The platelet-derived growth factor (PDGF) family of mitogens exerts vital functions during embryonal development, e.g. in the central nervous system, where PDGF drives the proliferation of oligodendrocyte precursors. PDGF and PDGF receptors are co-expressed in human glioblastoma (GBM). Whether an aberrant activation of the PDGF receptor pathway is a driving force in glioma development has remained an open question. In experimental animals, overexpression of PDGF has convincingly been shown to induce tumors, both in wild-type animals (marmoset, rat, mouse) and in mice with targeted deletions of suppressor genes, e.g. Tp53 or Ink4A. Targeting the PDGF receptor in tumor-bearing mice leads to growth inhibition and reversion of the transformed phenotype. Findings of PDGF receptor amplification or mutations in human GBM are strong indicators of a causative role of the PDGF receptor pathway. However, clinical trials using PDGF receptor antagonists have been disappointing. In conclusion, a PDGF receptor profile may be a biomarker for a subgroup of GBM originating from a PDGF receptor-responsive cell. Although compelling experimental and clinical evidence supports the notion that the PDGF receptor pathway is a driver in GBM, formal proof is still missing.
Brain tumors; molecular biology; oncogenes; tumor biology
Sodium palmitate causes apoptosis of β-cells, and the anti-apoptotic protein Bcl-2 has been shown to counteract this event. However, the exact mechanisms that underlie palmitate-induced pancreatic β-cell apoptosis and through which pathway Bcl-2 executes the protective effect are still unclear.
A stable Bcl-2-overexpressing RINm5F cell clone (BMG) and its negative control (B45) were exposed to palmitate for up to 8 h, and cell viability, mitochondrial membrane potential (Δψm), reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress, and NF-κB activation were studied in time course experiments.
Palmitate exposure for 8 h resulted in increased cell death rates, and this event was partially counteracted by Bcl-2. Bcl-2 overexpression promoted in parallel also a delayed induction of GADD153/CHOP and a weaker phosphorylation of BimEL in palmitate-exposed cells. At earlier time points (2–4 h) palmitate exposure resulted in increased generation of ROS, a decrease in mitochondrial membrane potential (Δψm), and a modest increase in the phosphorylation of eIF2α and IRE1α. BMG cells produced similar amounts of ROS and displayed the same eIF2α and IRE1α phosphorylation rates as B45 cells. However, the palmitate-induced dissipation of Δψm was partially counteracted by Bcl-2. In addition, basal NF-κB activity was increased in BMG cells.
Our results indicate that Bcl-2 counteracts palmitate-induced β-cell death by maintaining mitochondrial membrane integrity and augmenting NF-κB activity, but not by affecting ROS production and ER stress.
Bcl-2; mitochondrial membrane integrity; NF-κB; palmitate; pancreatic beta cell death; reactive oxygen species
To examine the effects of inhibition of cyclooxygenase (COX) on islet hormone secretion in vitro and on pancreatic islet blood flow in vivo.
Insulin release was measured in a static incubation system of islets isolated from Wistar-F rats after inhibition of COX-1 and COX-2 with SC 560 (COX-1), FR 122047 (COX-1), rofecoxib (COX-2), or indomethacin (both COX-1 and COX-2). In other rats organ blood flow values were measured with a microsphere technique during both normo- and hyperglycemia after administration of these enzyme inhibitors.
Serum insulin values were lower after pretreatment with a COX-1 inhibitor or a non-selective COX inhibitor in both control and glucose-injected rats in vivo, whereas COX-2 inhibition had no such effects. However, inhibition of COX had only minor effects on insulin release in vitro. Inhibition of COX affected neither total pancreatic nor islet blood flow in normoglycemic rats. Hyperglycemia caused an increase in both these flow values and in the duodenum. The increase in total pancreatic and duodenal blood flow was prevented by inhibition of COX-2 or non-selective COX inhibition. However, no effects on islet blood flow were seen after COX inhibition.
Inhibition of COX affects insulin release and blood glucose concentrations in vivo. However, COX inhibition has only minor effects on pancreatic islet blood flow, but prevents the glucose-induced increase in total pancreatic blood flow.
COX inhibition; insulin release; islet blood flow
The forkhead box M1 (FOXM1) transcription factor plays an important role in the metastases of many cancers. Down-regulation of FOXM1 by its inhibitor, thiostrepton, can inhibit the metastatic potential of some cancers; however, there are few studies regarding the functional signiﬁcance of FOXM1 and thiostrepton in the metastases of nasopharyngeal carcinoma (NPC) and the underlying mechanism.
