Endodiabology 2006; Issue 3 (October)
ENDODIABOLOGY
endodiabology.blogspot.com
NORTHEAST NEWSLETTER
FOR SPRs AND BOSSES TRAPPED IN THE NORTHERN DEANERY
OCTOBER 2006
Editors: Shaz Wahid and Petros Perros
Associate Editors: Freda Razvi, Akheel Syed and Ebaa Al-Ozairi
SpR PLACEMENTS (NTN year of training from 1st October 2006)
RVI- Beas Bhatacharya (4), Ravikumar Balasubramanian (3), Sukesh Chandran(3), Subir Ray (3), Ebaa Al-Ozairi (5)
Freeman- Akheel Syed(4), Muthu Jayapaul(4), Khaled Mansur-Dukhan (3)
North Tyneside/Wansbeck- Latika Sibal (5)/Preeti Rao
South Tyneside- Salman Razvi (5)
Gateshead- Reena Thomas (5)
Sunderland-Peter Carey(5), Eelin Lim(4)
North Tees/Hartlepool- Ravi Erukalapati(2)/Sony Anthony(5)
Middlesbrough- Jeevan Metafile (2), Shafer Kamarrudin (1), Recant Made
Carlisle- Kerry Livingstone (1)
Bishop Auckland / Durham- Arun(5)/ Asgar Madathil (3)
NGH/QEH- Ibrahim M Ibrahim (5)
Research with numbers (supervisor)- Andrew Advani (4-Toronto), Chandima Idampitiya (2-Srilanka), Arutchelvan Vijayaraman (3-Prof Home)
MEETINGS / LECTURES / ANNOUNCEMENTS
14th September 2006 GIM training ½ day. Contact Lorraine Waugh 0191 223 1247
11th October 2006 Diabetes Audit Group meeting (follows NRDSAG), Durham, from 2pm. Contact K Narayanan
20th October 2006 Deadline for case submission for Clinical cases meeting Lizy Jones (SFE)
31st October 2006 Northern Endocrine & Diabetes Autumn CME, James Cook University Hospital. Contacts Reena or Arut
31st October 2006 National training Scheme for the use of Thyroid ultrasound by endocrinologists, Croydon, London. See British Thyroid Association
1st November 2006 British Thyroid Association Annual meeting, London, British Thyroid Association
1st-2nd November 2006 ABCD Autumn Meeting, London, ABCD website
3rd November 2006 Closing date for abstract submission to DUK for APC in Glasgow 2007.
6th-7th November 2006 197th Meeting of the Society for Endocrinology Diamond Jubilee Kensington Town Hall, London, Contact SFE website
8th November 2006 RCP Updates in Medicine, Freeman Hospital. Contact Lorraine Waugh 0191 223 1247
15th November 2006 BES 2007 abstract submission deadline.
20th November 2006 UK NETS 4th National Conference (Neuroendocrine Tumour Society), RCPL, London. UK NET Society
29th November 2006 Northern Endocrine Region Research and Audit Group annual meeting, Lumley Castle, Durham 2pm-8pm. Contact Shahid Wahid
1st-2nd December 2006 Caledonian Society for Endocrinology Winter meeting, Peebles Hydro Hotel. Contact Chris Jones or CSE secretary
3-7th December 2006 IDF World Diabetes Congress, Cape Town SA. IDF website
17th January 2007 Northern Endocrine & Diabetes Winter CME, Freeman Hospital. Contacts Reena or Arut
21st February 2007 Clinical cases meeting, Royal Society for Medicine, London SFE website
5th-8th March 2007 BES 2007, ICC, Birmingham. SFE website
14th-16th March 2007 DUK APC 2007, ICC, Glasgow. Diabetes UK website
TRAINING ISSUES
Training E-mails From 1st June 2006 any e-mails related to training matters will be sent to endodiabology email . This will provide an archive for future reference on endodiabology website. It is essential that trainees forward an up to date e-mail to Shaz Wahid for notification purposes.
Registering with JCHMT/PMETB It is essential that all new SpRs (even LATs) register with the PMETB (used to be JCHMT). Not doing so means your training is not counted and you cannot have a RITA.
