Over 8000 new pancreatic cancers are diagnosed annually in the UK; most at an advanced stage, with only 3% 5-year survival. We aimed to identify and quantify the risk of pancreatic cancer for features in primary care.
A case–control study using electronic primary care records identified and quantified the features of pancreatic cancer. Cases, aged ⩾40 in the General Practice Research Database, UK, with primary pancreatic cancer were matched with controls on age, sex and practice. Putative features of pancreatic cancer were identified in the year before diagnosis. Odds ratios (OR) were calculated for features of cancer using conditional logistic regression. Positive predictive values (PPV) were calculated for consulting patients.
In all, 3635 cases and 16 459 controls were studied. Nine features were associated with pancreatic cancer (all P<0.001 except for back pain, P=0.004); jaundice, OR 1000 (95% confidence interval (CI) 4 302 500); abdominal pain, 5 (4.4, 5.6); nausea/vomiting, 4.5 (3.5, 5.7); back pain, 1.4 (1.1, 1.7); constipation, 2.2 (1.7, 2.8); diarrhoea, 1.9 (1.5, 2.5); weight loss, 15 (11, 22); malaise, 2.4 (1.6, 3.5); new-onset diabetes 2.1 (1.7, 2.5). Positive predictive values for patients aged ⩾60 were <1%, apart from jaundice at 22% (95% CI 14, 52), though several pairs of symptoms had PPVs >1%.
Most previously reported symptoms of pancreatic cancer were also relevant in primary care. Although predictive values were small – apart from jaundice – they provide a basis for selection of patients for investigation, especially with multiple symptoms.
pancreatic cancer; primary care; symptoms; diagnosis; positive predictive values
To assess whether the performance of a computer-assisted detection (CAD) algorithm for acute pulmonary embolism (PE) differs in pulmonary CT angiographies acquired at various institutions.
In this retrospective study, we included 40 consecutive scans with and 40 without PE from 3 institutions (n=240) using 64-slice scanners made by different manufacturers (General Electric; Philips; Siemens). CAD markers were classified as true or false positive (FP) using independent evaluation by two readers and consultation of a third chest radiologist in discordant cases. Image quality parameters were subjectively scored using 4/5-point scales. Image noise and vascular enhancement were measured. Statistical analysis was done to correlate image quality of the three institutions with CAD stand-alone performance.
Patient groups were comparable with respect to age (p=0.22), accompanying lung disease (p=0.12) and inpatient/outpatient ratio (p=0.67). The sensitivity was 100% (34/34), 97% (37/38) and 92% (33/36), and the specificity was 18% (8/44), 15% (6/41) and 13% (5/39). Neither significantly differed between the institutions (p=0.21 and p=0.820, respectively). The mean number of FP findings (4.5, 6.2 and 3.7) significantly varied (p=0.02 and p=0.03), but median numbers (2, 3 and 3) were comparable. Image quality parameters were significantly associated with the number of FP findings (p<0.05) but not with sensitivity. After correcting for noise and vascular enhancement, the number of FPs did not significantly differ between the three institutions (p=0.43).
CAD stand-alone performance is independent of scanner type but strongly related to image quality and thus scanning protocols.
To compare the prevalence and type of early developmental lesions in patients with a clinical presentation consistent with electrical status epilepticus in sleep either with or without prominent sleep-potentiated epileptiform activity (PSPEA).
We performed a case-control study and enrolled patients with 1) clinical features consistent with electrical status epilepticus in sleep, 2) ≥1 brain MRI scan, and 3) ≥1 overnight EEG recording. We quantified epileptiform activity using spike percentage, the percentage of 1-second bins in the EEG tracing containing at least 1 spike. PSPEA was present when spike percentage during non-REM sleep was ≥50% than spike percentage during wakefulness.