Expression of FOXM1 in NPC, normal nasopharyngeal tissues, a NPC cell line (C666-1), and a nasopharyngeal epithelial cell line (NP69) was investigated by immunohistochemical staining, qRT-PCR, and Western blot. The correlation between FOXM1 expression and the clinical characteristics of patients was analyzed. Moreover, the effects of thiostrepton on expression of FOXM1 in C666-1 and NP69 cells, and the invasion and migration ability of C666-1 cells were examined. The expressions of MMP-2, MMP-9, fascin-1, ezrin, and paxillin were determined after treatment with thiostrepton.
FOXM1 was overexpressed in NPC and C666-1 cells compared with normal nasopharyngeal tissues and NP69 cells. Overexpression of FOXM1 was associated with lymph node metastasis and advanced tumor stage. Moreover, thiostrepton inhibited expression of FOXM1 in C666-1 cells in a dose-dependent manner, but had a minimal effect on NP69 cells. Thiostrepton inhibited the migration and invasion ability of C666-1 cells by down-regulating the expression of MMP-2, MMP-9, fascin-1, and paxillin.
Overexpression of FOXM1 is associated with metastases of NPC patients. Thiostrepton inhibits the metastatic ability of NPC cells by down-regulating the expression of FOXM1, MMP-2, MMP-9, fascin-1, and paxillin.
Forkhead box M1 transcription factor (FOXM1); metastases; nasopharyngeal carcinoma; oncogene; thiostrepton
This study was designed to investigate whether a priming dose of ketamine-dexmedetomidine can effectively suppress fentanyl-induced coughing (FIC).
Altogether 400 patients of ASA I and II, aged 18–70 years, undergoing various elective surgical procedures, were randomly allocated into four groups of 100 patients each. Patients in the placebo group received volume-matched normal saline 0.15 mL/kg + normal saline 0.05 mL/kg. One group of patients was given ketamine 0.15 mg/kg + normal saline 0.05 ml/kg (KET), and another group dexmedetomidine 0.5 μg/kg + normal saline 0.05 ml/kg (DEX). Finally, one group of patients received ketamine 0.15 mg/kg + dexmedetomidine 0.5 μg/kg (KETODEX). After fentanyl administration, the onset time and severity of cough for 1 min were recorded. Cough severity was graded as mild (grade 1–2), moderate (grade 3–5), or severe (grade >5).
The incidence of FIC was 53%, 34%, 20%, and 9% in the placebo, DEX, KET, and KETODEX groups, respectively. The incidence of cough was significantly lower in the KETODEX group. Likewise, the onset time of cough was significantly delayed in the KETODEX group. Only nine patients in the KETODEX group had either mild (6%) or moderate (3%) cough, with none suffering from severe cough.
A priming dose of KETODEX effectively suppressed the cough reflex induced by fentanyl and delayed the onset time of cough. Therefore, treatment with KETODEX may be a clinically useful method for preventing FIC.
Anesthesia; fentanyl-induced coughing; dexmedetomidine; ketamine
The incidence of propofol injection pain during induction of general anesthesia varies from 28% to 90%. This prospective, randomized, double-blind, placebo-controlled study evaluated the effect of dexmedetomidine (DEX) for reducing the incidence and severity of propofol injection pain.
Patients undergoing elective surgical procedures were randomly allocated into seven groups of 30 patients each. Experimental treatments were intravenously administered over 10 min (total volume 10 mL) prior to intravenous propofol injection, as follows: group I, the control group, was given isotonic saline. Patients in groups II, III, and IV received DEX 0.25 µg/kg, 0.5 µg/kg, or 1.0 µg/kg, respectively, mixed with isotonic saline immediately before propofol injection. Patients in groups V, VI, and VII received DEX as above, but 5 minutes before propofol injection. Propofol consisted of 1% long-chain triglyceride propofol (2.5 mg/kg) injected at 1 mL/s.
Median propofol injection pain score was 0.00 (IQR 0.00–3.00) in patients who received 1.0 µg/kg DEX 5 min before the propofol injection (group VII), and only 1 patient (of 30) in this group received a pain score >2. The median pain score and number of patients with pain scores >2 in group VII were both significantly less than in the control (group I; p = 0.000, both). There were no differences in either mean arterial pressure or heart rate at any time point after DEX injection among the groups.
