Reporter nanoparticle that monitors its anticancer efficacy in real time.

The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.

Impact on cognitive functions following gamma knife radiosurgery for cerebral arteriovenous malformations.

BACKGROUND: Radiosurgery is an alternative to surgical resection of arteriovenous malformation (AVM). Very few studies have addressed the concern of radiation injury to the brain and its attendant adverse effects on cognitive function. MATERIALS AND METHODS: This prospective study included all patients who underwent gamma knife radiosurgery (GKRS) at our institute for cerebral AVM between 2006 and December 2008 (n = 34). All patients underwent neuropsychological evaluation before the procedure. Neuropsychological evaluation was repeated in eighteen patients 2 years following GKRS. Clinical outcome, AVM obliteration, and factors influencing outcome were analyzed in these eighteen patients. RESULTS: Before GKRS, more than 50% had significant impairment of neuropsychological functions compared to normal population norms. 66.6% achieved the excellent radiosurgical outcome. At 2 years follow-up, patients showed varied improvement in neuropsychological function in various categories. Pretherapeutic median value for percentage perseverative responses was 26.5 and at follow-up, it reduced to 18.2 (P = 0.039). Set shifting improved in 11 patients (61.1%), remained same in 5 patients (27.7%), and deteriorated in two patients (11.1%). Patients with a higher Spetzler-Martin grade AVM demonstrated a significantly more favorable shift in follow-up test values for set shifting function (P = 0.021). Patients with postradiation imaging changes had lesser tendency to improve in neuropsychological performance at follow-up. CONCLUSIONS: GKRS has no clinically harmful effect on cognitive and neuropsychological functioning in patients with brain AVM. On the contrary, there is an improvement in majority of patients at 2 years following radiosurgery when nidus is obliterated.

Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy.

The centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance "class effect." This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly with L-α-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluated in vitro. Antitumor efficacy was quantified in vivo using 4T1 breast cancer and K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody-drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBP in vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer treatment.

Cholesterol-tethered platinum II-based supramolecular nanoparticle increases antitumor efficacy and reduces nephrotoxicity.

Nanoscale drug delivery vehicles have been harnessed extensively as carriers for cancer chemotherapeutics. However, traditional pharmaceutical approaches for nanoformulation have been a challenge with molecules that exhibit incompatible physicochemical properties, such as platinum-based chemotherapeutics. Here we propose a paradigm based on rational design of active molecules that facilitate supramolecular assembly in the nanoscale dimension. Using cisplatin as a template, we describe the synthesis of a unique platinum (II) tethered to a cholesterol backbone via a unique monocarboxylato and O→Pt coordination environment that facilitates nanoparticle assembly with a fixed ratio of phosphatidylcholine and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino (polyethylene glycol)-2000]. The nanoparticles formed exhibit lower IC(50) values compared with carboplatin or cisplatin in vitro, and are active in cisplatin-resistant conditions. Additionally, the nanoparticles exhibit significantly enhanced in vivo antitumor efficacy in murine 4T1 breast cancer and in K-Ras(LSL/+)/Pten(fl/fl) ovarian cancer models with decreased systemic- and nephro-toxicity. Our results indicate that integrating rational drug design and supramolecular nanochemistry can emerge as a powerful strategy for drug development. Furthermore, given that platinum-based chemotherapeutics form the frontline therapy for a broad range of cancers, the increased efficacy and toxicity profile indicate the constructed nanostructure could translate into a next-generation platinum-based agent in the clinics.

Rapid self-healing hydrogels.

