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Pharmaceutical companies are under increasing scrutiny because of their strategy for gaining market access and reimbursement authorisation for novel drugs. The tool most often used is that of a randomised controlled trial (RCT) in a highly selected population that has a high chance of responding on the treatment but a low chance of developing side effects. This population differs to a large extent from real-life patients, who have diverging characteristics that can influence effectiveness and safety; these include co-morbidity, age and disease severity. The ultimate consequence is that evidence resulting from RCTs is not immediately transferable to clinical practice. This paper illustrates examples of drugs developed for rheumatoid arthritis and hepatitis C. We discuss research designs that can complement findings from RCTs, such as pragmatic trials, enriched trials, adaptive pathways, early access programs and patient registries. The aim is to stimulate debate among different stakeholders so that they answer the right question at the right time using a suitable research methodology.

If left untreated, hepatitis C infection can lead to hepatitis, liver fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, the standard-of-care was peginterferon with ribavirin. Sofosbuvir is a novel direct antiviral acting agent that targets hepatitis C. Administration of sofosbuvir leads to high cure rates, but is very expensive. Here we question the concept of the value-based pricing of sofosbuvir, and argue that the spiralling price of new drugs leads to an unsustainable healthcare system.

The frequency of certain medical procedures and their results vary strongly between countries, and also between regions within one country. These variations in clinical practice mean the quality of healthcare is suboptimal, result in unnecessary expense and patients are at risk of complications caused by unnecessary interventions. Patient Reported Outcome Measures (PROMs) are an instrument to clarify if a patient has benefited from a certain treatment. Systematic measurement of PROMs is necessary to show relevant differences in the effect of a therapy. If data of differences in results are combined with those of regional variations in clinical practice, it will become clear where too much or too less is treated. We expect that the systematic measurement of PROMs will make a valuable contribution to improving the quality of Dutch healthcare.

Small fibre neuropathy is a neuropathy of the small non-myelinated C-fibres and myelinated Aδ-fibres. Clinically, an isolated small fibre neuropathy is distinguished by sensory and autonomic symptoms, with practically no abnormalities on neurological examination other than possible distorted pain and temperature sensation. Specific diagnostic tests for small fibre neuropathy are skin biopsy, including a count of the intra-epidermal small nerve fibres that cross the basal membrane, and quantitative sensory and autonomic testing. Diabetes mellitus is the most frequent underlying cause of small fibre neuropathy. Other causes can be classified into the following categories: toxic (e.g. alcohol), metabolic, immune-mediated, infectious and hereditary. Recently, in a substantial proportion (29%) of a group of patients with idiopathic small fibre neuropathy, a SCN9A gene mutation was demonstrated, which leads to hyperexcitability of the dorsal root ganglion neurons. Treatment of small fibre neuropathy consists of symptomatic pain relief and, if possible, treatment of the underlying cause of the condition.

Objective: To investigate the role of art and culture in the recreational activities of doctors, accountants and lawyers., Design: Descriptive questionnaire study., Method: In this study, doctors, accountants and lawyers were asked to respond to an online questionnaire. They were presented with 13 questions or statements concerning their recreational activities and their active or passive involvement with art and culture. To gain an impression in which respect doctors, accountants and lawyers could be distinguished from each other, predictive models based on logistic regression with possible results 'doctor', 'accountant' or 'lawyer' were generated. On the basis of these models, a miniquiz was created, which could distinguish the typical doctor, accountant or lawyer after answering of dichotomous questions., Results: Among all respondents, museum and cinema visits were popular, sports or gardening were favourite activities, and apart from newspapers, the Internet was frequently consulted for news. It was remarkable that doctors and lawyers resembled each other in most of the areas investigated, whereas the accountants differed significantly. Doctors and lawyers particularly visited museums and dance, opera or theatre performances, and two-thirds themselves played music. The majority of these 2 groups also had an above average interest in art and culture, this being a significant part of the recreational activity. Therefore, we were able to differentiate between a doctor or lawyer and an accountant, but the difference between doctors and lawyers was less clear., Conclusion: Doctors and lawyers seemed to have comparable interests in art and culture, but accountants differed in important respects.