One hundred patients with PSPEA (cases) and 47 patients without PSPEA (controls) met the inclusion criteria during a 14-year period. Both groups were comparable in terms of clinical and epidemiologic features. Early developmental lesions were more frequent in cases (48% vs 19.2%, p = 0.002). Thalamic lesions were more frequent in cases (14% vs 2.1%, p = 0.037). The main types of early developmental lesions found in cases were vascular lesions (14%), periventricular leukomalacia (9%), and malformation of cortical development (5%). Vascular lesions were the only type of early developmental lesions that were more frequent in cases (14% vs 0%, p = 0.005).
Patients with PSPEA have a higher frequency of early developmental lesions and thalamic lesions than a comparable population of patients without PSPEA. Vascular lesions were the type of early developmental lesions most related to PSPEA.
OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1–3 h and secondary tumour cell necrosis between 6 and 72 h.
To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24 h, day 8 and day 15).
OXi4503 induced a selective dose-dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%).
These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503.
OXi4503; vascular disrupting agent; phase I trial; cell death mechanisms; M30 ELISA; M65 ELISA
There is increasing evidence that proteasomes have a biological role in the extracellular alveolar space, but inflammation could change their composition. We tested whether immunoproteasome protein-containing subpopulations are present in the alveolar space of patients with lung inflammation evoking the acute respiratory distress syndrome (ARDS). Bronchoalveolar lavage (BAL) supernatants and cell pellet lysate from ARDS patients (n = 28) and healthy subjects (n = 10) were analyzed for the presence of immunoproteasome proteins (LMP2 and LMP7) and proteasome subtypes by western blot, chromatographic purification, and 2D-dimensional gelelectrophoresis. In all ARDS patients but not in healthy subjects LMP7 and LMP2 were observed in BAL supernatants. Proteasomes purified from pooled ARDS BAL supernatant showed an altered enzyme activity ratio. Chromatography revealed a distinct pattern with 7 proteasome subtype peaks in BAL supernatant of ARDS patients that differed from healthy subjects. Total proteasome concentration in BAL supernatant was increased in ARDS (971 ng/mL ± 1116 versus 59 ± 25; P < 0.001), and all fluorogenic substrates were hydrolyzed, albeit to a lesser extent, with inhibition by epoxomicin (P = 0.0001). Thus, we identified for the first time immunoproteasome proteins and a distinct proteasomal subtype pattern in the alveolar space of ARDS patients, presumably in response to inflammation.
Background: The safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated.
Methods: Two prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC.
Results: Overall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8%−35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien–Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90–4200) ml and 189 (70–420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6–15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy.
Conclusions: Nephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial.
metastatic renal cancer; nephrectomy; sunitinib
Two biographies of Admiral Francis Beaufort (1774–1857) have stated that, aged 20–25 years, he suffered from porphyria cutanea tarda (PCT) that was ‘cured’ following severe blood loss during a naval skirmish. We have examined the evidence concerning the nature of his skin disease.
Primary records, most notably Beaufort's correspondence with his family, his journals and his father's diaries were sought out and analysed.
This case report is discussed in the context of 18th-century naval medicine and concepts and treatment of skin disease.
The description of his lesions, their age of onset, their progression and response to treatment, particularly topical tar and associated features are quite inconsistent with a diagnosis of PCT. His mother, Mary Waller Beaufort (1739–1821), consulted Dr Robert Darwin in 1803 about a painful skin disease affecting her legs. Detailed description of the lesions and a contemporary diagnosis are not available but possible diagnoses include chronic psoriasis and stasis eczema.
A more tenable diagnosis is that Francis Beaufort had chronic plaque psoriasis remitted by bed rest and convalescence in the sunny Mediterranean climate with cessation of alcohol consumption and improved nutrition as well as topical and oral medications.
Peroxisome proliferator activated receptor γ (PPARγ) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPARγ was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPARγ.
Mice with targeted disruption of the PPARγ gene in intestinal epithelial cells, generated using a villin‐Cre transgene and floxed PPARγ allele and designated PPARγΔIEpC, were compared with littermate mice having only the PPARγ floxed allele with no Cre transgene that expressed PPARγ in the gut, designated PPARγF/F. Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines.
