We describe the methodology for a major study investigating the impact of reconfigured cleft care in the United Kingdom (UK) 15 years after an initial survey, detailed in the Clinical Standards Advisory Group (CSAG) report in 1998, had informed government recommendations on centralization.
Setting and Sample Population
This is a UK multicentre cross-sectional study of 5-year-olds born with non-syndromic unilateral cleft lip and palate. Children born between 1 April 2005 and 31 March 2007 were seen in cleft centre audit clinics.
Materials and Methods
Consent was obtained for the collection of routine clinical measures (speech recordings, hearing, photographs, models, oral health, psychosocial factors) and anthropometric measures (height, weight, head circumference). The methodology for each clinical measure followed those of the earlier survey as closely as possible.
We identified 359 eligible children and recruited 268 (74.7%) to the study. Eleven separate records for each child were collected at the audit clinics. In total, 2666 (90.4%) were collected from a potential 2948 records. The response rates for the self-reported questionnaires, completed at home, were 52.6% for the Health and Lifestyle Questionnaire and 52.2% for the Satisfaction with Service Questionnaire.
Response rates and measures were similar to those achieved in the previous survey. There are practical, administrative and methodological challenges in repeating cross-sectional surveys 15 years apart and producing comparable data.
cleft lip; cleft palate; cross-sectional studies
Women with back pain and vertebral fractures describe different pain experiences than women without vertebral fractures, particularly a shorter duration of back pain, crushing pain and pain that improves on lying down. This suggests a questionnaire could be developed to identify older women who may have osteoporotic vertebral fractures.
Approximately 12 % of postmenopausal women have vertebral fractures (VFs), but less than a third come to clinical attention. Distinguishing back pain likely to relate to VF from other types of back pain may ensure appropriate diagnostic radiographs, leading to treatment initiation. This study investigated whether characteristics of back pain in women with VF are different from those in women with no VFs.
A case control study was undertaken with women aged ≥60 years who had undergone thoracic spinal radiograph in the previous 3 months. Cases were defined as those with VFs identified using the algorithm-based qualitative (ABQ) method. Six hundred eighty-three potential participants were approached. Data were collected by self-completed questionnaire including the McGill Pain Questionnaire. Chi-squared tests assessed univariable associations; logistic regression identified independent predictors of VFs. Receiver operating characteristic (ROC) curves were used to evaluate the ability of the combined independent predictors to differentiate between women with and without VFs via area under the curve (AUC) statistics.
One hundred ninety-seven women participated: 64 cases and 133 controls. Radiographs of controls were more likely to show moderate/severe degenerative change than cases (54.1 vs 29.7 %, P = 0.011). Independent predictors of VF were older age, history of previous fracture, shorter duration of back pain, pain described as crushing, pain improving on lying down and pain not spreading down the legs. AUC for combination of these factors was 0.85 (95 % CI 0.79 to 0.92).
We present the first evidence that back pain experienced by women with osteoporotic VF is different to back pain related solely to degenerative change.
Back pain; Case control study; Osteoporotic vertebral fracture; Self-reported pain descriptors
The Beck Depression Inventory, 2nd edition (BDI-II) is widely used in research on depression. However, the minimal clinically important difference (MCID) is unknown. MCID can be estimated in several ways. Here we take a patient-centred approach, anchoring the change on the BDI-II to the patient's global report of improvement.
We used data collected (n = 1039) from three randomized controlled trials for the management of depression. Improvement on a ‘global rating of change’ question was compared with changes in BDI-II scores using general linear modelling to explore baseline dependency, assessing whether MCID is best measured in absolute terms (i.e. difference) or as percent reduction in scores from baseline (i.e. ratio), and receiver operator characteristics (ROC) to estimate MCID according to the optimal threshold above which individuals report feeling ‘better’.
Improvement in BDI-II scores associated with reporting feeling ‘better’ depended on initial depression severity, and statistical modelling indicated that MCID is best measured on a ratio scale as a percentage reduction of score. We estimated a MCID of a 17.5% reduction in scores from baseline from ROC analyses. The corresponding estimate for individuals with longer duration depression who had not responded to antidepressants was higher at 32%.
MCID on the BDI-II is dependent on baseline severity, is best measured on a ratio scale, and the MCID for treatment-resistant depression is larger than that for more typical depression. This has important implications for clinical trials and practice.
Beck Depression Inventory; 2nd edition (BDI-II); depression; minimal clinically important difference; outcome assessment; primary care
Systematic reviews have highlighted that school-based diet and physical activity (PA) interventions have had limited effects. This study used qualitative methods to examine how the effectiveness of future primary (elementary) school diet and PA interventions could be improved.