Pretreatment with intravenous DEX 1 µg/kg 5 min prior to injection of long-chain triglyceride propofol is effective and safe in reducing the incidence and severity of pain due to propofol injection.
Dexmedetomidine; injection pain; propofol
Outsourcing radiological examinations from public university hospitals affects the patient, who has to attend a different clinic or hospital for the radiological examination. We currently have a limited understanding of how patients view outsourcing and their care related to MR examinations.
Aim. To examine the experiences of patients who are sent to private radiology units when their referrals for MR examinations are outsourced from a university hospital, as well as to explore factors which influence patient satisfaction regarding the quality of care related to the MR examination.
A group of patients (n = 160) referred for MR examinations and either examined at a university hospital or at an external private unit were interviewed. The interview was designed as a verbal questionnaire. Data were analyzed using Student’s t test, analysis of variance (ANOVA), and Pearson’s correlation.
Sixty-nine percent of the patients could neither choose nor influence the location at which they were examined. For those who could, aspects that influenced the patient’s choice of radiology department were: short waiting time 79% (127/160), ease of traveling to the radiology department 68% (110/160), and short distance to their home or work 58% (93/160). For 40% (60/160) of the patients, a short time in the waiting room was related to a positive experience of the MR examination.
Conclusion. If patients were informed about outsourcing and could also choose where to have their examination, key factors contributing to patient satisfaction could be met even when MR examinations are outsourced.
care quality; decision-making; health policy; outsourcing radiology
Patients with hereditary haemorrhagic telangiectasia (HHT) suffer from recurrent epistaxis and bleeding from gastrointestinal telangiectasias that occur despite otherwise normal haemostasis and result in iron deficiency anaemia with increasing severity. In advanced disease, anaemia may be severe, be irresponsive to iron supplementation, and may lead to red blood cell transfusion dependency.
We conducted a retrospective study at our Centre for Osler’s Disease to evaluate the effectiveness of adding an erythropoiesis-stimulating agent (ESA) to intravenous iron supplementation in the management of anaemic HHT patients. Blood values and treatment parameters were collected for nine months before combination therapy (iron supplementation only) and 12 months during combination therapy (iron supplementation plus ESA).
Four patients received intravenous iron and an ESA with mean weekly doses of 126 mg and 17,300 units (U), respectively. Mean haemoglobin improved significantly during combination therapy, from 106 g/L to 119 g/L (p < 0.001).
Conclusion. Anaemia can be alleviated in patients with HHT who are irresponsive to intravenous iron supplementation, by addition of an ESA. The proposed mechanism behind the iron irresponsiveness is that the anaemia is caused by a combination of recurrent haemorrhage and anaemia of chronic disease.
Anaemia; erythropoiesis-stimulating agents; hereditary haemorrhagic telangiectasia; iron
The aim of this study was to investigate whether poly(ADP-ribose) polymerase (PARP) inhibition improves endothelin-1 (ET-1)-induced endothelial dysfunction (ED).
Isolated rat thoracic aorta rings were incubated with ET-1 (10 nmol/L) in the presence or absence of either polyethylene glycol–superoxide dismutase (PEG-SOD; a cell-permeable superoxide radical scavenger, 41 U/mL) plus apocynin (a NADPH oxidase inhibitor, 300 µmol/L) or PJ34 (an inhibitor of polyADP-ribose polymerase, 3 µmol/L) for 18 h. Isometric tension studies were performed in response to acetylcholine (ACh; an endothelium-dependent vasodilator), sodium nitroprusside (SNP; an endothelium-independent vasodilator), and phenylephrine (Phe). PARP-1 and PAR (an end-product of PARP activity) expressions were evaluated by both Western blot and immunohistochemistry.
Incubation of thoracic aorta rings with ET-1 resulted in a significant inhibition of the response to ACh, while SNP-induced relaxation was unaffected. The contractile response to Phe increased in arteries that were incubated with ET-1. PARP-1 and PAR expressions increased after ET-1 incubation. The diminished vasoreactivity as well as changes in expressions of PARP-1 and PAR in ET-1-incubated vessels were improved by both PEG-SOD plus apocynin and PJ34.
Our studies demonstrate that ED induced by ET-1 seems to be effected via oxidative stress in the thoracic aorta endothelium with subsequent activation of the PARP pathway.