PPARγΔIEpC mice displayed reduced expression of the PPARγ target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPARγΔIEpC mice in comparison with PPARγF/F mice. Interleukin (IL)‐6, IL‐1β, and tumour necrosis factor α mRNA levels in colons of PPARγΔIEpC mice treated with DSS were higher than in similarly treated PPARγF/F mice. The PPARγ ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPARγF/F and PPARγΔIEpC mice.
These studies reveal that PPARγ expressed in the colonic epithelium has an endogenous role in protection against DSS induced colitis and that rosiglitazone may act through a PPARγ independent pathway to suppress inflammation.
peroxisome proliferator activated receptor γ; colitis; cytokines; inflammatory bile disease; rosiglitazone
Images in cardiology
To compare survival and adverse outcome of patients with non‐valvar atrial fibrillation (NVAF) treated with or without warfarin.
Record linkage method to identify patients with a previous hospital diagnosis of atrial fibrillation and to link these patients to international normalised ratio (INR) test results and mortality data.
Cardiff and the Vale of Glamorgan, Wales.
Main outcome measures
Mortality, specifically from ischaemic and thromboembolic events.
6108 patients were identified with NVAF, of whom 36.4% received warfarin. Mean survival in the warfarin and non‐warfarin groups was 52.0 months and 38.2 months, respectively (p < 0.001), and 14.4 months (p < 0.001) after adjustment for confounding factors. Warfarin treated patients in the upper quartile of INR control had significantly longer survival (57.5 months) than did those in the lowest quartile of control (38.1 months, p < 0.001). The risk of stroke in the warfarin group when treated was lower than that in the non‐warfarin group (relative rate (RR) 0.74, p < 0.001). The risk of death from ischaemic stroke was lower in the warfarin group (RR 0.43, p < 0.001). The risk of all ischaemic and embolic events in the warfarin group was lower when they were taking warfarin (RR 0.74, p < 0.001). The risk of bleeding in the warfarin group when treated was greater (RR 1.78, p = 0.001).
Patients with NVAF within the recommended target INR range of 2.0–3.0 survive longer and have reduced morbidity. Probably too few people are anticoagulated with warfarin in NVAF.
atrial fibrillation; warfarin; anticoagulation; stroke
Although anaemia is recognised as a feature of colorectal cancer, the precise risk is unknown. We performed a case–control study using electronic primary care records from the Health Improvement Network database, UK. A total of 6442 patients had a diagnosis of colorectal cancer, and were matched to 45 066 controls on age, sex, and practice. We calculated likelihood ratios and positive predictive values for colorectal cancer in both sexes across 1 g dl−1 haemoglobin and 10-year age bands, and examined the features of iron deficiency.In men, 178 (5.2%) of 3421 cases and 47 (0.2%) of 23 928 controls had a haemoglobin <9.0 g dl−1, giving a likelihood ratio (95% confidence interval) of 27 (19, 36). In women, the corresponding figures were 227 (7.5%) of 3021 cases and 58 (0.3%) of 21 138 controls, a likelihood ratio of 41 (30, 61). Positive predictive values increased with age and for each 1 g dl−1 reduction in haemoglobin. The risk of cancer for current referral guidance was quantified. For men over 60 years with a haemoglobin <11 g dl−1 and features of iron deficiency, the positive predictive value was 13.3% (9.7, 18) and for women with a haemoglobin <10 g dl−1 and iron deficiency, the positive predictive value was 7.7% (5.7, 11). Current guidance for urgent investigation of anaemia misses some patients with a moderate risk of cancer, particularly men.
anaemia; colorectal cancer; diagnosis; primary health care
Neutron radiation offers significant advantages for the study of biological molecular structure and dynamics. A broad and significant effort towards instrumental and methodological development to facilitate biology experiments at neutron sources worldwide is reviewed.
Neutron scattering; Neutron crystallography; Small angle neutron scattering; Reflectometry; Inelastic neutron scattering; Quasi-elastic neutron scattering; Proteins; Membranes; Macromolecular structure and dynamics
Problem: Healthcare organisations are expected both to monitor inequalities in access to health services and also to act to improve access and increase equity in service provision.
