Coenzyme Q is a lipid molecule required for respiration and antioxidant protection. Q biosynthesis in Saccharomyces cerevisiae requires nine proteins (Coq1p–Coq9p). We demonstrate in this study that Q levels are modulated during growth by its conversion from demethoxy-Q (DMQ), a late intermediate. Similar conversion was produced when cells were subjected to oxidative stress conditions. Changes in Q6/DMQ6 ratio were accompanied by changes in COQ7 gene mRNA levels encoding the protein responsible for the DMQ hydroxylation, the penultimate step in Q biosynthesis pathway. Yeast coq null mutant failed to accumulate any Q late biosynthetic intermediate. However, in coq7 mutants the addition of exogenous Q produces the DMQ synthesis. Similar effect was produced by over-expressing ABC1/COQ8. These results support the existence of a biosynthetic complex that allows the DMQ6 accumulation and suggest that Coq7p is a control point for the Q biosynthesis regulation in yeast.
Ubiquinone; coenzyme Q; mitochondria; yeast regulation
“Basal” breast cancers are dominating the breast research literature at present and pathologists are under increasing pressure to evaluate for such a phenotype by their surgical and oncological colleagues. There is also much confusion about how to assess cancers, which immunohistochemical markers to use, what meaning and benefit this provides, and what the surgeons and oncologists will do with the information. Much remains to be done to answer all these questions but here we try to shed light on some of the issues and suggest what is still to come.
In September 2006, the seven-valent pneumococcal conjugate vaccine (PCV7; Prevenar) was introduced into the childhood vaccination schedule in the United Kingdom. We monitored the population of invasive pneumococci in Scotland in the 5 years preceding the introduction of PCV7 by using serogrouping, multilocus sequence typing (MLST), and eBURST analysis. Here, we present a unique analysis of a complete national data set of invasive pneumococci over this time. We observed an increase in invasive pneumococcal disease (IPD) caused by serotypes 1, 4, and 6 and a decrease in serogroup 14-, 19-, and 23-associated disease. Analysis of sequence type (ST) data shows a significant increase in ST306, associated with serotype 1, and a decrease in ST124, associated with serotype 14. There have also been increases in the amounts of IPD caused by ST227 (serotype 1) and ST53 (serotype 8), although these increases were not found to reach significance (P = 0.08 and 0.06, respectively). In the course of the study period preceding the introduction of PCV7, we observed considerable and significant changes in serogroup and clonal distribution over time.
Family history of haematopoietic malignancies appears to be a risk factor for non-Hodgkin's lymphoma (NHL), but whether risk varies by family member's gender is unclear. Among 121 216 women participating in the prospective California Teachers Study, NHL risk varied by type of haematopoietic malignancy and gender of the relative.
non-Hodgkin's lymphoma; family history; haematopoietic malignancy; lymphoma; leukaemia
This article summarises the medical problems of travel to altitudes above 3000 m. These are caused by chronic hypoxia. Acute mountain sickness (AMS), a self limiting common illness is almost part of normal acclimatisation—a transient condition lasting for several days. However, in <2% of people staying above 4000 m, serious illnesses related to hypoxia develop – high altitude pulmonary oedema and cerebral oedema. These are potentially fatal but can be largely avoided by gradual ascent. Short vacations, pressure from travel companies and peer groups often encourage ascent to 4000 m more rapidly than is prudent. Sensible guidelines for ascent are outlined, clinical features, management and treatment of these conditions.
2H and 15N solid-state NMR spectroscopic techniques were used to investigate both the side chain and backbone dynamics of wild-type phospholamban (WT-PLB) and its phosphorylated form (P-PLB) incorporated into 1-palmitoyl-2-oleoyl-sn-glycerophosphocholine (POPC) phospholipid bilayers. 2H NMR spectra of site-specific CD3-labeled WT-PLB (at Leu51, Ala24, and Ala15) in POPC bilayers were similar under frozen conditions (-25 °C). However, significant differences in the line shapes of the 2H NMR spectra were observed in the liquid crystalline phase at and above 0 °C. The 2H NMR spectra indicate that Leu51, located toward the lower end of the transmembrane (TM) helix, shows restricted side chain motion, implying that it is embedded inside the POPC lipid bilayer. Additionally, the line shape of the 2H NMR spectrum of CD3-Ala24 reveals more side chain dynamics, indicating that this residue (located in the upper end of the TM helix) has additional backbone and internal side chain motions. 2H NMR spectra of both WT-PLB and P-PLB with CD3-Ala15 exhibit strong isotropic spectral line shapes. The dynamic isotropic nature of the 2H peak can be attributed to side chain and backbone motions to residues located in an aqueous environment outside the membrane. Also, the spectra of 15N-labeled amide WT-PLB at Leu51 and Leu42 residues showed only a single powder pattern component indicating that these two 15N-labeled residues located in the TM helix are motionally restricted at 25 °C. Conversely, 15N-labeled amide WT-PLB at Ala11 located in the cytoplasmic domain showed both powder and isotropic components at 25 °C. Upon phosphorylation, the mobile component contribution increases at Ala11. The 2H and 15N NMR data indicate significant backbone motion for the cytoplasmic domain of WT-PLB when compared to the transmembrane section.