Synthetic materials that are capable of autonomous healing upon damage are being developed at a rapid pace because of their many potential applications. Despite these advancements, achieving self-healing in permanently cross-linked hydrogels has remained elusive because of the presence of water and irreversible cross-links. Here, we demonstrate that permanently cross-linked hydrogels can be engineered to exhibit self-healing in an aqueous environment. We achieve this feature by arming the hydrogel network with flexible-pendant side chains carrying an optimal balance of hydrophilic and hydrophobic moieties that allows the side chains to mediate hydrogen bonds across the hydrogel interfaces with minimal steric hindrance and hydrophobic collapse. The self-healing reported here is rapid, occurring within seconds of the insertion of a crack into the hydrogel or juxtaposition of two separate hydrogel pieces. The healing is reversible and can be switched on and off via changes in pH, allowing external control over the healing process. Moreover, the hydrogels can sustain multiple cycles of healing and separation without compromising their mechanical properties and healing kinetics. Beyond revealing how secondary interactions could be harnessed to introduce new functions to chemically cross-linked polymeric systems, we also demonstrate various potential applications of such easy-to-synthesize, smart, self-healing hydrogels.

Innocuous full-length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons.

Fragments of botulinum neurotoxin (BoNT) have been explored as potential targeting moieties and carriers of biomolecules into neurons, although with lower binding and translocation efficiency compared with intact proteins. This study exploits a detoxified recombinant form of full-length BoNT/B (BoTIM/B) fused with core streptavidin (CS-BoTIM/B) for lentiviral targeting to central and autonomic neurons. CS-BoTIM/B underwent an activity-dependent entry into cultured spinal cord neurons. Coupling CS-BoTIM/B to biotinylated lentivirus-encoding green fluorescent protein (GFP) endowed considerable neuron selectivity to the vector as evident from the preferential expression of the reporter in neurons co-cultured with skeletal muscle cells. CS-BoTIM/B-guided lentiviral transduction with the expression of a SNARE protein, SNAP-25 (S25), rendered non-susceptible to proteolysis by three BoNT serotypes, yielded a sizable decrease in cleaved S25 upon exposure of spinal cord neurons to these toxins. This was accompanied by synaptic transmission being spared from blockade by BoNT/A or BoNT/E, reflecting adequate translation and functional competence of recombinant multi-toxin-resistant S25. The augmented neurotropism conveyed on the lentivirus by CS-BoTIM/B was also demonstrated in vivo through enhanced expression of a reporter in intramural ganglionic neurons in the rat trachea, after injection of the targeted GFP-encoding lentivirus. Thus, a novel and realistic prospect for gene therapy of peripheral neuropathies is offered in this study through lentiviral targeting to neurons by CS-BoTIM/B.

Interhemispheric epidermoids--an uncommon lesion in an uncommon location: a report of 15 cases.

Of the intracranial epidermoids, interhemispheric epidermoids are extremely rare and only about 19 cases have been reported. This is a retrospective study of 15 patients with interhemispheric epidermoids surgically treated over a 13-year period. The age at the time of presentation varied between 17 and 45 years and there were 9 males. The presenting feature was seizures (focal with secondary generalization) in 12 patients, hemiparesis in 5 and features of raised intracranial pressure in 3. On computerized tomography scan the lesions were hypodense in the interhemispheric region. On magnetic resonance imaging, the lesions were located in the interhemispheric region with heterogenous signal intensities. Restricted diffusion was evident on diffusion-weighted images and apparent diffusion co-efficient images. All the lesions were predominantly located in the anterior interhemispheric region, with either basal or parietal extension along the interhemispheric fissure. Eleven patients underwent frontal or fronto-parietal craniotomies, 3 underwent bifrontal craniotomies and 1 patient underwent supra-orbital craniotomy and endoscopic procedure. Total excision could be achieved in 11 patients; near-total, in 3; and partial excision, in 1 patient. Follow-up was available in 10 patients. Three patients had recurrence of lesion at 5½, 8 and 10 years, respectively.

Efficacy of various spray disinfectants on irreversible hydrocolloid impression materials: an in vitro study.