Design: Locally developed action research projects with an explicit objective of reducing inequalities in access.
Setting: Eight different health care services in the Yorkshire and Humber region, including community based palliative care, general practice asthma care, hospital based cardiology clinics, and termination of pregnancy services.
Key measures for improvement: Changes in service provision, increasing attendance rates in targeted groups.
Strategies for change: Local teams identified the population concerned and appropriate interventions using both published and grey literature. Where change to service provision was achieved, local data were collected to monitor the impact of service change.
Effects of change: A number of evidence based changes to service provision were proposed and implemented with variable success. Service uptake increased in some of the targeted populations.
Lessons learnt: Interventions to improve access must be sensitive to local settings and need both practical and managerial support to succeed. It is particularly difficult to improve access effectively if services are already struggling to meet current demand. Key elements for successful interventions included effective local leadership, identification of an intervention which is both evidence based and locally practicable, and identification of additional resources to support increased activity. A "toolkit" has been developed to support the identification and implementation of appropriate changes.
A recombinantly produced murine leptin analog (MLA) antagonizes leptin-induced signaling in cell lines that express the long form of the leptin receptor. However, the effects of MLA on the activity of leptin-sensitive neurons and on central neural controls of food intake have not been reported. Here we report effects of MLA on food intake and body weight in adult rats and on the activity of cultured rat vagal afferent neurons. Daily intracerebroventricular coinjection of MLA with exogenous leptin significantly attenuated leptin-induced reduction of 48-h food intake and body weight. Coinjection of MLA with leptin also reduced leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. In addition, chronic intracerebroventricular MLA infusion over 14 d via osmotic minipumps significantly increased daily food intake, rate of body weight gain, fat-pad mass, and circulating plasma leptin concentrations. Surprisingly, however, MLA did not antagonize leptin-evoked increases in cytosolic calcium concentrations in vagal afferent neurons in primary culture. Rather, MLA itself produced acute activation selectively in leptin-responsive vagal afferent neurons. These data suggest that MLA is an antagonist for the central effects of leptin on food intake and body weight but an agonist at sites where leptin induces acute neuronal activation. This mixed antagonist/agonist action suggests either 1) that the coupling of a single leptin receptor (ObRb) to acute activation of neurons occurs by a signaling mechanism different from those that mediate centrally evoked reductions in food intake and body weight or 2) that acute neuronal activation and centrally induced reductions of food intake and body weight are mediated by different leptin receptor subtypes.
Objective: To evaluate how well patients with non-valvar atrial fibrillation (NVAF) were maintained within the recommended international normalised ratio (INR) target of 2.0–3.0 and to explore the relation between achieved INR control and clinical outcomes.
Design: Record linkage study of routine activity records and INR measurements.
Setting: Cardiff and the Vale of Glamorgan, South Wales, UK.
Participants: 2223 patients with NVAF, no history of heart valve replacement, and with at least five INR measurements.
Main outcome measures: Mortality, ischaemic stroke, all thromboembolic events, bleeding events, hospitalisation, and patterns of INR monitoring.
Results: Patients treated with warfarin were outside the INR target range 32.1% of the time, with 15.4% INR values > 3.0 and 16.7% INR values < 2.0. However, the quartile with worst control spent 71.6% of their time out of target range compared with only 16.3% out of range in the best controlled quartile. The median period between INR tests was 16 days. Time spent outside the target range decreased as the duration of INR monitoring increased, from 52% in the first three months of monitoring to 30% after two years. A multivariate logistic regression model showed that a 10% increase in time out of range was associated with an increased risk of mortality (odds ratio (OR) 1.29, p < 0.001) and of an ischaemic stroke (OR 1.10, p = 0.006) and other thromboembolic events (OR 1.12, p < 0.001). The rate of hospitalisation was higher when INR was outside the target range.
Conclusions: Suboptimal anticoagulation was associated with poor clinical outcomes, even in a well controlled population. However, good control was difficult to achieve and maintain. New measures are needed to improve maintenance anticoagulation in patients with NVAF.
