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Objective. Anakinra is approved for the treatment of RA and cryopyrin-associated periodic syndromes (CAPS). While the anakinra safety profile is well established in RA, the long-term safety profile in severe CAPS is less well documented and will therefore be discussed in this report. Methods. A prospective, open-label, single centre, clinical cohort study was conducted at the National Institutes of Health in the USA, from 2003 to 2010, investigating the efficacy and safety of anakinra treatment for up to 5 years in 43 patients with CAPS. Safety was evaluated using adverse event (AE) reports, laboratory assessments, vital signs and diary reports. Results. In total, 1233 AEs were reported during the study, with a yearly rate of 7.7 AEs per patient. The event rate decreased over time, and dose escalation during the study did not affect AE frequency. Anakinra had similar safety profiles in adults and children. The most frequently reported AEs were typical CAPS disease symptoms such as headache and arthralgia. Injection site reactions occurred mainly during the first month of anakinra treatment. In total, 14 patients experienced 24 serious AEs (SAEs), all of which resolved during the study period. The most common types of SAEs were infections such as pneumonia and gastroenteritis. There were no permanent discontinuations of treatment due to AEs. Conclusion. In this study anakinra treatment of patients with severe CAPS for up to 5 years was safe and well tolerated both in paediatric and adult patients, with most AEs emerging during the first months after treatment initiation. Trial registration: ClincialTrials.gov, clinicaltrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00069329","term_id":"NCT00069329"}}NCT00069329

Purpose: Validation of a non-invasive CT method for detection of acetabular cup migration after total hip arthroplasty in a phantom study. Material and Methods: 26 CT examinations were obtained of a pelvic model while altering the position of the acetabular cup. Using a previously described program for volume merging, the pelvi in different examinations were fused and the 3D alterations of the position of the acetabular cup were evaluated visually and numerically and correlated to direct measurements on the model. Results: Visually, two independent examiners differentiated between 0, 1 and 2 to 3 mm migration with 100% specificity and sensitivity. Numerically, the mean error over all cases between model and CT measurements was 0.04 mm (SD ± 0.33). The mean absolute error between model and CT data was 0.26 mm (SD ± 0.19). Intra- and interobserver 95% accuracy and repeatability limits were below 0.5/0.7 mm, respectively. No significant interobserver difference occurred. The data were normally distributed and not dependent on observer. Conclusion: The accuracy of this non-invasive method out-performs routine plain radiography. The method gives both visual and numerical correlates to migration and can be used in clinical practice.

The regulation of the insulin-like growth factor-II gene (IGF2) is complex and involves the usage of four promoters resulting in different 5' untranslated regions, but with a common translated product. The IGF2 gene product is a mitogenic and survival factor that has been suggested to be important for a normal fetal development and cancer. In this paper we present evidence suggesting that the human IGF2 gene is regulated by GH, and that this regulation occurs in a promoter-specific way. Three lines of evidence support this finding. First, in vivo data from patients treated with GH (one injection or daily injections for 5 consecutive days) showed an increase in the IGF2 P2 promoter derived transcript after acute treatment, and of the P4 promoter transcript after short-term treatment while the P1 promoter derived transcript did not show any significant change. Secondly, isolated human liver cells treated with GH for 2 h displayed an upregulation of the P2 promoter derived transcript. Thirdly, employing transfection experiments in GH-receptor positive CHO cells with P2 and P4 promoter-luciferase constructs, an upregulation by GH was evident, while a P1 promoter construct was unresponsive. We suggest that GH may be a physiological regulator of IGF2 in humans.

GH is important for the hepatic low density lipoprotein (LDL) receptor induction that occurs after estrogen treatment. GH treatment increases liver LDL receptors and lowers plasma LDL cholesterol in man. Estrogen treatment enhances biliary secretion of cholesterol, resulting in supersaturation of bile and an increased risk of gallstone formation. The present study was undertaken to investigate whether GH treatment also influences biliary lipid metabolism in humans. Twelve healthy male volunteers (mean age, 31 +/- 1 yr) were studied before and during the third week of treatment with recombinant human GH (0.1 IU/kg.day). Plasma lipids, bile acid kinetics, and biliary lipid composition were monitored. Plasma total and LDL cholesterol levels were reduced by 10% in response to therapy. However, no significant changes were observed in the biliary lipid composition or cholesterol saturation of gallbladder bile. Furthermore, there were no changes in chenodeoxycholic acid or cholic acid kinetics. The reduction of plasma LDL cholesterol in response to GH treatment in healthy adult men is not associated with detectable changes in biliary lipid metabolism. Thus, in contrast to estrogen, GH therapy of adults probably does not result in an increased risk of cholesterol gallstone development.