BACKGROUND: Most of the materials (casts, impressions, etc.) that are sent to the dental laboratories show the presence of numerous pathogenic microorganisms. All the spray disinfectants are not equally effective against these microorganisms. AIMS AND OBJECTIVES: The aim was to compare the effectiveness of different spray disinfectants on irreversible hydrocolloid impressions and to find out the most effective dilution, contact time, and effect against each microorganism studied. MATERIALS AND METHODS: The effects of four spray disinfectants, 5.25% sodium hypochlorite, 0.525% sodium hypochlorite, 1:213 (1 part in 213 parts of water) povidone iodine, and 2% glutaraldehyde along with control (distilled water) on irreversible hydrocolloid impressions contaminated with Staphylococcus aureus, Bacillus subtilis and Streptococcus viridans were studied. RESULTS: Sodium hypochlorite, 5.25%, showed 1-min exposure time which was able to effect a 4 log 10 reduction in bacterial counts against S. aureus and S. viridans followed by 0.525% sodium hypochlorite and 2% glutaraldehyde for 10 min. None were able to effect a 4 log10 reduction against B. subtilis. CONCLUSION: Sodium hypochlorite with a concentration of 5.25% was the most effective disinfectant and required the shortest contact time (1 min). Not all ADA-approved concentrations of surface disinfectants work equally well on irreversible hydrocolloid impression materials.

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis.

Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.

Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy.

Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

Is there a need to diagnose Rathke's cleft cyst preoperatively?

BACKGROUND: Rathke's cleft cyst is a rare benign sellar lesion. The exact preoperative diagnosis of this lesion by clinical and radiological features is difficult. Hence it is often misdiagnosed as craniopharyngioma. AIM: To identify the radiological pointers for pre operative diagnosis of Rathke's cleft cyst. MATERIALS AND METHODS: This study presents the details of nine patients who were operated in our institution between 1998 and 2008. Radiological and histopathological variations were studied. RESULTS: The possibility of Rathke's cleft cyst was considered pre operatively in one patient only. On reviewing the images, characteristic imaging findings were observed in a few cases. CONCLUSION: As minimally invasive trans-sphenoidal approach is sufficient for treating these lesions, pre operative diagnosis is important.

Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis.

OBJECTIVE: Dysregulation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a hallmark of human cancer, occurring in a majority of tumors. Activation of this pathway is critical for transformation and also for the angiogenic switch, which is a key step for tumor progression. The objective of this study was to engineer a PI3K inhibitor-loaded biodegradable nanoparticle and to evaluate its efficacy. METHODS AND RESULTS: Here we report that a nanoparticle-enabled targeting of the PI3K pathway results in inhibition of downstream Akt phosphorylation, leading to inhibition of proliferation and induction of apoptosis of B16/F10 melanoma. It, however, failed to exert a similar activity on MDA-MB-231 breast cancer cells, resulting from reduced internalization and processing of nanoparticles in this cell line. Excitingly, the nanoparticle-enabled targeting of the PI3K pathway resulted in inhibition of endothelial cell proliferation and tubulogenesis, two key steps in tumor angiogenesis. Furthermore, it inhibited both B16/F10- and MDA-MB-231-induced angiogenesis in a zebrafish tumor xenotransplant model. CONCLUSION: Our study, for the first time, shows that targeting of the PI3K pathway using nanoparticles can offer an attractive strategy for inhibiting tumor angiogenesis.

Fullerenol-cytotoxic conjugates for cancer chemotherapy.

In the present study, we report the novel application of polyhydroxylated fullerenes (fullerenols) in cancer drug delivery. The facile synthetic procedure for generating multiple hydroxyl groups on the fullerene cage offers scope for high drug loading in addition to conferring hydrophilicity. Doxorubicin, a first line cancer chemotherapeutic, was conjugated to fullerenols through a carbamate linker, achieving ultrahigh loading efficiency. The drug-fullerenol conjugate was found to be relatively stable in phosphate buffer saline but temporally released the active drug when incubated with tumor cell lysate. The fullerenol-doxorubicin conjugate suppressed the proliferation of cancer cell-lines in vitro through a G2-M cell cycle block, resulting in apoptosis. Furthermore, in an in vivo murine tumor model, fullerenol-doxorubicin exhibited comparable antitumor efficacy as free drug without the systemic toxicity of free doxorubicin. Additionally, we demonstrate that the fullerenol platform can be extended to other chemotherapeutic agents, such as the slightly water-soluble cisplatin, and can emerge as a new paradigm in the management of cancer.