Data are from the Active For Life Year 5 (AFLY5) study, which was a cluster randomised trial conducted in 60 UK primary schools. Year 5 (8–9 years of age) pupils in the 30 intervention schools received a 12-month intervention. At the end of the intervention period, interviews were conducted with: 28 Year 5 teachers (including 8 teachers from control schools); 10 Headteachers (6 control); 31 parents (15 control). Focus groups were conducted with 70 year 5 pupils (34 control). Topics included how the AFLY5 intervention could have been improved and how school-based diet and PA interventions should optimally be delivered. All interviews and focus groups were transcribed and thematically analysed across participant groups.
Analysis yielded four themes.
Child engagement: Data suggested that programme success is likely to be enhanced if children feel that they have a sense of autonomy over their own behaviour and if the activities are practical.
School: Finding a project champion within the school would enhance intervention effectiveness. Embedding diet and physical activity content across the curriculum and encouraging teachers to role model good diet and physical activity behaviours were seen as important.
Parents and community: Encouraging parents and community members into the school was deemed likely to enhance the connection between schools, families and communities, and “create a buzz” that was likely to enhance behaviour change.
Government/Policy: Data suggested that there was a need to adequately resource health promotion activity in schools and to increase the infrastructure to facilitate diet and physical activity knowledge and practice.
Discussion and Conclusions
Future primary school diet and PA programmes should find ways to increase child engagement in the programme content, identify programme champions, encourage teachers to work as role models, engage parents and embed diet and PA behaviour change across the curriculum. However, this will require adequate funding and cost-effectiveness will need to be established.
Diet; Physical activity; RCT; Process evaluation; Schools; Children
The dynamical structure of the brain’s electrical signals contains valuable information about its physiology. Here we combine techniques for nonlinear dynamical analysis and manifold identification to reveal complex and recurrent dynamics in interictal epileptiform discharges (IEDs). Our results suggest that recurrent IEDs exhibit some consistent dynamics, which may only last briefly, and so individual IED dynamics may need to be considered in order to understand their genesis. This could potentially serve to constrain the dynamics of the inverse source localization problem.
Electroencephalography (EEG); Manifold Learning; Graph Signal Processing; Nonlinear Dynamics
It is a long debated question whether catalytic activities of enzymes, which lie on the millisecond timescale, are possibly already reflected in variations in atomic thermal fluctuations on the pico- to nanosecond timescale. To shed light on this puzzle, the enzyme human acetylcholinesterase in its wild-type form and complexed with the inhibitor huperzine A were investigated by various neutron scattering techniques and molecular dynamics simulations. Previous results on elastic neutron scattering at various timescales and simulations suggest that dynamical processes are not affected on average by the presence of the ligand within the considered time ranges between 10 ps and 1 ns. In the work presented here, the focus was laid on quasi-elastic (QENS) and inelastic neutron scattering (INS). These techniques give access to different kinds of individual diffusive motions and to the density of states of collective motions at the sub-picoseconds timescale. Hence, they permit going beyond the first approach of looking at mean square displacements. For both samples, the autocorrelation function was well described by a stretched-exponential function indicating a linkage between the timescales of fast and slow functional relaxation dynamics. The findings of the QENS and INS investigation are discussed in relation to the results of our earlier elastic incoherent neutron scattering and molecular dynamics simulations.
molecular dynamics; motional correlation; human acetylcholinesterase; neutron scattering
To measure the experience and perpetration of negative behaviour, including domestic violence and abuse (DVA), and investigate its associations with health conditions and behaviours in men attending general practice.
Cross-sectional questionnaire-based study conducted between September 2010 and June 2011.
16 general practices in the south west of England.
Male patients aged 18 or older, attending alone, who could read and write English. A total of 1403 of eligible patients (58%) participated in the survey and 1368 (56%) completed the questions relevant to this paper. 97% of respondents reported they were heterosexual.
Main outcome measures
Lifetime occurrence of negative behaviour consistent with DVA, perceived health impact of negative behaviours, associations with anxiety and depression symptoms, and cannabis use in the past 12 months and binge drinking.