The authors correlated the radiologic and histopathologic characteristics of 108 retinoblastomas in 98 patients. Calcifications were demonstrable bu CT scans in 92.6% of the cases, whereas only 82% wer evident upon routine histologic study. Cases of severe invasion of the optic nerve beyond the lamina cribrosa and up to the surgical margin of the nerve were detected by CT scans. Lesser degrees of invasion could not be determined by the same method. Orbital extension was also demonstrable, whereas invasion limited to the sclera was rarely accessible to CT diagnosis. Choroidal invasion was not detectable. Computerized tomography detected enlargement of the ipsilateral lacrimal gland in 17.5% of patients. This phenomenon correlates with invasion of the choroid and the optic nerve.

Background Cryopyrin-Associated Periodic Syndromes (CAPS) include a group of rare inherited autoinflammatory diseases consisting of Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome and the most severe form, Neonatal Onset Multisystem Inflammatory Disease (NOMID). Anakinra is an IL-1-receptor antagonist that has proven effective and safe in the treatment of severe CAPS1 with reported sustainable reduction of chronic inflammation, organ specific inflammation, steroid use and a growth catch-up after long-term use2. The beneficial effect of anakinra on bone mineral density (BMD) has been reported in a small cohort of patients with rheumatoid arthritis3 but BMD data in patients with severe CAPS have not yet been investigated. Objectives To evaluate the changes in BMD in patients with severe CAPS during anakinra treatment up to 60 months. Methods A prospective, open-label, single arm study of anakinra including 43 patients was conducted at the National Institutes of Health1. The study included yearly assessment of BMD using dual energy X-ray absorptiometry (DEXA) scans (g/cm2) with a Hologic Densitometer. The BMD was assessed at the total hip, intertrochanteric, femoral neck and L1-L4 (anterior posterior) and evaluated using age-, gender-, and race-matched Z-scores based on DEXA assessments (normal Z-score: -2 to +2) at baseline and up to 60 months. The changes from baseline were estimated in the intention-to-treat population using a mixed model for repeated measures (MMRM) and the proportions of patients with abnormally low values (

Background Cryopyrin-Associated Periodic Syndromes (CAPS) include a group of rare inherited autoinflammatory diseases consisting of Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome and the most severe form, Neonatal-Onset Multisystem Inflammatory Disease (NOMID). One goal of anakinra therapy is to reduce the concomitant use of steroids. Side effects involving the cardiovascular system and infections are the most frequently reported adverse events (AEs) in steroid-treated patients with rheumatic diseases 1 . An analysis of a previous data cut of this study indicated a substantial decrease in the mean daily prednisone-equivalent dose in 16 patients with severe CAPS treated with anakinra for up to 60 months 2 . Objectives The objective of the present analysis is to further evaluate the steroid-sparing potential and its consequences in an expanded cohort of patients with severe CAPS treated with anakinra. Methods A prospective, open-label, single arm study of anakinra including 43 patients was conducted at the National Institutes of Health 3 . The primary efficacy endpoint, Diary Symptom Sum Score (DSSS), collected daily up to 60 months, included 5 symptoms (fever, rash, joint pain, vomiting, headache), each scored from 0 (no symptoms) to 4 (severe symptoms). Use of steroid medication was obtained from the patient diary. The prednisone dose was to be decreased by 20% at each study visit in which the subject9s disease activity was “moderately” or “significantly” improved. Different types of steroids were converted into prednisone-equivalent doses to enable comparisons. The AEs were analyzed with the infection rate (number of infections per patient years of treatment). Results The proportion of steroid-treated patients in the ITT population decreased from 47.1% at baseline to 33.3% at Month 60. Among the patients using steroids at baseline the mean (SEM) prednisone-equivalent dose was 0.76 (0.31) mg/kg at baseline, but doses were promptly tapered during the first 6 months to 0.15 (0.03) mg/kg. At Month 36 and Month 60 there was a further decline in the prednisone-equivalent dose to 0.08 (0.02) and 0.05 (0.02) mg/kg, respectively. DSSS decreased rapidly both in patients not using steroids and in patients reducing the steroid dose. The decrease was maintained up to Month 60 (p Conclusions The steroid dose among patients using steroids at baseline decreased from 0.76 mg/kg/day to 0.05 mg/kg/day after 60 months of anakinra treatment and the positive anakinra treatment effect was independent of reduced steroid use. The infection rate decreased in patients who reduced or stopped steroid use during the study. Overall, it can be concluded that steroids could be tapered and in some cases stopped without affecting the positive effect of anakinra treatment and that the reduced steroid use coincided with a decreased risk for infections. References Hoes et al. Ann Rheum Dis. 2007;66:1560-67. Sibley et al. Arthritis Rheum. 2012;64:2375-86. Goldbach-Mansky et al. NEJM. 2006;355:581-92. Acknowledgements The authors would like to thank Dr. Goldbach-Mansky and the NIH team. Disclosure of Interest T. Kullenberg Employee of: Sobi, B. Hallen Shareholder of: Sobi, H. Olivecrona Employee of: Sobi, M. Leinonen Consultant for: Sobi