Log Book/Portfolio Documentation It is a trainee’s responsibility to make sure their portfolio/log book is prospectively completed and the necessary signatures obtained. Any experience that is not signed off by your educational supervisor at the time cannot be counted towards training.
Assessment tools Please see the JCHMT website. As of October 2005 Multisource feedback (MSF) and Directly Observed Procedural Skills (DOPS) have been formally introduced and Mini Clinical Evaluation Exercise (Mini-CEX) will go live from October 2006. It is the trainee’s responsibility to give all the appropriate forms to their Educational or Clinical Supervisor. It is the trainee’s responsibility to make sure that the appropriate assessment summaries are available in their portfolio for RITA purposes, e.g. MSF Summary Form.
Mini-CEX documentation Mini-CEXs are compulsory from 1st October 2006. When undertaking a Mini-CEX retain 1 copy for yourself, give 1 copy to your Mini-CEX supervisor and have 1 copy available for the RITA panel. The Programme Director will retain this copy for the PIMD. Make sure that a Mini-CEX RITA summary is also completed for your RITA in May 2007.
MSF documentation It is essential that the SpR does not see any original MSF forms from individuals as it is an anonymous exercise. Make sure that the official MSF RITA summary form is completed and 1 copy made available for the RITA panel. This will be retained by the Programme Director for the PIMD.
MMC As of Jan 2007 all applications for Higher Specialist Training will be co-ordinated nationally via electronic applications. Our specialty will be given a list of applicants by March 2007. There will be a structured interview for vacancies on the rotation from August 2007 during March-April with a second round in May-June. The STC are finalising dates and the structure of the interview. This will probably take the format of OSCE stations. Any Consultants interested in partaking in the interviews please let Shaz Wahid know ASAP. The muddy water is slowly becoming clearer!
Training Committee Committee Chair – Jola Weaver; Regional Speciality Advisor – Richard Quinton; Programme Director – Shaz Wahid; Consultant members – Jean Macleod, Simon Pearce (Research Advisor), Simon Eaton and Ronan Canavan; SpR representatives – Arutchelvam Vijayaraman and Andrew Advani.
NEW FACES ON THE SCENE
Welcome to Shafi Kamarrudin, Kerry Livingstone, Recant Made and Preeti Rao. They have joined the rotation as new SpRs.
Welcome to Dr Paul Peter as the new Consultant Physician at CDDAH Trust based at Bishop Auckland
OLD FACES ON THE GO
Isha Malik has transferred her NTN to the London Deanery where her husband works as an SpR
Some of you may remember Karen Adamson as a former SpR in the region. She has been appointed as Consultant Physician at St. John’s Hospital in Livingstone.
NEWS FROM THE NORTHEAST
Bill Kelly’s Festschrift is planned for Friday 13th October 2006, 1430 at James Cook University Hospital. Contact Rudy Bilous .
Congratulations to Eelin Lim on obtaining the Research Fellow post with Professor Taylor from Jan 2007. She will be undertaking magnetic spectroscopy studies in relation to metabolism.
Andrew Advani has gone to Toronto for 1 year to undertake some more research
Congratulations to Peter Carey on obtaining his MD.
Congratulations to Arun on obtaining his MD.
Congratulations to Simon Ashwell on obtaining the Consultant post at JCUH. He will officially start in December 2006.
Rahul Nayar has been appointed as the new Consultant at Sunderland from February 2007. You may remember him more affectionately as Raz when he was on the rotation as a SpR.
Chandima Idampitiya has gone to Sri Lanka for a 1-year research sabbatical
Well done to Arut on winning the Prize for best presentation at the SPARROWS feed back meeting, furthermore Arut is the new SpR representative on the STC following Simon Ashwell’s Consultanthood
LETTERS
Contributions for this section can include meeting reports, research experiences, book reviews, experiences abroad, and anything else you feel may benefit trainees and trainers around the region. The success of this section really does depend on YOU.