Objective: To assess genetic, clinical and morphological characteristics of hereditary pancreatitis, a rare type of chronic pancreatitis with an early onset of symptoms, which is, among others, caused by mutations in the PRSS1 gene., Design: Observational cohort study., Method: The study population consisted of 496 patients (27,375 person-years) who were referred to Radboud University Nijmegen Medical Centre for molecular diagnosis of hereditary pancreatitis during period 2000 to 2007. 61 patients with a positive family history of hereditary pancreatitis were selected. Analysis for PRSS1 gene mutations was performed by complete sequence analysis of the exons. All patients received a structured questionnaire., Results: From 25 families 61 patients were included (2,047 person-years). PRSS1 mutations were detected in 52 patients (85.2%): p.R122H (67.2%), p.N29I (14.8%), p.E79K (1.6%), p.N29T (1.6%). In the 40 patients whose clinical data were known the median age at diagnosis was 10.5 years (range: 0-42 years). Pain was reported in 28 (70% of 40 patients in whom all information was complete). 27 patients (67.5%) were admitted to the hospital once or more due to the attacks of pancreatitis. Exocrine and endocrine dysfunction was seen in 6 patients (15%). 24 patients (60%) had undergone a surgical intervention, 10 of whom had undergone a pancreaticojejunostomy. A family history of pancreatic carcinoma was found in 5 patients (12.5%)., Conclusion: The percentage of PRSS1 mutation was high (85.2%) among this Dutch population that was selected on basis of a positive family history of hereditary pancreatitis. Most patients had no chronic pain.

Complications occurred in a 41-year-old woman (case 1) following a first attempt to remove a partial denture by oesophagoscopy. These were: laceration of the oesophagus with subsequent mediastinitis, pneumothorax, and pneumopericardium. With a second oesophagoscopy the denture was removed from the oesophagus using a flexible endoscope with a latex hood. Following antibiotic treatment the patient recovered. With a 45-year-old man (case 2) who had also swallowed a denture, the denture initially could not be localized. It was eventually recovered from the gastric antrum using a flexible scope with a latex hood, also in the second attempt. Psychiatric and mentally handicapped patients run a high risk of denture ingestion. Ingested dental prostheses are often radiolucent, and are difficult to visualize using conventional radiological methods. Extraction of the ingested foreign objects can lead to severe complications. This is why in this type of case, we recommend having an expert remove from a foreign object with the use of a flexible scope fitted with a latex hood. It is advisable to make removable dental prostheses radiopaque or to avoid using them with the identified risk-group.

The main options for secondary prevention of gastrooesophageal variceal bleeding are endoscopic therapy and treatment with propranolol. Creation ofa transjugular intrahepatic portosystemic shunt (TIPS) is currently considered a valuable secondary 'rescue' treatment when other therapies fail. Recent data suggest that the use of covered stents markedly increases the efficacy of TIPS, compared with conventional uncovered stents. Therefore, a multicentre randomised trial was designed to compare the effects of TIPS using covered stents with those of endoscopic therapy plus propranolol in patients with a first or second episode ofgastro-oesophageal variceal bleeding. TIPS will be performed in 4 university centres with relevant expertise. The trial will hopefully gain nationwide support, and all centres in The Netherlands are cordially invited to participate.

Complications occurred in a 41-year-old woman following an attempt to remove a partial denture by oesophagoscopy. These were: laceration of the oesophagus with subsequent mediastinitis, pneumothorax, and pneumopericardium. At a second oesophagoscopy the denture was removed from the oesophagus using a flexible hood. Following antibiotic treatment the patient recovered. In a 45-year-old man who had also swallowed a denture, the denture could not initially be localized. It was eventually recovered from the antrum using a flexible scope with a flexible hood. The patient was discharged from hospital in a good condition. Psychiatric and mentally handicapped patients run a high risk of denture ingestion. Ingested dental prostheses are often radiolucent, and are difficult to visualize using radiological methods. Extraction of the ingested foreign objects can lead to severe complications. This is why in this type of case, we recommend the use of a flexible scope and a flexible hood attachment.