Loss of heterozygosity (LOH) may vary almost randomly within a colorectal tumour due to the heterogeneous morphologic character of these tumours. Despite this, as a rule, single biopsies are the source of genetic material used in studies of markers important for prognosis, clinical behaviour of the disease, or susceptibility of specific tumours to different treatment modalities.To evaluate the importance of intratumoural variation for the results of analysis of LOH and point mutations in colorectal cancer and to determine the frequency of genetic alterations in different types of pre-neoplastic areas of the tumours, 36 consecutively operated patients with colorectal cancer were studied. After fixation, specimens were mounted on large slides containing the whole tumour. The specimens were sub classified into different areas defined as normal tissue, normal tissue closely adjacent the tumour mass, adenoma, dysplasia and invasive cancer cells. These areas were dissected and subjected to DNA extraction.The extracted genomic DNA was studied for LOH at chromosome 5q, 17p, and 18q and for k-ras mutations. Overall, a correlation between the intratumoural degree of neoplastic progression and the frequency of LOH and k-ras mutations was seen. These correlations were significant (p0.008) except for dysplasia/adenomatous tissue versus invasive cancer. Microsatellite instability was found in 9% of the tumours, all except one in invasive parts of the tumours.This study demonstrates a statistical correlation between intratumoural differences in neoplastic degree of dedifferentiation and genetic instability in terms of LOH and point mutations of the k-ras gene in colorectal carcinoma. The importance of a careful dissection in order to localise the region with the highest probability of genetic aberrations and multiple biopsing must not be neglected. The observation that the prevalence of k-ras mutations and LOH are correlated to the degree of dedifferentiation within a colorectal tumour is in line with the concept that selected cell clones are responsible for the neoplastic progression of the tumour.

3D detection of centerpoints of prosthetic cup and head after total hip arthroplasty (THA) using CT.Two CT examinations, 10 min apart, were obtained from each of 10 patients after THA. Two independent examiners placed landmarks in images of the prosthetic cup and head. All landmarking was repeated after 1 week. Centerpoints were calculated and compared.Within volumes, all measurements of centerpoints of cup and head fell, with a 95% confidence, within one CT-voxel of any other measurement of the same object. Across two volumes, the mean error of distance between center of cup and prosthetic head was 1.4 mm (SD 0.73). Intra- and interobserver 95% accuracy limit was below 2 mm within and below 3 mm across volumes. No difference between intra- and interobserver measurements occurred. A formula for converting finite sets of point landmarks in the radiolucent tread of the cup to a centerpoint was stable. The percent difference of the landmark distances from a calculated spherical surface was within one CT-voxel. This data was normally distributed and not dependent on observer or trial.The true 3D position of the centers of cup and prosthetic head can be detected using CT. Spatial relationship between the components can be analyzed visually and numerically.

CAPS is a rare monogenic autoinflammatory syndrome consisting of a spectrum of three conditions: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and the most severe form, NOMID/CINCA. Progressive hearing loss is a characteristic of severe CAPS [1]. Previous analyses showed that long-term anakinra treatment stabilized the progression of hearing loss [2,3]. CAPS patients with different NLRP3 mutations have distinctly different trajectories of hearing loss, suggesting a mutation-specific risk that should be considered when making treatment decisions [4].