The association between the staging of colorectal cancer and mortality is well known. Much less researched is the relationship between the duration of symptoms and outcome, and whether particular initial symptoms carry a different prognosis. We performed a cohort study of 349 patients with primary colorectal cancer in whom all their prediagnostic symptoms and investigation results were known. Survival data for 3–8 years after diagnosis were taken from the cancer registry. Six features were studied: rectal bleeding, abdominal pain, diarrhoea, constipation, weight loss, and anaemia. Two of these were significantly associated with different staging and mortality. Rectal bleeding as an initial symptom was associated with less advanced staging (odds ratio from one Duke's stage to the next 0.50, 95% confidence interval 0.31, 0.79; P=0.003) and with reduced mortality (Cox's proportional hazard ratio (HR) 0.56 (0.41, 0.79); P=0.001. Mild anaemia, with a haemoglobin of 10.0–12.9 g dl−1, was associated with more advanced staging (odds ratio 2.2 (1.2, 4.3); P=0.021) and worse mortality (HR 1.5 (0.98, 2.3): P=0.064). When corrected for emergency admission, sex, and the site of the tumour, the HR for mild anaemia was 1.7 (1.1, 2.6); P=0.015. No relationship was found between the duration of symptoms and staging or mortality.
colorectal cancer; primary health care; diagnosis; mortality
Most colorectal cancers are diagnosed after the onset of symptoms. However, the risk of colorectal cancer posed by particular symptoms is largely unknown, especially in unselected populations like primary care. This was a population-based case–control study in all 21 general practices in Exeter, Devon, UK, aiming to identify and quantify the prediagnostic features of colorectal cancer. In total, 349 patients with colorectal cancer, aged 40 years or more, and 1744 controls, matched by age, sex and general practice, were studied. The full medical record for 2 years before diagnosis was coded using the International Classification of Primary Care-2. We calculated odds ratios for variables independently associated with cancer, using multivariable conditional logistic regressions, and then calculated the positive predictive values of these variables, both individually and in combination. In total, 10 features were associated with colorectal cancer before diagnosis. The positive predictive values (95% confidence interval) of these were rectal bleeding 2.4% (1.9, 3.2); weight loss 1.2% (0.91, 1.6); abdominal pain 1.1% (0.86, 1.3); diarrhoea 0.94% (0.73, 1.1); constipation 0.42% (0.34, 0.52); abnormal rectal examination 4.0% (2.4, 7.4); abdominal tenderness 1.1% (0.77, 1.5); haemoglobin <10.0 g dl−1 2.3% (1.6, 3.1); positive faecal occult bloods 7.1% (5.1, 10); blood glucose>10 mmol l−1 0.78% (0.51, 1.1): all P<0.001. Earlier diagnosis of colorectal cancer may be possible using the predictive values for single or multiple symptoms, physical signs or test results.
colorectal cancer; primary health care; diagnosis; referral and consultation
Imprinted gene(s) on human chromosome 7q32-qter have been postulated to be involved in intrauterine growth restriction associated with Silver-Russell syndrome (SRS) as 7–10% of patients have mUPD(7). Three imprinted genes, MEST, MESTIT1, and COPG2IT1 on chromosome 7q32, are unlikely to cause SRS since epigenetic and sequence mutation analyses have not shown any changes. One hundred kilobases proximal to MEST lies a group of four carboxypeptidase A (CPA) genes. Since most imprinted genes are found in clusters, this study focuses on analysing these CPAs for imprinting effects based on their proximity to an established imprinted domain. Firstly, a replication timing study across 7q32 showed that an extensive genomic region including the CPAs, MEST, MESTIT1, and COPG2IT1 replicates asynchronously. Subsequently, SNP analysis by sequencing RT-PCR products of CPA1, CPA2, CPA4, and CPA5 indicated preferential expression of CPA4. Pyrosequencing was used as a quantitative approach, which confirmed predominantly preferential expression of the maternal allele and biallelic expression in brain. CPA5 expression levels were too low to allow reliable evaluation of allelic expression, while CPA1 and CPA2 both showed biallelic expression. CPA4 was the only gene from this family in which an imprinting effect was shown despite the location of this family of genes next to an imprinted cluster. As CPA4 has a potential role in cell proliferation and differentiation, two preferentially expressed copies in mUPD patients with SRS syndrome would result in excess expression and could alter the growth profiles of these subjects and give rise to intrauterine growth restriction.