Two female patients, 86 and 80 years of age, had been treated with blood transfusions for several years and several months, respectively, due to iron-deficiency anaemia caused by gastrointestinal blood loss. Angiodysplasias were detected and subsequently coagulated in the course of repeated gastroscopies and colonoscopies. Due to the failure of this treatment, treatment with thalidomide was started. Thereafter, the gastrointestinal bleeding stopped and there was no longer any need for blood transfusions. Treatment with thalidomide seems an effective therapy for patients with frequently recurring gastrointestinal blood loss due to angiodysplasias who no longer tolerate conventional and invasive procedures due to their physical condition.

Primary erythermalgia is a rare autosomal dominant inherited disorder characterized by recurrent attacks of red, warm and painful burning extremities. The gene involved in primary erythermalgia, SCN9A, encodes for a voltage dependent sodium channel alpha subunit (NaV1.7). NaV1.7 is located in dorsal root ganglions and in nociceptive peripheral neurons. It has been hypothesized that mutations lead to a gain of function and hyperexcitability of peripheral sensory neurons contributing to symptoms in primary erythermalgia.

Liver abscesses were found in two women aged 23 and 34 years who suffered from Crohn's disease. The first patient was seen because of fever and thoracic pain and had been treated with infliximab. The second patient, who was pregnant, presented with abdominal pain that was thought to be due to an exacerbation of her inflammatory bowel disease. Ultrasonography and CT revealed that both patients had large liver abscesses. Both received antibiotic treatment, the first patient underwent drainage of the abscess, and the second underwent puncture twice, resulting in clinical improvements in both patients. In contrast to intra-abdominal abscesses, liver abscesses are rarely seen in patients with Crohn's disease. The clinical presentation can be mistaken for an exacerbation of Crohn's disease, but the diagnosis can be made easily using ultrasonography or CT. Treatment consists of (ultrasound-guided) percutaneous drainage and administration of antibiotics.

Polycystic liver disease (PCLD, MIM 174050) is a dominantly inherited condition characterised by the presence in the liver of multiple cysts of biliary epithelial origin. It must be distinguished from autosomal dominant polycystic kidney disease type 1 (ADPKD-1, MIM 173900) and type 2 (ADPKD-2). Both disorders may be complicated by polycystic liver disease, but renal involvement is absent in PCLD. PCLD is often asymptomatic, but if symptoms arise, they are usually due to the mass effect of cysts. The phenotype is more severe in females and correlates with the number of pregnancies or estrogen use. The gene for PCLD has been assigned to chromosome 19p13.2-13.1. Two separate large-scale positional cloning efforts have managed to identify PRKCSH as the gene underlying PCLD. Up to now, all mutations found in PRKCSH introduce stopcodons in the m-RNA, resulting in premature termination of translation to protein. This suggests a loss of function of the encoding protein. The protein, designated by us as hepatocystin, is predicted to be localised in the endoplasmic reticulum. Multiple biological roles have been suggested for hepatocystin, such as a substrate for phosphorylation by protein kinase C, binding to advanced glycation endproducts, and a function as the non-catalytic beta-subunit of glucosidase-II. The role of hepatocystin in PCLD, however, remains to be elucidated.

A 21-year-old man was admitted because of upper abdominal pain and cholestasis. Endoscopic retrograde cholangiopancreatography was suggestive of primary sclerosing cholangitis. During follow-up the patient developed symptoms which were not compatible with primary sclerosing cholangitis, i.e. icterus and weight loss. Finally the patient died, almost three years after presentation, because of a metastatic adenocarcinoma which had arisen from biliary papillomatosis. Biliary papillomatosis is characterised by papillary adenomatous proliferation of the bile duct epithelium. It has a high chance of malignant degeneration. The only curative option would have been transplantation of the liver and biliary system, but this ought to have happened at an early stage before malignant degeneration had occurred.