We investigated the acute (4-5 h) and short-term (5 days) effects of GH treatment on hepatic messenger RNA (mRNA) levels of the genes for the insulin-like growth factors (IGFs), insulin-like growth factor binding protein-1, -2, and -3 (IGFBPs), and the acid labile subunit (ALS), as well as serum levels of these proteins in humans. At the mRNA level, we observed an increase in IGF-1 transcription (+173%) following GH treatment in the acute group, which remained elevated in the short-term treatment group. IGFBP-2 mRNA decreased after short-term GH treatment, without changes in IGFBP-1 or -3 expression. The ALS transcript level increased after 5 days. In serum, we found increased levels of IGF-I and insulin, and decreased levels of IGF-II, in the short-term treatment group. IGFBP-1 decreased in both treatment groups, whereas IGFBP-2 was reduced after 5 days treatment. ALS increased in the short-term group. We observed increased IGFBP-3 serum levels after 5 days of GH treatment, likely due to increased formation of the ternary complex. Our results show that the metabolic effects by GH on the IGF axis are complex. In addition to a direct stimulation of IGF-I and ALS expression, GH inhibits IGFBP-1 serum levels and IGFBP-2 expression in an indirect manner, possibly facilitating enhanced IGF bioavailability to target tissues.

Background/Purpose: Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare inherited autoinflammatory diseases consisting of a spectrum of three conditions: FCAS, Muckle-Wells Syndrome and the most severe form, NOMID. Anakinra was recently approved in the US for treatment of NOMID and in the European Union for treatment of CAPS. The objective of the present analysis is to assess the response rate to anakinra treatment and time to changes in symptom severity after initiation, withdrawal and re-institution of the treatment in patients with severe CAPS. Methods: A prospective, open-label withdrawal design study of anakinra treatment with long-term extension including 43 patients was conducted at the National Institutes of Health (Goldbach-Mansky et al 2006, Sibley et al 2012). The primary efficacy endpoint, the Diary Symptom Sum Score (DSSS) collected daily up to 60 months included 5 symptoms (fever, rash, joint pain, vomiting, headache); each scored from 0 (no symptoms) to 4 (severe symptoms). Earlier data demonstrated that rash and conjunctivitis disappeared in 3 days in all patients, the DSSS was decreased at 3 months and all patients except one met the criteria of a flare during the 7-day withdrawal phase (Goldbach-Mansky et al 2006). In the present analysis, we defined the response as at least 50% improvement from baseline in the weekly average DSSS. The mean changes in DSSS were estimated with Mixed Model for Repeated Measures (MMRM). Results: Twenty nine out of the 43 enrolled patients provided valid DSSS data for the analysis. A majority of the patients were children (17% 80% of the patients met the response criteria. Eleven consecutive patients participated in the withdrawal phase at 3 months of treatment. After treatment withdrawal the average DSSS increased from 0.6 to 5.2 (p

Anakinra is a recombinant, non-glycosylated form of the human IL-1 receptor antagonist, which recently was approved in US for neonatal onset multisystem inflammatory disease (NOMID), the most severe form of the Cryopyrin-Associated Periodic Syndromes (CAPS). This autoinflammatory disease can be effectively controlled by daily subcutaneous administrations of Kineret[1-3]. The recommended initial dose is 1-2 mg/kg/day and the average maintenance dose is 3-4 mg/kg/day.