In the present case series, three patients for whom regional anesthesia may have been the optimum technique for controlling postoperative pain are discussed. However, due to prevailing circumstances, regional anesthesia could not be provided. An intravenous infusion of lidocaine at 4 mg/min was administered perioperatively as an alternative ‘rescue’ analgesic technique. This infusion rate, based on previous extensive pharmacokinetic studies, is widely considered to be safe. Postoperative pain was lower than expected for the type of surgery. Anecdotal experience suggests that hospital length of stay may also be reduced, with both patient and economic benefits.
Analgesia; Lidocaine; Postoperative pain
Methods: An experienced neurology ward sister was trained in the differential diagnosis of headache disorders. Over six months, patients with non-acute headache disorders and role players trained to present with benign or sinister headaches were seen by both the nurse and a consultant neurologist. Both reached independent diagnoses of various headache disorders.
Results: Consultants diagnosed 239 patients with tension-type headache (47%), migraine (39%), or other headache disorders (14%). The nurse agreed with the consultant in 92% of cases of tension-type headache, 91% of migraine, and 61% of other diagnoses. Where the nurse did not agree with the diagnosis, most would have been referred for a consultant opinion. Both the nurse and the doctors misdiagnosed the same three of 13 role players. The investigation rate of the consultants varied between 18% and 59%. Only one clinically relevant abnormality was found on head scans and this was strongly suspected clinically.
Conclusions: A headache nurse specialist can be trained to diagnose tension-type headache and migraine. A nationwide nurse led diagnostic headache service could lead to substantial reduction in neurology waiting times.
Objective: To explore the views of bereaved relatives about quality of survival after radiotherapy for malignant cerebral glioma.
Design: Semistructured interviews with the bereaved relatives of 56 previously studied patients with glioma.
Setting: Patients treated at six London hospitals from 1990 to 1992 surviving between one and 46 months (median, eight).
Subjects: Fifty six relatives (44 spouses, 12 others) seen four to six months after bereavement and 20 again at 13 months.
Main outcome measures: Views about quality of life and satisfaction with radiotherapy.
Results: Relatives described quality of life as "good or acceptable" when patients carried on some normal activities or enjoyed social relationships. They described restricted and dependent states, constant deterioration, or loss of social interaction as giving "poor or unacceptable" quality of life. Length of time lived in such states also appeared important. Relatives' views of good or acceptable quality of life were independently related to low initial cognitive or personality change or low distress in the patient after diagnosis, and to their subsequent survival free from physical disability for at least one month. Satisfaction with radiotherapy was related to low initial distress, some degree of surgical resection, and overall length of survival longer than six months.
Conclusions: Carefully exploring the views of bereaved relatives can bring a useful perspective to difficult treatment decisions. Their values support including disability and distress in quality of life measures, but cast doubt on the QALY-type approach of using full years of survival or time free from disability to judge whether treatments are worthwhile.
We have studied loss of heterozygosity at the BRCA1 and BRCA2 loci in 992 normal cell clones derived from topographically defined areas of normal tissue in four samples from BRCA1/BRCA2 mutation carriers. The frequency of loss of heterozygosity in the clones was low (1.01%), but it was found in all four samples, whether or not a tumour was present. Topographical mapping revealed that the genetic changes were clustered in some breast samples. Our study confirms the previous finding that a field of genetic instability can exist around a tumour, suggesting that sufficient tissue must be removed at surgery to avoid local recurrence. We also demonstrate that such a field of genetic change can exist in morphologically normal tissue before a tumour develops and, for the first time, we demonstrate that the field is of a size greater than one terminal duct-lobular unit. The genetic changes are not identical, however, which suggests that genetic instability in these regions may play an early role in tumour development. We also confirm and extend our original observation of loss of the wild-type BRCA1 allele in some clones, and loss of the mutant allele in others, demonstrating that loss of either allele is a stochastic event.