Preparation for educational/clinical supervision-Shaz Wahid
Developing ones pastoral role as an educational or clinical supervisor is essential. The PIMD is now awash with courses and many local Trusts have developed in-house programmes because of Foundation training. It can sometimes be confusing for the “new” Consultant as to what is essential. The Good Practice in Educational Supervision Course ran by the PIMD is very good and it is worth topping this up by attending any in-house course in relation to Foundation Training. It is essential to have an idea of the new work-based assessments (Mini-CEX, CbD, MSFs). All local Trusts have an obligation to provide training in the latter and run local courses. Again well worth going to one and topping up by browsing the relevant web sites. What I have described so far is the bare minimum to get by. To increase ones effectiveness I would highly recommend the PIMD run course “Dealing with Trainees in difficulty”. It is practical and full of sound advice. Most local Trusts are running a similar session, but I would still recommend the PIMD course. If you have plans to sit on interview panels (sit is probably not the correct term, as the OSCE style interview station is planned for most interviews in relation to training grades) the Good Practice in Recruitment & Selection Course is mandatory and there are plans to make training in “ethnic & cultural awareness” mandatory for interview purposes. Most local Trusts run such a course. RITAs will be the norm for all Training Grades from August 2007, hence if you have plans to be on any RITA panel training is mandatory. All local Trusts should run a course. For those of you wishing to develop advanced skills formal training in mentoring is essential. Also attending “practical” courses on “on the job training” is good value, e.g. Action Learning. The one thing I still have not worked out is when to re-do the courses (especially the mandatory ones) ??? every 3-yrs. Comments welcome.
The Scottish Junior Diabetes Forum, 2005 – Peter Carey
Being of Irish decent, and married to a Scot, I don’t need much persuading to try anything celtic, particularly if it’s derived from a single malt. Having heard Stuart Bennett sing the praises of the Caledonian Society for Endocrinology meeting on numerous occasions, I was intrigued when I received an email inviting Northern region SpRs to attend the Scottish Junior Diabetes Forum. This is a Pfizer sponsored meeting which has been running for over 25 years and is held annually at Dunkeld House Hotel, some twenty odd miles north of Perth.
As you might expect of a SpR meeting, it was relaxed and friendly, with the opening item on the agenda “19.00 - The bar on the right”. Dinner followed an informal talk, and the socialising continued after dinner in the small hours. However, this is no “jolly” and the scientific sessions the following morning were of an exceptionally high standard, on subjects as diverse as anti-platelet therapy in type 2 diabetes, glucose tolerance during long-term analogue therapy for acromegaly, automated grading of diabetic retinopathy, recovery of cognitive function after insulin-induced hypoglycaemia in type 1 diabetes, insulin resistance in the vascular endothelium, insulin signalling and, my personal favourite, effect (or lack thereof) of acute inhibition of lipolysis on postprandial hepatic glucose production.
This year’s meeting is to be held on Nov 17- 18th and invites should be sent out soon. I would recommend this meeting to all SpRs but particularly to those of you who have recently been, or are at present conducting research as it allows an excellent opportunity to present your work to a friendly audience. The meeting has traditionally been open to Northern region SpRs, but we have been noticeable by our absence of late, and the organisers are keen to encourage attendance from just south of the border. Further details can be obtained by contacting Fraser Gibb.
BMJ Learning -Shaz Wahid
I would highly recommend joining this service for CME purposes. It has a wide variety of topics from clinical to non-clinical of interest to Trainees and Consultants. Although the specialty side might be a bit thin and outdated, the General medicine is well covered. I recently benefited from undertaking the modules on AF and PE. The radiology modules are excellent. CPD points are available and topics informing appraisal and revalidation are aplenty. It can be done at ones own pace and is not onerous. Well worth a look in.