Endothelial dysfunction; endothelin-1; poly(ADP-ribose) polymerase (PARP)
Senile systemic amyloidosis (SSA) derived from wild-type transthyretin is a fairly common condition of old individuals, particularly men. The main presentation is by cardiac involvement, which can lead to severe restrictive cardiomyopathy. SSA is, however, a systemic disease, and amyloid deposits may appear in many other tissues but are thought to be without clinical symptoms outside the heart. Amyloid is a very common finding in cartilage and ligaments of elderly subjects, and transthyretin has been demonstrated in some deposits. Lumbar spinal stenosis is also a condition of usually elderly individuals in whom narrowing of the lumbar spinal canal leads to compression of nerves to the lower limbs.
We questioned whether lumbar spinal stenosis sometimes could be a manifestation of undiagnosed SSA. In this first report we have studied the presence of amyloid in material obtained at surgery for spinal stenosis in 26 patients. Amyloid was found in 25 subjects. Transthyretin was demonstrated immunohistochemically in 5 out of 15 studied resected tissues. Four of the positive materials were analyzed with Western blot revealing both full-length transthyretin (TTR) and C-terminal TTR fragments, typically seen in SSA.
We conclude that lumbar spinal stenosis quite frequently may be a consequence of SSA and that further studies are warranted.
apolipoprotein A-I; lumbar spinal stenosis; senile systemic amyloidosis; transthyretin
The aetiology and early pathophysiological mechanisms of aortic aneurysm formation are still unknown and challenging to study in vivo. Positron emission tomography (PET) is a potentially valuable instrument for non-invasive in vivo pathophysiological studies. No specific tracer to identify the pathophysiological process of aneurysmal dilatation is yet available, however. The aim of this study was to explore if different PET tracers could be useful to image aneurysmal disease.
Methods and results
Human aneurysmal aortic tissue, collected during elective resection of abdominal aortic aneurysm (AAA) of asymptomatic patients, was investigated in vitro by means of autoradiography with [68Ga]CRP-binder targeting C-reactive protein, [11C]DAA1106 targeting translocator protein (18 kDa), [11C]D-deprenyl with unknown target receptor, [11C]deuterium-L-deprenyl targeting astrocytes, [18F]fluciclatide targeting integrin αVβ3, [68Ga]IMP461 and bi-specific antibody TF2 052107 targeting carcinoembryonic antigen, [18F]F-metomidate targeting mitochondrial cytochrome P-450 species in the adrenal cortex, and [18F]vorozole targeting aromatase. Of the investigated tracers, only [18F]fluciclatide exhibited specific binding, whereas the other PET tracers failed to show specific uptake in the investigated tissue and are probably not useful for the intended purpose.
It seems likely that αVβ3 integrin expression in AAA can be visualized with PET and that the αVβ3 selective tracer, [18F]fluciclatide, may be suitable for in vivo molecular imaging of asymptomatic AAA. Additional evaluation of [18F]fluciclatide and αVβ3 integrin expression in AAA will be performed in vitro as well as in vivo.
[18F]fluciclatide; abdominal aortic aneurysm; autoradiography; inflammation; PET; positron emission tomography
The increase of live kidney donation (LKD) demands that we scrutinize its long-term consequences. Socialized medicine in Sweden has allowed us to survey long-term consequences of LKD with a high response rate.
Between 1974 and 2008, 455 LKDs were performed; 28 donors were deceased and 14 had moved abroad at the time of the survey. Of the remaining 413, 96% agreed to participate in a retrospective study with laboratory testing and answering a questionnaire.
Mean age at donation was 49 ± 10 years, and the mean time since nephrectomy was 11 ± 7 years (range 1–33). No death was of renal cause. S-creatinine at follow-up was 93 ± 18 μmol/L, 28% had treated hypertension, of whom only 52% had BP <140/90. Eleven per cent had spot microalbuminuria, and 1% were diagnosed with diabetes mellitus. Seventy-one per cent had check-ups at least every second year, but 14% had no check-ups. Eighty per cent would be willing to donate again if it were possible, and only 3% regretted the donation.
Renal function is well preserved in the long term after donation, no case of end-stage renal disease was identified, and a large majority of our donors would donate again if it were possible. Although rates of microalbuminuria and hypertension were at expected levels, a significant number of donors demonstrated elevated blood pressure levels and inadequate antihypertensive treatment. A relatively large number of donors did not receive regular check-ups. Both of these issues demonstrate the need for a better-structured lifelong follow-up.