Systematic review: frequency and reasons for consultation for gastro-oesophageal reflux disease and dyspepsia.

BACKGROUND: Upper gastrointestinal symptoms impose a substantial illness burden and management costs. Understanding perceptions and reasons for seeking healthcare is a prerequisite for meeting patients' needs effectively. AIM: To review systematically findings on consultation frequencies for gastro-oesophageal reflux disease (GERD) and dyspepsia and patients' reasons for consultation. METHODS: Systematic literature searches. RESULTS: Reported consultation rates ranged from 5.4% to 56% for GERD and from 26% to 70% for dyspepsia. Consultation for GERD was associated with increased symptom severity and frequency, interference with social activities, sleep disturbance, lack of timetabled work, higher levels of comorbidity, depression, anxiety, phobia, somatization and obsessionality. Some consulted because of fears that their symptoms represented serious disease; others avoided consultation because of this. Inconsistent associations were seen with medication use. Patients were less likely to consult if they felt that their doctor would trivialize their symptoms. Few factors were consistently associated with dyspepsia consultation. However, lower socio-economic status and Helicobacter pylori infection were associated with increased consultation. CONCLUSION: Patients' perceptions of their condition, comorbid factors and external reasons such as work and social factors are related to consultation rates for GERD. Awareness of these factors can guide the clinician towards a more effective strategy than one based on drug therapy alone.

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy.

The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.

Symptoms in patients on long-term proton pump inhibitors: prevalence and predictors.

BACKGROUND: Symptom control in primary care patients on long-term proton pump inhibitor (PPI) treatment is poorly understood. AIM: To explore associations between symptom control and demographics, lifestyle, PPI use, diagnosis and Helicobacter pylori status. METHODS: A cross-sectional survey (n = 726) using note reviews, questionnaires and carbon-13 urea breath testing. Determinants of symptom control [Leeds Dyspepsia Questionnaire (LDQ), Carlsson and Dent Reflux Questionnaire (CDRQ), health-related quality-of-life measures (EuroQoL: EQ-5D and EQ-VAS)] were explored using stepwise linear regression. RESULTS: Moderate or severe dyspepsia symptoms occurred in 61% of subjects (LDQ) and reflux symptoms in 59% (CDRQ). Age, gender, smoking and body mass index had little or no influence upon symptom control or PPI use. Average symptom scores and PPI use were lower in patients with non-ulcer dyspepsia and gastro-protection than gastro-oesophageal reflux disease (GERD) and uninvestigated dyspepsia. H. pylori infection was associated with lower reflux symptom scores only in patients with GERD and uninvestigated dyspepsia. EQ-5D was not able to discriminate between diagnostic groups, although the EQ-VAS performed well. CONCLUSIONS: A majority of patients suffered ongoing moderate or severe symptoms. GERD and uninvestigated dyspepsia were associated with poorer long-term symptom control; H. pylori appeared to have a protective effect on reflux symptoms in these patients.

Helicobacter pylori eradication in long-term proton pump inhibitor users is highly cost-effective: economic analysis of the HELPUP trial.