22.7% (95% CI 20.2% to 24.9%) of men reported ever experiencing negative behaviour (feeling frightened, physically hurt, forced sex, ask permission) from a partner. All negative behaviours were associated with a twofold to threefold increased odds of anxiety and depression symptoms in men experiencing or perpetrating negative behaviours or both. 34.9% (95% CI 28.7% to 41.7%) of men who reported experiencing negative behaviour from a partner, and 30.8% (95% CI 23.7% to 37.8%) of men who perpetrated negative behaviours said they had been in a domestically violent or abusive relationship. No associations with problematic drinking were found; there was a weak association with cannabis use.
DVA is experienced or perpetrated by a large minority of men presenting to general practice, and these men were more likely to have current symptoms of depression and anxiety. Presentation of anxiety or depression to clinicians may be an indicator of male experience or perpetration of DVA victimisation.
PRIMARY CARE; prevalence; domestic violence and abuse; cross sectional survey; male patients
Background: Integrated tuberculosis-human immunodeficiency virus (TB-HIV) service delivery as part of maternal health services, including antenatal care (ANC), is widely recommended. This study assessed the implementation of collaborative TB-HIV service delivery at a hospital-based ANC service unit.
Methods: A record review of a random sample of 308 pregnant women attending the ANC service between April 2011 and February 2012 was conducted. Data were extracted from registers and patient case notes. Outcomes included the proportion of women who underwent HIV counselling and testing (HCT), CD4 count testing, antiretroviral treatment (ART), cotrimoxazole preventive treatment (CPT), TB screening and isoniazid preventive treatment (IPT). Analysis measured variations in patient characteristics associated with service delivery.
Results: All women underwent HCT; 80% of those who tested HIV-positive were screened for TB. Most (85.9%) of the HIV-positive women received a CD4 count. However, only 12.9% of eligible women received ART prophylaxis onsite, only 35.7% were referred for initiation of ART, only 42.3% commenced IPT and none received CPT or further investigations for TB. HIV-negative women had 2.6 higher odds (95%CI 1.3–5.3) of receiving TB screening than their HIV-positive counterparts.
Conclusions: Although the identification of HIV-positive women and TB suspects was adequate, implementation of other TB-HIV collaborative activities was sub-optimal.
HIV counselling and testing; CD4 count testing; antiretroviral treatment; cotrimoxazole preventive treatment; TB screening; isoniazid preventive treatment
Background and aims
We investigated whether objectively measured sedentary time was associated with markers of inflammation in adults with newly diagnosed type 2 diabetes.
Methods and results
We studied 285 adults (184 men, 101 women, mean age 59.0 ± 9.7) who had been recruited to the Early ACTivity in Diabetes (Early ACTID) randomised controlled trial. C-reactive protein (CRP), adiponectin, soluble intracellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), and accelerometer-determined sedentary time and moderate-vigorous physical activity (MVPA) were measured at baseline and after six-months. Linear regression analysis was used to investigate the independent cross-sectional and longitudinal associations of sedentary time with markers of inflammation.
At baseline, associations between sedentary time and IL-6 were observed in men and women, an association that was attenuated following adjustment for waist circumference. After 6 months of follow-up, sedentary time was reduced by 0.4 ± 1.2 h per day in women, with the change in sedentary time predicting CRP at follow-up. Every hour decrease in sedentary time between baseline and six-months was associated with 24% (1, 48) lower CRP. No changes in sedentary time between baseline and 6 months were seen in men.
Higher sedentary time is associated with IL-6 in men and women with type 2 diabetes, and reducing sedentary time is associated with improved levels of CRP in women. Interventions to reduce sedentary time may help to reduce inflammation in women with type 2 diabetes.
•Sedentary time is associated with inflammation in adults with type 2 diabetes.•Reducing sedentary time in women improved C-reactive protein.•Interventions to reduce sedentary time may reduce cardiovascular risk in women.
Sedentary time; Type 2 diabetes; Breaks in sedentary time; Inflammation
A well-characterized potential marker for addiction is impulsive choice, stably measured by delay discounting (DD) paradigms. While genetic influences partly account for inter-individual variance in impulsivity, environmental factors such as parenting practices may have an important role. The present study investigates how inconsistent fulfillment of delayed reward promises impacts on DD. A combined correlational and experimental functional magnetic resonance imaging (fMRI) design was performed in a sample of 48 healthy adolescents (13–15 years). More specifically, neural activation during a DD task was investigated at two assessment points (T0 and T1). Adolescents' self-reports of parenting and substance use were assessed at T0. Between assessment points, we experimentally varied the reliability of delayed reward promises, measuring the impact of this intervention on DD and neural value processing at T1. In the correlational part, same-sex parent reward inconsistency was associated with steeper DD and an attenuated subjective value (SV) representation in the nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC). Steeper DD was in turn associated with alcohol use during the past year. In the experimental part, the reward inconsistency manipulation resulted in an attenuation of the NAcc SV representation, similar to the parental inconsistency effect. Together, our correlational and experimental findings raise new light on how parents may influence their children's degree of impulsivity, making parenting a potential target in addiction prevention.