Follow-up; kidney; live; live donors; long-term
Atelectasis is common during and after general anaesthesia. We hypothesized that a ventilation strategy, without recruitment manoeuvres, using a combination of continuous positive airway pressure (CPAP) or positive end-expiratory pressure (PEEP) and a reduced end-expiratory oxygen fraction (FETO2) before ending mask ventilation with CPAP after extubation would reduce the area of postoperative atelectasis.
Thirty patients were randomized into three groups. During induction and emergence, inspiratory oxygen fractions (FIO2) were 1.0 in the control group and 1.0 or 0.8 in the intervention groups. No CPAP/PEEP was used in the control group, whereas CPAP/PEEP of 6 cmH2O was used in the intervention groups. After extubation, FIO2 was set to 0.30 in the intervention groups and CPAP was applied, aiming at FETO2 < 0.30. Atelectasis was studied by computed tomography 25 min postoperatively.
The median area of atelectasis was 5.2 cm2 (range 1.6–12.2 cm2) and 8.5 cm2 (3–23.1 cm2) in the groups given FIO2 1.0 with or without CPAP/PEEP, respectively. After correction for body mass index the difference between medians (2.9 cm2) was statistically significant (confidence interval 0.2–7.6 cm2, p = 0.04). In the group given FIO2 0.8, in which seven patients were ex- or current smokers, the median area of atelectasis was 8.2 cm2 (1.8–14.7 cm2).
Compared with conventional ventilation, after correction for obesity, this ventilation strategy reduced the area of postoperative atelectasis in one of the intervention groups but not in the other group, which included a higher proportion of smokers.
Atelectasis; CPAP; general anaesthesia; oxygen fraction; PEEP; ventilation strategy
Commonly used inhalational hypnotics, such as sevoflurane, are pro-inflammatory, whereas the intravenously administered hypnotic agent propofol is anti-inflammatory and anti-oxidative. A few clinical studies have indicated similar effects in patients. We examined the possible association between patient survival after radical cancer surgery and the use of sevoflurane or propofol anaesthesia.
Patients and methods
Demographic, anaesthetic, and surgical data from 2,838 patients registered for surgery for breast, colon, or rectal cancers were included in a database. This was record-linked to regional clinical quality registers. Cumulative 1- and 5-year overall survival rates were assessed using the Kaplan–Meier method, and estimates were compared between patients given propofol (n = 903) or sevoflurane (n = 1,935). In a second step, Cox proportional hazard models were calculated to assess the risk of death adjusted for potential effect modifiers and confounders.
Differences in overall 1- and 5-year survival rates for all three sites combined were 4.7% (p = 0.004) and 5.6% (p < 0.001), respectively, in favour of propofol. The 1-year survival for patients operated for colon cancer was almost 10% higher after propofol anaesthesia. However, after adjustment for several confounders, the observed differences were not statistically significant.
Propofol anaesthesia might be better in surgery for some cancer types, but the retrospective design of this study, with uneven distributions of several confounders, distorted the picture. These uncertainties emphasize the need for a randomized controlled trial.
Anaesthetics; intravenous; inhalational; neoplasm recurrence; local; epidemiology; survival
Accumulating evidence suggests that enhanced inflammatory responses contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Blood transfusion can trigger an enhancement of acute inflammatory responses. Therefore, we hypothesized that perioperative blood transfusion is associated with a higher risk of POCD in aged patients following total hip replacement surgery.
Material and methods
Patients older than 65 years undergoing elective total hip replacement surgery were enrolled from October 2011 to December 2012. Neurocognitive tests were evaluated at baseline and at 7 d after surgery by a Mini-Mental State Test. Multivariate logistic regression analysis was used to determine risk factors associated with POCD.
Fifty-six patients (27.3%) developed POCD 7 d postoperatively. Patients who developed POCD were older, had a lower education level and preoperative hemoglobin concentration, had more blood loss, and had a lower body weight (p < 0.05). Patients with POCD were more likely to receive red blood cells (RBCs) transfusion (51.8% versus 31.5%; p < 0.05). A multivariable logistic regression model identified older age, lower education level, and perioperative blood transfusion of more than 3 units as independent risk factors for POCD 7 d postoperatively.
Our data suggested that perioperative blood transfusion of more than 3 units of RBCs is an independent risk factor for POCD in aged patients following total hip replacement surgery.
Elderly; hip replacement surgery; postoperative cognitive dysfunction; RBCs transfusion
The purpose was to analyse the properties of two models for the assessment of return to work after sickness certification, a manual one based on clinical judgement including non-measurable information (‘gut feeling’), and a computer-based one.