Background In severe forms of the rare monogenic autoinflammatory syndrome CAPS (NOMID, also denoted CINCA), persistent systemic and organ specific inflammation includes rash, central nervous system, and eye and cochlear inflammation leading to progressive hearing and vision loss. CAPS is caused by an uncontrolled IL-1β release, demonstrated by the often complete response after treatment with the IL-1 blocker anakinra (Kineret®) in all three entities of CAPS 1,2,3 Objectives To characterize the long-term efficacy and safety of Kineret® in patients with severe CAPS. Methods A prospective, open-label withdrawal design study with long-term extension including 43 patients (7 adult and 36 pediatric) was conducted at the NIH (study 03-AR-0298). Diary disease sum scores (DSSS), inflammatory serum markers, CNS inflammation, hearing, vision, joint status, quality of life, and safety were evaluated for up to 5 years, and the pharmacokinetics and dosing of Kineret® in CAPS patients were evaluated. Results The median follow up time for the 43 patients was 4.9 years (range Conclusions Kineret® treatment for up to 5 years in severe CAPS patients was safe and resulted in the control of disease symptoms, inflammatory markers, CNS inflammation, and stabilized organ function. Careful monitoring with rapid individual dosing adjustments is important to achieve optimal control of organ inflammation. References Hawkins PN et al. N Engl J Med 2003;348:2583–4 Hoffman HM et al. Lancet 2004;364:1779–85. Goldbach-Mansky et al.N Engl J Med 2006;355:581–92. Sibley CH et al. Arthritis Rheum 2012;64:2375–2386. Disclosure of Interest H. Olivecrona Employee of: Swedish Orphan Biovitrum AB, M. Alden Raboisson Employee of: Swedish Orphan Biovitrum AB, K. Soderberg Employee of: Swedish Orphan Biovitrum AB, B. Hallen Employee of: Swedish Orphan Biovitrum AB, M. Leinonen Consultant for: Swedish Orphan Biovitrum AB, C. Sibley: None Declared, N. Plass: None Declared, C. Brewer: None Declared, K. King: None Declared, C. Zalewski: None Declared, J. Kim: None Declared, R. Bishop: None Declared, S. Hill: None Declared, S. Paul: None Declared, D. Stone: None Declared, D. Chapelle: None Declared, J. Butman: None Declared, R. Goldbach-Mansky Grant/research support from: Swedish Orphan Biovitrum AB, Regeneron, and Novartis

Background CAPS is a rare monogenic autoinflammatory syndrome consisting of a spectrum of three conditions: FCAS, Muckle-Wells syndrome (MWS), and the most severe form, NOMID/CINCA. Progressive hearing loss is a characteristic of severe CAPS1. Previous analyses showed that long-term Kineret treatment stabilized the progression of hearing loss2. Objectives To evaluate whether long-term Kineret treatment stabilizes hearing loss among pediatric patients, with focus on the subset of infants/toddlers. Methods A prospective open-label study with long-term extension including 43 patients was conducted at the National Institutes of Health (NIH study 03-AR-0298)1,2. The patients were classified as children (age Results The baseline 4F-PTA correlated with age at treatment start so that older patients presented with more hearing loss. The MMRM analysis of 4F-PTA included 12 children (median follow-up (FU) 60 months) and 9 adolescents/adults (median FU 54 months). The mean (SD) baseline 4F-PTA in the best ear based on air conduction was 27.6 (19.6) dB HL in children and 53.5 (32.2) dB HL in adolescents/adults. No significant changes were seen in mean 4F-PTA at any time point up to 5 years in either children or adolescents/adults; thus, hearing remained stable. The estimated change from baseline to 5 years was -1.0 dB HL (95% CI -8.6 to 6.6) in children and 2.7 dB HL (95% CI -2.1 to 7.5) in adolescents/adults. Comparable findings were seen in the worst ear and for both ears based on bone conduction assessments. In the subset of 5 infants/toddlers (median FU 48 months), the audiogram monitoring was started after 1-3 years of treatment. The hearing in the best ear remained normal (4F-PTA ≤20 dB HL) in all infants/toddlers at all visits except one transient elevation to 21 dB HL. One of the 5 infants/toddlers presented with a moderate conductive hearing loss (4F-PTA 65 dB HL) in the worst ear associated with middle ear effusion. The audiogram results were supported by non-increased proportion of cochlear enhancement. Conclusions Correlation between the audiogram and age at treatment start is consistent with progressive hearing loss observed in untreated NOMID patients. Kineret treatment for up to 5 years stabilized the progression of hearing loss in both pediatric and adolescent/adult patients as well as in infants/toddlers. Efforts should be made for early diagnosis of the disease and early treatment initiation. References Goldbach-Mansky et al. N Engl J Med 2006;355:581–92. Sibley et al. Arthritis Rheum 2012;2375–86 Disclosure of Interest M. Leinonen Consultant for: Swedish Orphan Biovitrum AB, K. Soderberg Employee of: Swedish Orphan Biovitrum AB, H. Olivecrona Employee of: Swedish Orphan Biovitrum AB, M. Alden Raboisson Employee of: Swedish Orphan Biovitrum AB, C. Sibley: None Declared, C. Brewer: None Declared, N. Plass: None Declared, K. King: None Declared, C. Zalewski: None Declared, J. Kim: None Declared, D. Stone: None Declared, D. Chapelle: None Declared, R. Goldbach-Mansky Grant/research support from: Swedish Orphan Biovitrum AB, Regeneron, and Novartis