ADA WASHINGTON 2006 – Sukesh Chandran
I really enjoyed my trip to ADA Washington. Although I could not travel to Washington with my Newcastle colleagues, we had good time together. Most memorable was the “Newcastle Dinner” when all the Newcastle consultants and SpRs who attended the conference got together. Conference schedule was hectic and there were drug company meetings which started at 5.30 in the morning. Out of the various topics that I attended I liked the talks on GLP-1 analogues used for the treatment of Type 2 DM. It sounds very promising and in the US they have been using in clinical practice.GLP-1 is secreted by L cells of the gut. Its actions are:
1. Enhances glucose dependent insulin secretion by Beta cells.
2. Suppresses inappropriately elevated Glucagon secretion. It does not impair normal Glucagon response to Hypoglycaemia.
3. Restores 1st phase insulin response to Carbohydrates.
4. Reduces weight.
5. Reduces Triglycerides, BNP and PAI-1 activity.
6. Reduces BP.
7. Promotes B cell proliferation and B cell mass.
8. Reduces appetite and food intake.
9. Improves regulation of gastric emptying rate.
Exenatide – GLP-1 analogue is given s/c twice a day within 1 hour before food. Starting dose is 5 mcg which can be increased to 10 mcg. It is usually well tolerated. Adverse effects are nausea and vomiting, diarrhoea, headache and dizziness. Hypoglycaemia is noted especially when combined with SU or SU+Metformin. One of the speakers shared the experience of using Exenatide in PCOS. It sounds like GLP-1 analogues will play an important role in managing patients with Type 2 DM. It might still take a couple of years before it is available in the UK. I enjoyed attending ADA and recommend this to all my SpR colleagues.
SPARROWS 2006 – Arutchelvam Vijayaraman
SPARROWS 2006 took six of us to Washington to attend the Annual scientific sessions of the American Diabetes Association. It was wonderful to go with five other friends including Latika, Ana, Peter, Sukesh and Andrew. As there were so many parallel sessions I made a plan listing the sessions to attend which was very helpful (though the world cup football interfered with the planning a lot!)We presented our experiences on return. I share the ideas I gathered from attending some of the sessions.
Metabolic syndrome and its single traits as risk factors for atherosclerotic vascular disease in type 2 diabetes: DIG(Diabetes In Germany) Study, Carsta Koehler et al, Dresden, Germany
This Population based observational study aimed at investigating the association between metabolic syndrome (MS), its single traits, and their combinations with Atherosclerotic Vascular disease (AVD).
MS defined by NCEP-III.
AVD –defined- MI /coronary revascularization/ stroke
The study was performed in238 sites with 4020 patients with type 2 DM.
Average duration 8.4 years
HbA1c –average 7.0%
74.4%of DIG population had MS,91% had Hypertension,55% had high TG,50% had obesity,9% reduced HDL
Highest odds ratio for AVD for a single trait was for hypertension
men 4.2(2.1-8.4)
women 7.7 (1.9-31.4)
All combinations with hypertension had OR more than 5.6(significantly higher in women)
IL-1 Receptor Antagonist (IRAP) Therapy for 13 Weeks Improves Glycemic Control and b-Cell Function in Patients with Type 2 Diabetes. Thomas R. Mandrup-Poulsen
Hyperglycaemia induced apoptosis leading to beta cell mass reduction is mediated by IL-1.This is blocked by the acute phase protein IL-1 RA which has a reduced level in type 2 diabetes. This study aimed at demonstrating that use of ILRA in type 2 diabetes to improve glycaemic control. It was a randomized, placebo controlled, parallel group, double masked study using recombinant ,non glycosylated human IL-1Ra -100 mg/day SC or placebo for 13 weeks. Patients were followed for 39 weeks. The results showed statistically significant improvement in HbA1c.Beta cell function and insulin sensitivity improved significantly in the IL-Ra group but deteriorated in the placebo group.
It was great to watch the presentations as we learnt how a research finding should be presented in a forum like ADA. We get to learn new research ideas .It was a great place to develop professional networking. The liaisons developed there helped me to get good guest speakers for our diabetes & endocrine CME. I highly recommend that the registrars use the opportunity and apply for a SPARROWS position when it is called for in next few months, to attend ADA 2007 in Chicago.
Watch this space for further reports from the ADA2006 in the February 2007 issue.
RECENT PUBLICATIONS FROM THE NORTHEAST
Please send us your recent publication for inclusion in the next newsletter.