normal breast; loss of heterozygosity; BRCA1; BRCA2
Histopathologic features of breast cancer such as tumour size, grade and axillary lymph node (LN) status variably reflect tumour biology and time. Recent evidence suggests that the biological character of breast cancer is established at an early stage and has a major impact on clinical course. The aim of this study was to distinguish the impact of biology on breast cancer histopathology by comparing features of breast cancers diagnosed following population mammographic screening with prevalent vs incident detection and screening interval. Central histopathology review data from 1147 cases of ductal in situ and/or invasive breast cancer were examined. Size, grade and LN status of invasive cancers were positively correlated (P<0.001). Prevalent invasive cancers were larger (P<0.001) and more likely to be LN positive (P=0.02) than incident cases, but grade was not associated with screening episode (P=0.7). Screening interval for incident cancers was positively associated with invasive cancer size (P=0.05) and LN status (P=0.002) but not grade (P=0.1). Together, these data indicate that biology and time both impact on size and LN status of invasive breast cancer, but grade reflects biology alone. In view of the clinical importance of breast cancer biology, grade as its most direct indicator assumes particular significance.
breast cancer; histopathology; mammographic screening
Brachial plexus injury is an unusual and under-recognised complication of coronary artery bypass grafting especially when internal mammary artery harvesting takes place. It is believed to be due to sternal retraction resulting in compression of the brachial plexus. Although the majority of cases are transient, there are cases where the injury is permanent and may have severe implications as illustrated in the accompanying case history.
A randomized double-blind trial with a 7-valent pneumococcal conjugate vaccine was conducted in The Netherlands among 383 children, aged 1 to 7 years, with a history of recurrent acute otitis media. No effect of vaccination on the pneumococcal colonization rate was found. However, a shift in serotype distribution was clearly observed (R. Veenhoven et al., Lancet 361:2189-2195, 2003). We investigated the molecular epidemiology of 921 pneumococcal isolates retrieved from both the pneumococcal vaccine (PV) and control vaccine (CV) groups during the vaccination study. Within individuals a high turnover rate of pneumococcal restriction fragment end labeling genotypes, which was unaffected by vaccination, was observed. Comparison of the genetic structures before and after completion of the vaccination scheme revealed that, despite a shift in serotypes, there was clustering of 70% of the pneumococcal populations. The remaining isolates (30%) were equally observed in the PV and CV groups. In addition, the degree of genetic clustering was unaffected by vaccination. However, within the population genetic structure, nonvaccine serotype clusters with the serotypes 11, 15, and 23B became predominant over vaccine-type clusters after vaccination. Finally, overall pneumococcal resistance was low (14%), and, albeit not significant, a reduction in pneumococcal resistance as a result of pneumococcal vaccination was observed. Molecular surveillance of colonization in Dutch children shows no effect of pneumococcal conjugate vaccination on the degree of genetic clustering and the genetic structure of the pneumococcal population. However, within the genetic pneumococcal population structure, a clear shift toward nonvaccine serotype clusters was observed.
Aims: To describe the laboratory confirmation of meningococcal disease, using culture and non-culture based techniques, between 1993 and 1999 as part of a national service in Scotland.
Methods: Samples from patients with suspected meningococcal disease in Scotland were analysed by culture and non-culture based techniques to gain a laboratory confirmation of disease. Data were analysed to establish the number of disease cases, the serogroups of the organisms involved, and the importance of the techniques used.
Results: Between 1993 and 1999, there was a total of 1749 notified cases of meningococcal disease in Scotland. Culture based methods provided a laboratory confirmation of 788 cases whereas non-culture techniques confirmed 461 cases.
Conclusions: Non-culture techniques were a useful addition to culture based techniques in Scotland and improved the dataset required for public health management, disease surveillance, and vaccine policy.
meningococcal disease; Neisseria meningitidis; non-culture diagnosis
Pneumococcal conjugate polysaccharide (Pnc) vaccines are now available, and the need for an improved understanding of circulating pneumococcal serotypes and sequence types (STs) is recognized. Three hundred sixty-eight pneumococci isolated in cases of invasive disease in Scotland in the first 6 months of 2003 were analyzed. The isolates belonged to 30 serotypes, and there was a strong correlation between serotype and ST, although only nine serotypes consisted of a single ST. The following serotypes coexisted with the following numbers of STs: serotype 14, 10 STs, serotype 8, 8 STs; serotype 4, 6 STs; serotype 22F, 8 STs; serotype 9V, 7 STs; serotype 23F, 6 STs; serotype 6B, 6 STs; serotype 1, 3 STs; serotype 3, 3 STs; and serotype 7F, 3 STs. Our data also showed a strong association between ST and serotype, although 19 STs contained multiple serotypes. Of the 10 most common STs, 6 coexisted with a single serotype each. Vaccine coverage in all age groups was 94.9% for the 23-valent polysaccharide vaccine and 50.7, 55.4, and 64.1% for the 7-, 9-, and 11-valent Pnc vaccines, respectively. For those under the age of 2 years, 79% coverage would be provided by the 7-, 9-, and 11-valent Pnc vaccines.