Background Interleukin-1 (IL-1) is a potent mediator of of inflammation. Kineret is a recombinant, non-glycosylated form of the human IL-1 receptor antagonist (IL-1Ra). The safety profile of Kineret is well documented in Rheumatoid Arthritis (RA) with most frequently reported AEs being injection site reactions (ISRs) and headache. Recently anakinra has been used in patients with various autoinflammatory diseases including CAPS and conditions with clinical or in vitro evidence for for IL-1 involvement 1, 2 . Objectives To characterize long-term safety of Kineret in pediatric and adult patients with severe CAPS (NOMID/CINCA). Methods A prospective, open-label study including 43 patients (7 adult, 36 pediatric) was conducted at the National Institutes of Health (NIH study 03-AR-0298). Safety was evaluated for up to 5 years, using adverse event (AE) reports, laboratory assessments and vital signs. Results Age at recruitment was 0.7 - 46.3 years. Total Kineret exposure was 159.8 patient years (128.0 patient years for doses 1-3.5 mg/kg/day, 31.9 patient years for doses ≥3.5 mg/kg/day). There were no deaths or discontinuations due to AEs. 24 serious adverse events (SAEs) were reported in 14 patients. The most common SAEs were infections; with pneumonia (n=3) and gastroenteritis (n=2) being the most frequent. Overall, the most commonly reported AEs were events that also may be symptoms of CAPS (headache, arthralgia, pyrexia, rash) and upper respiratory tract infections. In total 7.7 AEs were reported/patient year; 86.0% were mild. The AE reporting frequency was highest during the first 6 months. Ten patients reported 17 ISRs, 13 were mild, 4 moderate and none required temporary or permanent discontinuation. The majority of ISRs occurred during the first month. The frequency of ISRs in this study was similar to that seen in placebo-treated patients in RA studies. There were 273 infections reported. Upper respiratory tract infections and nasopharyngitis were most common. Kineret was temporarily stopped during one infection. In 5 patients the Kineret dose was increased due to concomitant disease flares, in all other cases Kineret treatment was continued unchanged. Dose (1-3.5 mg/kg/day vs. ≥3.5 mg/kg/day), gender or presence of NLRP3 mutation did not affect the AE reporting frequency. AE profiles in pediatric and adult patients were similar, with the exception of infections and related symptoms being more frequent in patients Conclusions Kineret is well tolerated when administered for up to 5 years to patients with severe CAPS. There is no indication of increasing frequency of AEs when higher doses of Kineret are used. No new clinically relevant AEs emerged compared to the established safety profile of Kineret. The frequency of treatment induced ISRs in severe CAPS is low. There were no permanent discontinuations of Kineret treatment due to AEs. Continued Kineret treatment during infections were well tolerated and could be considered in severe CAPS to avoid flares. References Dinarello Charles A. et al. Nat Rev Drug Discov 2012, 11: 633-652 Sibley Cailin H. et al. Arthritis Rheum 2012, 64: 2375–2386 Disclosure of Interest T. Kullenberg Employee of: Swedish Orphan Biovitrum AB, M. Lofqvist Employee of: Swedish Orphan Biovitrum AB, H. Olivecrona Employee of: Swedish Orphan Biovitrum AB, N. Plass: None Declared, B. Kost: None Declared, C. Sibley: None Declared, R. Goldbach-Mansky Grant/research support from: Swedish Orphan Biovitrum AB, Regeneron, and Novartis

Growth hormone (GH) has an important role in the regulation of hepatic LDL receptor expression and plasma lipoprotein levels. This investigation was undertaken to evaluate if these effects of GH on hepatic LDL receptors are direct or mediated by insulin-like growth factor I (IGF-I). Two models were studied in which substitution with GH is important for the regulation of hepatic LDL receptors: hypophysectomized rats receiving high-dose ethynylestradiol or challenge with dietary cholesterol. The hypophysectomized rats were hormonally substituted by infusion with dexamethasone and L-thyroxine, and either GH or IGF-I. In both models, GH was essential for maintaining normal expression of LDL receptors. In contrast, despite fully normalized plasma levels, IGF-I did not support the expression of hepatic LDL receptors. Analysis of plasma lipoproteins revealed that substitution with GH, but not with IGF-I, reduced LDL and intermediate density lipoproteins. In addition, determination of hepatic mRNA levels for apo B-100 and apo B-48 indicated that GH may be more effective than IGF-I in the promotion of apo B mRNA editing. In conclusion, GH has specific effects on hepatic LDL receptor expression and plasma lipoprotein levels that are not mediated by IGF-I.