Owen CJ, Eden JA, Jennings CE, Wilson V, Cheetham TD, Pearce SH. Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population. J Mol Endocrinol. 2006; 37: 97-104.
Arun CS, Young D, Batey D, Shotton M, Mitchie D, Stannard K, Taylor R Establishing an ongoing quality assurance in retinal screening programme. Diabetic Medicine 23: 629-34, 2006.
Taylor R. Digami too? Diabetologia 49:1134-7; 2006.
Taylor R. Handbook of Retinal Screening in Diabetes. Wiley London 2006 (a book and linked web-site primarily for retinal screeners but containing all the info needed for SpR's and consultants about screening for diabetic retinopathy)
Pitteloud N, Meysing A, Quinton R, Acierno JS, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P-MG, Mohammadi M, Crowley WF, Jr. 2004 Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Molecular & Cellular Endocrinology. 2006, 254-255, 60-69.
Aspray TJ, Nesbit K, Cassidy TP, Farrow E, Hawthorne G. Diabetes in British Nursing and residential homes: a pragmatic screening study. Diabetes Care 2006;29:707-708.
Aspray TJ, Stevenson P, Abdy SE, Rawlings DJ, Holland T, Francis RM. Low bone mineral density measurements in care home residents-a treatable cause of fractures. Age Ageing 2006;35:37-41.
Syed AA, Irving JA, Redfern CP, Hall AG, Unwin NC, White M, Bhopal RS, Weaver JU. Association of glucocorticoid receptor polymorphism A3669G in exon 9beta with reduced central adiposity in women. Obesity (Silver Spring). 2006 May;14(5):759-64.
RECENT PUBLICATIONS IN DIABETES & ENDOCRINOLOGY THAT HIT THE NEWS OR THAT MAY HAVE A SIGNIFICANT IMPACT ON MANAGEMENT
Pituitary Adenoma Predisposition Caused by Germline Mutations in the AIP Gene. Outi Vierimaa, Marianthi Georgitsi, et al . Science 2006; 312: 1228-1230.
Pituitary adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with pituitary adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two AIP mutations account for 16% of all patients diagnosed with pituitary adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of pituitary adenoma; thus, AIP is an example of a low-penetrance tumor susceptibility gene (Submitted by Richard Quinton)
High-dose atorvastatin after stroke or transient ischemic attack. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, RudolphAE, et al A; Stroke Prevention byAggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med. 200;355:549-59.
4731 patients who had had a stroke or TIA within one to six months before study entry, had LDL cholesterol levels of 2.6 to 4.9 mmol/L, and had no known coronary heart disease were randomized to double-blind treatment with 80 mg of atorvastatin per day or placebo. The primary end point was a first nonfatal or fatal stroke. The mean LDL cholesterol level during the trial was 1.9 mmol/L among patients receiving atorvastatin and 3.3 mmol/L among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2%) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2%; adjusted hazard ratio, 0.84; 95%confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5% (hazard ratio, 0.80;0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. In conclusion, in patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke.
Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. Babenko AP, Polak M, et al. N Engl J Med. 2006;355:456-66.
The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. The authors hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin were screened and the electrophysiologic activity of mutant and wild-type K(ATP) channels were assayed. Seven missense mutations in nine patients were identified. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. The authors have shown that dominant mutations in ABCC8 accounted for 12% of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.
Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. Pearson ER, Flechtner I, et al; Neonatal Diabetes International Collaborative Group. N Engl J Med. 2006;355:467-77.
Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. The authors assessed glycaemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90%) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated haemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1% before treatment to 6.4% after 12 weeks of treatment, P<0.001). Improved glycaemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. In conclusion, sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism.
Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. Moll E, Bossuyt PM, et al . BMJ. 2006;332:1485.