All subjects aged 18 to 63 years, sickness-certified at a primary health care centre in Sweden during 8 months (n = 943), and followed up for 3 years.
Baseline information included age, sex, occupational status, sickness certification diagnosis, full-time or part-time current sick-leave, and sick-leave days during the past year. Follow-up information included first and last day of each occurring sick spell. In the manual model all subjects were classified, based on baseline information and gut feeling, into a high-risk (n = 447) or a low-risk group (n = 496) regarding not returning to work when the present certificate expired. It was evaluated with a Cox’s analysis, including time and return to work as dependent variables and risk group assignment as the independent variable, while in the computer-based model the baseline variables were entered as independent variables.
Concordance between actual return to work and return to work predicted by the analysis model was 73%–76% during the first 28–180 days in the manual model, and approximately 10% units higher in the computer-based model. Based on the latter, three nomograms were constructed providing detailed information on the probability of return to work.
The computer-based model had a higher precision and gave more detailed information than the manual model.
Gut feeling; long-term sick-leave; nomogram; return to work; risk assessment; sickness certification
Multidisciplinary rehabilitation programmes can improve physical functioning and help patients with long-term pain back to work. Little is known, however, of the extent to which such rehabilitation also affects life satisfaction, pain severity, and disability. We wanted to evaluate if a 5-week rehabilitation programme for patients with long-term pain improves life satisfaction and decreases pain severity and disability.
The subjects were 164 patients aged 18–65 years from a pain rehabilitation clinic. Most of them were referred from primary care units. One group of repeated tests was used. Participants were asked to fill out the LiSat-11 checklist and parts of the Multidimensional Pain Inventory (MPI), including pain severity, at admission, at discharge, and 1 year after the rehabilitation programme.
Satisfaction with life as a whole, and six of ten LiSat-11 domains improved during the follow-up, though none reached the levels for the general population. MPI subscales pain severity,
life control, and affective distress improved, whereas no change was observed for general activity. Patients older than 38 years decreased more in MPI affective distress than younger patients. Gender, pain severity, and work status before the programme did not significantly influence the outcome.
The results indicate that multidisciplinary rehabilitation improves life satisfaction, reduces pain severity, and reduces negative psychological, social, and behavioural effects of pain. These outcome variables relate to domains known to be of interest for patients and should therefore be considered for evaluation of rehabilitation programmes for long-term pain.
Chronic disease; chronic pain; combined modality treatment; disability evaluation; quality of life; questionnaires; rehabilitation
We present the case of a 27-year-old female with subcortical osteonecrosis of the humeral capitulum. Percutaneous retrograde drilling of the lesion and application of recombinant human bone morphogenetic protein (BMP)-7 were combined with autologous bone grafting. At follow-up the patient was almost pain-free, had normalized her range of motion, and radiography showed consolidation of the lesion without any heterotopic bone formation. By timing surgery prior to subchondral collapse, biomechanical stability of the subchondral bone was maintained. To our knowledge, this is the first report on the treatment of an osteonecrosis in this location with a BMP, and this strategy could potentially be applied in other locations with juxta-articular osteonecrosis.
Bone graft; bone morphogenetic protein; elbow; osteochondritis dissecans; osteonecrosis
Human use of antibiotics has driven the selective enrichment of pathogenic bacteria resistant to clinically used drugs. Traditionally, the selection of resistance has been considered to occur mainly at high, therapeutic levels of antibiotics, but we are now beginning to understand better the importance of selection of resistance at low levels of antibiotics. The concentration of an antibiotic varies in different body compartments during treatment, and low concentrations of antibiotics are found in sewage water, soils, and many water environments due to natural production and contamination from human activities. Selection of resistance at non-lethal antibiotic concentrations (below the wild-type minimum inhibitory concentration) occurs due to differences in growth rate at the particular antibiotic concentration between cells with different tolerance levels to the antibiotic. The minimum selective concentration for a particular antibiotic is reached when its reducing effect on growth of the susceptible strain balances the reducing effect (fitness cost) of the resistance determinant in the resistant strain. Recent studies have shown that resistant bacteria can be selected at concentrations several hundred-fold below the lethal concentrations for susceptible cells. Resistant mutants selected at low antibiotic concentrations are generally more fit than those selected at high concentrations but can still be highly resistant. The characteristics of selection at low antibiotic concentrations, the potential clinical problems of this mode of selection, and potential solutions will be discussed.
Antibiotic resistance; environmental contamination; fitness cost; selection; sub-MIC