Problem solving and critical thinking are important components of problem based learning (PBL). The driving forces are the students' interest, involvement and sense of responsibility. A curriculum comprising a combination of PBL and conventional instruction was introduced during the surgery course at Huddinge Hospital in the autumn term 1993. The results showed the level of knowledge attained by the students to be comparable with that attained under conventional instruction. The authors of the article conclude that good results can be obtained by introducing PBL in isolated sections of medical education within the framework of an otherwise traditional curriculum.

GH appears to play an important role in mediating the increase in hepatic LDL receptor expression that occurs in response to pharmacological oestrogen treatment. Furthermore, in normal individuals there is evidence of an increased number of hepatic LDL receptors in response to GH, resulting in an accelerated elimination rate of the LDL particle and a subsequent lowering of LDL cholesterol. Further studies on lipoprotein metabolism in patients with GH deficiency, and also in patients with hypercholesterolaemia, would therefore be of interest.

Observation of a case of progressive bilateral parietal thinning within a period of 14 years induced us to study skull films of 3,636 consecutive patients. Parietal thinning was found in 86 patients (2.37%). It was more common in women, with a sex ratio of 1:1.9. The mean age of the females was 72 years, and that of the males 63 years. Previous skull films of 25 of these patients were available and showed progression in 10. It is concluded that parietal thinning is a slowly progressive disease of middle-aged and old patients and is not an anatomical variant or congenital dysplasia of the diploe.

Patients with chronic toxic encephalopathy caused by occupational exposure to organic solvents and diagnosed between 1976 and 1981 have been re-examined during a follow up period of 21-88 months (median 48). Thirty two patients underwent computed brain tomography (CT), were retested psychometrically, and the results were compared with a group of age matched control subjects from the same socioeconomic level. The age of the patients was 33-69 (median 55) and they had been exposed to organic solvents for 7-50 years (median 26). The CT examinations were quantified by linear measurements on the films of the four largest sulci, the minimum width of the cella media and the third ventricle. Bifrontal horn, bicaudate, and third ventricle--Sylvian fissure distances were also measured; and measurements were adjusted for variation in skull diameter. No differences were found between the patients and controls. Most of the measures were correlated with age, to a somewhat higher degree in the patients. The patient-control differences did not increase with increasing age of the subjects. Psychometrically the patients performed worse than the controls despite adjustments for possible differences of intellectual level in the two groups. In the patients correlations were found between some of the CT measures and psychometric test performances suggesting slower psychomotor speed and attention difficulties among subjects with central and cortical brain substance reduction. No such correlation was found in the control group. It is concluded that patients with solvent induced chronic toxic encephalopathy have no severe loss of brain substance.

During a 14-day period, 45 of 78 rabbits were treated intravenously with chlorpromazine (5 mg kg-1 day-1). Metrizamide or iohexol was injected subarachnoidally and the neurotoxic effects of each substance on rabbit behaviour were evaluated for 3 h in both chlorpromazine-treated and non-treated rabbits. Chlorpromazine increased both the excitative and the depressive effects of metrizamide and the depressive effects of iohexol. No signs of excitation were observed in chlorpromazine-treated and non-treated rabbits after subarachnoid injections of iohexol. In spite of a free flow of clear fluid from the needle both before and after the intended subarachnoid injection, radiography disclosed that 26 of 67 suboccipital injections inadvertently resulted in a subdural deposition of the contrast medium. Contrast medium effects following subdural injection significantly differed from those following subarachnoid injection.

Although several reports were published on the effectiveness of computer tomography (CT) in the diagnosis of intracranial tumours (Ambrose 1973, Baker et al. 1974, Gawler et al. 1974, New et al. 1974, 1975, Paxton & Ambrose 1974, Greitz 1975), these early results do not seem to have been compared with those obtained following the technical improvements in the field of computer tomography. These improvements include the use of a higher matrix and the routine intravenous administration of high doses of contrast material. In previously published material, infratentorial tumours seemed to be less accurately demonstrated than supratentorial lesions. A review of the more recent cases of posterior fossa tumours examined at the Department of Neuroradiology was therefore made and the results were related to those earlier obtained (Greitz 1975). An attempt was also made to assess the theoretical limitations of detecting small intracranial tumours.