This randomized study compared the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in 228 women with newly diagnosed polycystic ovary syndrome in 20 Dutch hospitals. The primary outcome measure was ovulation. Secondary outcome measures were ongoing pregnancy, spontaneous abortion, and clomifene resistance. 111 women were allocated to clomifene citrate plus metformin (metformin group) and 114 women were allocated to clomifene citrate plus placebo (placebo group). The ovulation rate in the metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference - 8%, 95% confidence interval - 20% to 4%). There were no significant differences in either rate of ongoing pregnancy (40% v 46%; - 6%, - 20% to 7%) or rate of spontaneous abortion (12% v 11%; 1%, - 7% to 10%). A significantly larger proportion of women in the metformin group discontinued treatment because of side effects (16% v 5%; 11%, 5% to 16%). In this study metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome.
Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. Graham TE, Yang Q, Bluher M, et al. N Engl J Med. 2006;354:2552-63.
Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. The authors studied whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity, and whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes (an early pathological feature of insulin resistance). Serum RBP4, insulin resistance, and components of the metabolic syndrome were measured in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes. Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased HDL cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated. The authors have shown that RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.
TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. Florez JC, Jablonski KA, et al. Diabetes Prevention Program Research Group. N Engl J Med. 2006;355:241-50.
Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. The authors studied whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo. These variants were genotyped in 3548 participants with Cox regression analysis using genotype, intervention, and their interactions as predictors. The effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year were assessed. Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95% confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372. In conclusion, common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance.
Osteoporosis. Philip Sambrook & Cyrus Cooper. Lancet 2006;367:2010-2018.
This is an excellent review on osteoporoses and must reading for trainees.
Assessing kidney function-measured and estimated glomerular filtration rate. LA Stevens et al. NEJM 2006;354:2473-2483.
Given the move towards routinely using eGFR this is a very timely review of the subject discussing common pitfalls and tips on interpretation and application of eGFR.
Challenges of training doctors in the new English NHS. Linda Hutchison. BMJ 2006;332:1502-1506.
A reasonable article highlighting the effect of market forces on medical education. MMC should have taken this into account when introducing all this change and the mismatch in numbers is not helping.
Paget’s disease of bone. Michael Whyte. NEJM 2006;355:593-600.
An excellent review for both Trainees and Trainers.
Resistant or difficult-to-control hypertension. Marvin Moser & John Setaro. NEJM 2006;355:385-392.
Although full of the “American” approach I picked up some useful tips for my own clinical practice. Well worth a read.
Structure of the insulin receptor ectodomain reveals a folded-over conformation. McKern NM, Lawrence MC, Streltsov VA, et al. Nature 2006;443:218-221.
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14, grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding (Suggested by Simon Pearce)
NHS reorganisation: Who’s kicking who? Nigel Hawkes. BMJ 2006;333:645-648.
A rather witty account and summary of all the recent new policy shifts in the NHS, however the lack of mention of MMC detracts from the overall message. Also, the interpretation that not much has changed and that the “Trusts” still have the power is confusing from a personal perspective. I can tell you that Primary Care have been doing their fair share of “kicking”.
NEXT NEWSLETTER Due out beginning of February 2007 so keep the gossip coming.
endodiabology.blogspot.com
NORTHEAST NEWSLETTER
FOR SPRs AND BOSSES TRAPPED IN THE NORTHERN DEANERY
OCTOBER 2006
Editors: Shaz Wahid and Petros Perros
Associate Editors: Freda Razvi, Akheel Syed and Ebaa Al-Ozairi
SpR PLACEMENTS (NTN year of training from 1st October 2006)
RVI- Beas Bhatacharya (4), Ravikumar Balasubramanian (3), Sukesh Chandran(3), Subir Ray (3), Ebaa Al-Ozairi (5)
Freeman- Akheel Syed(4), Muthu Jayapaul(4), Khaled Mansur-Dukhan (3)
North Tyneside/Wansbeck- Latika Sibal (5)/Preeti Rao
South Tyneside- Salman Razvi (5)
Gateshead- Reena Thomas (5)
Sunderland-Peter Carey(5), Eelin Lim(4)
North Tees/Hartlepool- Ravi Erukalapati(2)/Sony Anthony(5)
Middlesbrough- Jeevan Metafile (2), Shafer Kamarrudin (1), Recant Made
Carlisle- Kerry Livingstone (1)
Bishop Auckland / Durham- Arun(5)/ Asgar Madathil (3)
NGH/QEH- Ibrahim M Ibrahim (5)
Research with numbers (supervisor)- Andrew Advani (4-Toronto), Chandima Idampitiya (2-Srilanka), Arutchelvan Vijayaraman (3-Prof Home)
MEETINGS / LECTURES / ANNOUNCEMENTS
14th September 2006 GIM training ½ day. Contact Lorraine Waugh 0191 223 1247
11th October 2006 Diabetes Audit Group meeting (follows NRDSAG), Durham, from 2pm. Contact K Narayanan
20th October 2006 Deadline for case submission for Clinical cases meeting Lizy Jones (SFE)
31st October 2006 Northern Endocrine & Diabetes Autumn CME, James Cook University Hospital. Contacts Reena or Arut
31st October 2006 National training Scheme for the use of Thyroid ultrasound by endocrinologists, Croydon, London. See British Thyroid Association
1st November 2006 British Thyroid Association Annual meeting, London, British Thyroid Association
1st-2nd November 2006 ABCD Autumn Meeting, London, ABCD website
3rd November 2006 Closing date for abstract submission to DUK for APC in Glasgow 2007.
