural US communities.

Community-Acquired Infections↗
PubMed2001

Infection of hamsters with epidemiologically important strains of Clostridium difficile.

Five different toxigenic strains of Clostridium difficile of known human epidemiologic importance were tested for virulence in hamsters. Three strains-types B1, J9, and K14-have caused hospital outbreaks. Type Y2 is associated with a high rate of asymptomatic colonization in patients. The fifth strain, type CF2, is a toxin A-negative, toxin B-positive strain implicated in multiple human cases of C. difficile-associated diarrhea. Groups of 10 hamsters per strain were given 1 dose of clindamycin, followed 5 days later with gastric inoculation of 100 cfu of C. difficile. Hamsters given types B1, J9, K14, or Y2 showed 90%-100% colonization (albeit at a slower rate with type Y2) and 100% mortality of colonized animals. Hamsters challenged with type CF2 showed 60% (P= .01) colonization and 30% mortality (P= .0003). The hamster model demonstrated pathogenicity differences between a toxin variant strain and standard toxigenic strains but no significant differences among the standard strains.

Animals↗
PubMed2001

Adverse events regional feasibility study: methodological results.

AIMS: To assess the feasibility of research into the occurrence, causation and prevention of adverse events (AEs) in New Zealand public hospitals. METHODS: A two-stage retrospective review was carried out on 1,575 medical records selected by systematic list sample from admissions for 1995 in three public hospitals in the Auckland region. Following initial screening, medical records were subject to structured implicit review using a standardised protocol. Feasibility measures, using international benchmarks where possible, were: adequacy of sample selection; completeness of medical records; reliability and validity of screener and reviewer judgements; internal consistency and face validity of AE determination and preventability assessment. RESULTS: The sample selection procedure was effective, although nearly 10% of records could not be secured. Information in medical records was sufficient for the identification and analysis of AEs. Adequate levels of agreement were achieved for screener and reviewer judgements, with kappa scores ranging between 0.302 and 0.622 and positive predictive values between 50.0% and 89.7%. The criteria for AE determination showed internal consistency and face validity, as did those for preventability. CONCLUSIONS: Research into the occurrence, causation and prevention of AEs in New Zealand health care settings is methodologically feasible and meets international benchmark standards.

Algorithms↗
PubMed2001

Adverse events regional feasibility study: indicative findings.

AIMS: To identify substantive findings of potential clinical and managerial significance from a regional feasibility study of adverse events (AEs). METHODS: A standardised protocol using structured implicit review was applied to 142 AEs generated in an audit study of three public hospitals in the Auckland region for admissions in 1995. Areas of potential significance addressed were: timing, location and impact of AEs; preventability; and clinical context and predictability. RESULTS: 142 cases were identified as AEs (10.7% of 1,326 screened records). In 102 cases, 7.7% of all screened records, it was considered to be more likely than not that health care management contributed to the AE. About half the reported AEs occurred before the index admission, the majority outside hospital. Over half of all events resulted in disability that was resolved within a month. An average 6.7 extra days stay in hospital were attributable to AEs. For 60% of AEs the evidence for preventability was either low or nonexistent. Areas of potential prevention were predominantly educational. Over half of all AEs occurred in a surgical context. Medical AEs were more likely to have occurred outside hospital, to be drug-related, to be associated with an acute admission, to be classified as highly preventable, and to have a greater impact on hospital stay. CONCLUSIONS: Although the data generated by a feasibility study must be treated with caution, the pattern of results is consistent with comparable Australian findings and is of potential clinical and managerial significance.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2001

How does drug and alcohol misuse develop among people with psychotic illness? A literature review.

BACKGROUND: There is little evidence contributing to the understanding of why people with schizophrenia and other psychotic illnesses use drugs and alcohol. METHOD: A comprehensive literature search for evidence relevant to each of the following questions was undertaken, each of which is relevant to understanding why individuals with schizophrenia and other functional psychotic illnesses use drugs and alcohol: (1) Is substance misuse more prevalent among those with psychotic illness than the general Population? (2) Which problem generally develops first in dual diagnosis? (3) Can substance misuse cause schizophrenia and other functional psychotic illnesses? (4) Does dual diagnosis have a neurobiological Basis? (5) Is personality disorder a mediating factor in the relationship between psychotic illnesses and substance misuse? (6) Do individuals with psychotic illness use substances as self-medication? (7) Have changes in the care and social circumstances of people with psychotic illness, particularly deinstitutionalisation, led to a rise in substance misuse in this Population? (8) Do the social situations and social difficulties of people with psychotic illness lead to substance misuse? and (9) Do individuals with psychotic illness tend to begin using drugs and alcohol within mental health service settings or in the company of other users of such services? RESULTS: There is some evidence to support the idea that people with schizophrenia and other psychotic disorders use substances to reduce general dysphoria, and possibly negative symptoms. Social environment and experiences are also likely to be factors in the development of substance misuse in this group, but there is a dearth of empirical evidence. CONCLUSIONS: There is a need for further research, especially concerning the social contexts of substance and alcohol misuse and the ways in which patterns of misuse develop among people with schizophrenia and other psychotic illnesses.

Alcoholism↗
PubMed2001

The ins and outs of calreticulin: from the ER lumen to the extracellular space.

Calreticulin was first isolated 26 years ago. Since its discovery as a minor Ca(2+)-binding protein of the sarcoplasmic reticulum, the appreciation of its importance has grown, and it is now recognized to be a multifunctional protein, most abundant in the endoplasmic reticulum (ER). The protein has well-recognized physiological roles in the ER as a molecular chaperone and Ca(2+)-signalling molecule. However, it has also been found in other membrane-bound organelles, at the cell surface and in the extracellular environment, where it has recently been shown to exert a number of physiological and pathological effects. Here, we will focus on these less-well-characterized functions of calreticulin.

Animals↗