BACKGROUND: Proton pump inhibitor (PPI) use is costly and about two-thirds of prescribing is long-term. Although 20-50% of patients may be infected with Helicobacter pylori, eradication is not normal clinical practice. AIM: To establish if H. pylori eradication in long-term PPI users is cost-effective. METHODS: Long-term PPI-using patients (n = 183) testing positive for H. pylori were randomly assigned to true or placebo eradication therapy. Patients provided 2-year resource data, and 1-year symptom severity scores. A within-trial cost effectiveness analysis was conducted from a British health service perspective. RESULTS: Significant reductions in resource use occurred comparing eradication with placebo. After 2 years, PPI prescriptions (full-dose equivalents) fell by 3.9 (P < 0.0001); clinician (GP) consultations by 2.4 (P = 0.0001); upper gastrointestinal (GI) endoscopies by 14.8% (P = 0.008); clinician GI-related home visits by 19.9% (P = 0.005) and abdominal ultrasound scans fell by 20.3% (P = 0.005). Average net savings/patient were pound93 (95% CI: 33-153) after costs of detection and eradication had been deducted. At 1 year, Leeds Dyspepsia Questionnaire symptoms fell by 3.1 (P = 0.005) and quality-of-life measures improved (EuroQol-5D: 0.089, P = 0.08; visual analogue scale: 5.6, P = 0.002) favouring eradication. CONCLUSION: Helicobacter pylori eradication in infected, long-term PPI users is an economically dominant strategy, significantly reducing overall healthcare costs and symptom severity.

Helicobacter pylori eradication in long-term proton pump inhibitor users in primary care: a randomized controlled trial.

BACKGROUND: Two-thirds of proton pump inhibitor prescribing in the UK is for long-term therapy. AIM: To determine the impact of eradication in long-term proton pump inhibitor users infected with Helicobacter pylori. METHODS: A total of 184 H. pylori-positive patients were randomly assigned to true or placebo eradication therapy. The primary outcome was the change in proton pump inhibitor usage measured by prescriptions; secondary outcomes were changes of proton pump inhibitor doses, dyspepsia symptoms, general practitioner consultations and quality of life measures. RESULTS: In the year following H. pylori eradication proton pump inhibitor prescriptions fell compared with placebo (-1.7, 95% CI: -2.3 to -1.1, P < 0.001); when adjusted to full-dose equivalent prescriptions the reduction was more marked (-2.2, 95% CI: -3.0 to -1.4, P < 0.001). Both general practitioner consultations (-1.0, 95% CI: -1.8 to -0.1, P = 0.026) and symptoms measured on the Leeds Dyspepsia Questionnaire (-3.1, 95% CI: -5.3 to -0.9, P = 0.005) were reduced. Quality of life and self-rating measures also favoured eradication (EQ-5D: 0.09, P = 0.08 and VAS: 5.6, P = 0.002). The Carlsson and Dent Reflux Questionnaire found no difference between groups (-0.3, P = 0.65), possibly balancing decreased overall symptoms with increased prominence of heartburn in the eradication group. CONCLUSIONS: Helicobacter pylori eradication in infected, long-term proton pump inhibitor users in primary care reduced both the overall severity of symptoms and use of health care.

Use of proton pump inhibitors: an exploration of the attitudes, knowledge and perceptions of general practitioners.

BACKGROUND/AIM: Proton pump inhibitor (PPI) prescribing is costly. The volume of PPI prescription is also increasing, despite little evidence that would justify the increase. General practitioners (GPs) are largely responsible for PPI prescribing, yet knowledge of their views concerning PPIs which might explain the apparent anomaly of prescribing costly drugs without justification is lacking. The aim of this study is therefore to investigate how GPs make decisions about PPI prescribing. METHOD: Qualitative study design using focus groups of 34 GPs and 15 training GPs analysed according to grounded theory principles and use of constant comparative analysis. RESULTS: The participants showed agreement about the clinical factors potentially relevant to PPI prescribing such as age of presentation and endoscopy, issues of Helicobacter pylori eradication and issues around malignancy. There was considerable controversy, however, as to how to apply those factors in real clinical consultations. GPs in training and academic GPs tended to be more conservative; service-based GPs more pragmatic. There was agreement about the need to review long-term PPI medication, but controversy about whether the conventional 'step-up step-down' approach was realistic in practice. Good agreement was apparent about the effectiveness, the cost implications, and some of the ethical issues surrounding PPIs, but considerable controversy as to how far such factors should influence prescribing of PPIs. CONCLUSION: The GPs showed good understanding and knowledge of the issues surrounding PPI prescribing. There was considerable controversy as to how such knowledge should be translated into practice.