6th-7th November 2006 197th Meeting of the Society for Endocrinology Diamond Jubilee Kensington Town Hall, London, Contact SFE website
8th November 2006 RCP Updates in Medicine, Freeman Hospital. Contact Lorraine Waugh 0191 223 1247
15th November 2006 BES 2007 abstract submission deadline.
20th November 2006 UK NETS 4th National Conference (Neuroendocrine Tumour Society), RCPL, London. UK NET Society
29th November 2006 Northern Endocrine Region Research and Audit Group annual meeting, Lumley Castle, Durham 2pm-8pm. Contact Shahid Wahid
1st-2nd December 2006 Caledonian Society for Endocrinology Winter meeting, Peebles Hydro Hotel. Contact Chris Jones or CSE secretary
3-7th December 2006 IDF World Diabetes Congress, Cape Town SA. IDF website
17th January 2007 Northern Endocrine & Diabetes Winter CME, Freeman Hospital. Contacts Reena or Arut
21st February 2007 Clinical cases meeting, Royal Society for Medicine, London SFE website
5th-8th March 2007 BES 2007, ICC, Birmingham. SFE website
14th-16th March 2007 DUK APC 2007, ICC, Glasgow. Diabetes UK website
TRAINING ISSUES
Training E-mails From 1st June 2006 any e-mails related to training matters will be sent to endodiabology email . This will provide an archive for future reference on endodiabology website. It is essential that trainees forward an up to date e-mail to Shaz Wahid for notification purposes.
Registering with JCHMT/PMETB It is essential that all new SpRs (even LATs) register with the PMETB (used to be JCHMT). Not doing so means your training is not counted and you cannot have a RITA.
Log Book/Portfolio Documentation It is a trainee’s responsibility to make sure their portfolio/log book is prospectively completed and the necessary signatures obtained. Any experience that is not signed off by your educational supervisor at the time cannot be counted towards training.
Assessment tools Please see the JCHMT website. As of October 2005 Multisource feedback (MSF) and Directly Observed Procedural Skills (DOPS) have been formally introduced and Mini Clinical Evaluation Exercise (Mini-CEX) will go live from October 2006. It is the trainee’s responsibility to give all the appropriate forms to their Educational or Clinical Supervisor. It is the trainee’s responsibility to make sure that the appropriate assessment summaries are available in their portfolio for RITA purposes, e.g. MSF Summary Form.
Mini-CEX documentation Mini-CEXs are compulsory from 1st October 2006. When undertaking a Mini-CEX retain 1 copy for yourself, give 1 copy to your Mini-CEX supervisor and have 1 copy available for the RITA panel. The Programme Director will retain this copy for the PIMD. Make sure that a Mini-CEX RITA summary is also completed for your RITA in May 2007.
MSF documentation It is essential that the SpR does not see any original MSF forms from individuals as it is an anonymous exercise. Make sure that the official MSF RITA summary form is completed and 1 copy made available for the RITA panel. This will be retained by the Programme Director for the PIMD.