Rasmussen's encephalitis is a rare syndrome characterized by intractable seizures, often associated with epilepsia partialis continua and symptoms of progressive hemispheric dysfunction. Seizures are usually the hallmark of presentation, but antiepileptic drug treatment fails in most patients and is ineffective against epilepsia partialis continua, which often requires surgical intervention. Co-occurrence of focal cortical dysplasia has only rarely been described and may have implications regarding pathophysiology and management. We describe a rare case of dual pathology of Rasmussen's encephalitis presenting as a focal cortical dysplasia (FCD) and discuss the literature on this topic.
Rasmussen's encephalitis; Focal cortical dysplasia
Dysregulation of Sonic hedgehog (Shh) signaling has been implicated in glioma pathogenesis. Yet, the role of this pathway in gliomagenesis remains controversial because of the lack of relevant animal models. Using the cytokeratin 5 promoter, we ectopically expressed a constitutively active zebrafish Smoothened (Smoa1) in neural progenitor cells and analyzed tumorigenic capacity of activated Shh signaling in both transient and stable transgenic fish. Transient transgenic fish overexpressing Smoa1 developed retinal and brain tumors, suggesting smoa1 is oncogenic in the zebrafish central nervous system (CNS). We further established stable transgenic lines that simultaneously developed optic pathway glioma (OPG) and various retinal tumors. In one of these lines, up to 80% of F1 and F2 fish developed tumors within 1 year of age. Microarray analysis of tumor samples showed upregulated expression of genes involved in the cell cycle, cancer signaling and Shh downstream targets ptc1, gli1 and gli2a. Tumors also exhibited specific gene signatures characteristic of radial glia and progenitor cells as transcriptions of radial glia genes cyp19a1b, s100β, blbp, gfap and the stem/progenitor genes nestin and sox2 were significantly upregulated. Overexpression of GFAP, S100β, BLBP and Sox2 was confirmed by immunofluorescence. We also detected overexpression of Mdm2 throughout the optic pathway in fish with OPG, therefore implicating the Mdm2–Tp53 pathway in glioma pathogenesis. In conclusion, we demonstrate that activated Shh signaling initiates tumorigenesis in the zebrafish CNS and provide the first OPG model not associated with neurofibromatosis 1.
zebrafish; Sonic hedgehog (Shh) pathway; activated Smoothened (Smoa1); optic pathway glioma (OPG)
Over 15 000 new oesophago-gastric cancers are diagnosed annually in the United Kingdom, with most being advanced disease. We identified and quantified features of this cancer in primary care.
Case–control study using electronic primary-care records of the UK patients aged ⩾40 years was performed. Cases with primary oesophago-gastric cancer were matched to controls on age, sex and practice. Putative features of cancer were identified in the year before diagnosis. Odds ratios (ORs) were calculated for these features using conditional logistic regression, and positive predictive values (PPVs) were calculated.
A total of 7471 cases and 32 877 controls were studied. Sixteen features were independently associated with oesophago-gastric cancer (all P<0.001): dysphagia, OR 139 (95% confidence interval 112–173); reflux, 5.7 (4.8–6.8); abdominal pain, 2.6 (2.3–3.0); epigastric pain, 8.8 (7.0–11.0); dyspepsia, 6 (5.1–7.1); nausea and/or vomiting, 4.9 (4.0–6.0); constipation, 1.5 (1.2–1.7); chest pain, 1.6 (1.4–1.9); weight loss, 8.9 (7.1–11.2); thrombocytosis, 2.4 (2.0–2.9); low haemoglobin, 2.4 (2.1–2.7); low MCV, 5.2 (4.2–6.4); high inflammatory markers, 1.7 (1.4–2.0); raised hepatic enzymes, 1.3 (1.2–1.5); high white cell count, 1.4 (1.2–1.7); and high cholesterol, 0.8 (0.7–0.8). The only PPV >5% in patients ⩾55 years was for dysphagia. In patients <55 years, all PPVs were <1%.
Symptoms of oesophago-gastric cancer reported in secondary care were also important in primary care. The results should inform guidance and commissioning policy for upper GI endoscopy.
oesophago-gastric cancer; primary care; symptoms; diagnosis; positive predictive values
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