Gilbert's syndrome consists of a mild unconjugated hyperbilirubinemia occurring in the absence of liver disease or haemolysis. Total plasma bilirubin can be as high as 80 mumol/l and mild intermittent jaundice does occur. The inheritance pattern is probably autosomal recessive. It has been estimated that some 10-15% of the Western population suffers from Gilbert's syndrome. Bilirubin-uridinediphosphate-glucuronosyltransferase (UGT1A1) is the only enzyme involved in the conjugation of bilirubin. In patients with Gilbert's syndrome, hepatic glucuronidation by UGT1A1 is reduced to about 30% of normal. In Western populations a variant TATAA element in the upstream promotor region of the UGT1A1 gene is firmly associated with the disease. Crigler-Najjar types I and II are autosomal recessive disorders associated with near (type II) or complete absence (type I) of UGT1A1 enzyme activity. There is a persistent unconjugated hyperbilirubinemia (range 300-850 mumol/l) with the plasma concentrations being higher in type I than in type II. Genetic mutations in exon 1-5 cause both Crigler-Najjar type I and type II.

A 63-year-old male was referred because of colicky pain due to an intussusception of a Meckel's diverticulum and of the ileum into the cecum.

Familial Hibernian fever (FHF) is a rare hereditary syndrome that causes periodic attacks of fever and inflammation. It is an autosomal dominantly inherited disorder. The gene involved in FHF encodes for a receptor for tumour necrosis factor (TNFR1). These mutations are thought to result in impaired shedding of the receptor from the cell membrane, leading to deficient curtailing of the inflammatory reaction. The acronym TRAPS (TNF-receptor associated periodic syndrome) has been proposed as a more accurate name.

Hereditary pancreatitis is an autosomal dominant form of chronic pancreatitis. It presents with recurrent attacks of acute pancreatitis, usually starting in early childhood. The attacks may vary from mild abdominal pain to pancreatic necrosis, splenic vein thrombosis, pseudocysts and death. Ultimately chronic pancreatitis ensues with unrelenting pain, calcifications, endocrine and exocrine dysfunction. The penetrance is estimated at 80%. With the use of genetic linkage analysis the gene for hereditary pancreatitis was placed on the long arm of chromosome 7 (7q35). Mutational analysis identified cationic trypsinogen as the disease gene. Cationic trypsinogen mutations are thought to result in resistance of this molecule to autolysis.

Three patients, men aged 67, 68 en 61, had for many years suffered from recurrent iron deficient anaemia and were found to have an aortic stenosis. Coloscopy identified angiodysplastic lesions, and we suspected additional lesions in the small intestine. Despite surgical and endoscopic treatment, gastrointestinal bleeding recurred. Replacement of the stenosed aortic valve with a bioprosthesis led to a recovery in the haemoglobin levels of all three patients. Angiodysplasias are a common source of gastrointestinal bleeding with an invisible origin. Data from the literature suggest an association between aortic stenosis and angiodysplasia although epidemiological evidence is lacking.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a rare autosomal recessive disorder. Patients suffer from recurrent attacks (3-6 days) with fever, abdominal distress, lymphadenopathy, skin lesions and arthralgias. Patients display a constantly elevated serum IgD which serves as a biological marker of the disease. Recently, the gene for HIDS was discovered by two independent groups using positional and functional cloning methods. One group used linkage analysis (positional cloning) and was able to locate the gene for HIDS on the long arm of chromosome 12 (12q24). Mevalonate kinase was an interesting candidate gene because patients with a near complete absence of this enzyme (mevalonic aciduria) do exhibit attacks of fever. Indeed subsequent data showed that there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene. The other group detected slightly elevated urinary excretion of mevalonic acid during attacks in a HIDS patient (functional cloning). The enzyme activity of mevalonate kinase was lower in cultured cells and sequence analysis identified several missense mutations in cDNA encoding for mevalonate kinase. Mevalonate kinase is a key enzyme in the cholesterol synthesis pathway and it is rather surprising that a defect in the cholesterol metabolism can cause a periodic inflammatory disease such as HIDS.

In two male patients, aged 53 and 21 years, lithium intoxication was suspected. The diagnosis was apparently confirmed by blood testing (the lithium concentrations amounted to 3.68 and 1.82 mmol/l, respectively). Retrospectively however it was found that blood sampling tubes with lithium-heparin as the anticoagulant had been used. No lithium intoxication was present in the patients. Clear instructions in writing are necessary to prevent this error.