Follicular dendritic cells (FDCs) play a central role in controlling B-cell response maturation, isotype switching and the maintenance of B-cell memory. These functions are based on prolonged preservation of antigen and its presentation in its native form by FDCs. However, when entrapping entire pathogens, FDCs can turn into dangerous long-term reservoirs that may preserve viruses or prions in highly infectious form.
Despite various efforts, the ontogeny of FDCs has remained elusive. They have been proposed to derive either from bone marrow stromal cells, myeloid cells or local mesenchymal precursors. Still, differentiating FDCs from their precursors in vitro may allow addressing many unsolved issues associated with the (patho-) biology of these important antigen-presenting cells. The aim of our study was to demonstrate that FDC-like cells can be deduced from monocytes, and to develop a protocol in order to quantitatively generate them in vitro.
Employing highly purified human monocytes as a starter population, low concentrations of Il-4 (25 U/ml) and GM-CSF (3 U/ml) in combination with Dexamethasone (Dex) (0.5 μM) in serum-free medium trigger the differentiation into FDC-like cells. After transient de-novo membrane expression of alkaline phosphatase (AP), such cells highly up-regulate surface expression of complement receptor I (CD35). Co-expression of CD68 confirms the monocytic origin of both, APpos and CD35pos cells. The common leukocyte antigen CD45 is strongly down-regulated. Successive stimulation with TNF-α up-regulates adhesion molecules ICAM-1 (CD54) and VCAM (CD106). Importantly, both, APpos as well as APneg FDC-like cells, heterotypically cluster with and emperipolese B cells and exhibit the FDC characteristic ability to entrap functionally preserved antigen for prolonged times. Identical characteristics are found in monocytes which were highly expanded in vitro by higher doses of GM-CSF (25 U/ml) in the absence of Dex and Il-4 before employing the above differentiation cocktail.
In this work we provide evidence that FDC-like cells can be derived from monocytes in vitro. Monocyte-derived FDC-like cells quantitatively produced offer a broad utility covering basic research as well as clinical application.
An experimental system of Mycobacterium tuberculosis growth in a carbon-limited chemostat has been established by the use of Mycobacterium bovis BCG as a model organism. For this model, carbon-limited chemostats with low concentrations of glycerol were used to simulate possible growth rates during different stages of tuberculosis. A doubling time of 23 h (D = 0.03 h−1) was adopted to represent cells during the acute phase of infection, whereas a lower dilution rate equivalent to a doubling time of 69 h (D = 0.01 h−1) was used to model mycobacterial persistence. This chemostat model allowed the specific response of the mycobacterial cell to carbon limitation at different growth rates to be elucidated. The macromolecular (RNA, DNA, carbohydrate, and lipid) and elemental (C, H, and N) compositions of the biomass were determined for steady-state cultures, revealing that carbohydrates and lipids comprised more than half of the dry mass of the BCG cell, with only a quarter of the dry weight consisting of protein and RNA. Consistent with studies of other bacteria, the specific growth rate impacts on the macromolecular content of BCG and the proportions of lipid, RNA, and protein increased significantly with the growth rate. The correlation of RNA content with the growth rate indicates that ribosome production in carbon-limited M. bovis BCG cells is subject to growth rate-dependent control. The results also clearly show that the proportion of lipids in the mycobacterial cell is very sensitive to changes in the growth rate, probably reflecting changes in the amounts of storage lipids. Finally, this study demonstrates the utility of the chemostat model of mycobacterial growth for functional genomic, physiology, and systems biology studies.