MMC As of Jan 2007 all applications for Higher Specialist Training will be co-ordinated nationally via electronic applications. Our specialty will be given a list of applicants by March 2007. There will be a structured interview for vacancies on the rotation from August 2007 during March-April with a second round in May-June. The STC are finalising dates and the structure of the interview. This will probably take the format of OSCE stations. Any Consultants interested in partaking in the interviews please let Shaz Wahid know ASAP. The muddy water is slowly becoming clearer!
Training Committee Committee Chair – Jola Weaver; Regional Speciality Advisor – Richard Quinton; Programme Director – Shaz Wahid; Consultant members – Jean Macleod, Simon Pearce (Research Advisor), Simon Eaton and Ronan Canavan; SpR representatives – Arutchelvam Vijayaraman and Andrew Advani.
NEW FACES ON THE SCENE
Welcome to Shafi Kamarrudin, Kerry Livingstone, Recant Made and Preeti Rao. They have joined the rotation as new SpRs.
Welcome to Dr Paul Peter as the new Consultant Physician at CDDAH Trust based at Bishop Auckland
OLD FACES ON THE GO
Isha Malik has transferred her NTN to the London Deanery where her husband works as an SpR
Some of you may remember Karen Adamson as a former SpR in the region. She has been appointed as Consultant Physician at St. John’s Hospital in Livingstone.
NEWS FROM THE NORTHEAST
Bill Kelly’s Festschrift is planned for Friday 13th October 2006, 1430 at James Cook University Hospital. Contact Rudy Bilous .
Congratulations to Eelin Lim on obtaining the Research Fellow post with Professor Taylor from Jan 2007. She will be undertaking magnetic spectroscopy studies in relation to metabolism.
Andrew Advani has gone to Toronto for 1 year to undertake some more research
Congratulations to Peter Carey on obtaining his MD.
Congratulations to Arun on obtaining his MD.
Congratulations to Simon Ashwell on obtaining the Consultant post at JCUH. He will officially start in December 2006.
Rahul Nayar has been appointed as the new Consultant at Sunderland from February 2007. You may remember him more affectionately as Raz when he was on the rotation as a SpR.
Chandima Idampitiya has gone to Sri Lanka for a 1-year research sabbatical
Well done to Arut on winning the Prize for best presentation at the SPARROWS feed back meeting, furthermore Arut is the new SpR representative on the STC following Simon Ashwell’s Consultanthood
LETTERS
Contributions for this section can include meeting reports, research experiences, book reviews, experiences abroad, and anything else you feel may benefit trainees and trainers around the region. The success of this section really does depend on YOU.
Preparation for educational/clinical supervision-Shaz Wahid
Developing ones pastoral role as an educational or clinical supervisor is essential. The PIMD is now awash with courses and many local Trusts have developed in-house programmes because of Foundation training. It can sometimes be confusing for the “new” Consultant as to what is essential. The Good Practice in Educational Supervision Course ran by the PIMD is very good and it is worth topping this up by attending any in-house course in relation to Foundation Training. It is essential to have an idea of the new work-based assessments (Mini-CEX, CbD, MSFs). All local Trusts have an obligation to provide training in the latter and run local courses. Again well worth going to one and topping up by browsing the relevant web sites. What I have described so far is the bare minimum to get by. To increase ones effectiveness I would highly recommend the PIMD run course “Dealing with Trainees in difficulty”. It is practical and full of sound advice. Most local Trusts are running a similar session, but I would still recommend the PIMD course. If you have plans to sit on interview panels (sit is probably not the correct term, as the OSCE style interview station is planned for most interviews in relation to training grades) the Good Practice in Recruitment & Selection Course is mandatory and there are plans to make training in “ethnic & cultural awareness” mandatory for interview purposes. Most local Trusts run such a course. RITAs will be the norm for all Training Grades from August 2007, hence if you have plans to be on any RITA panel training is mandatory. All local Trusts should run a course. For those of you wishing to develop advanced skills formal training in mentoring is essential. Also attending “practical” courses on “on the job training” is good value, e.g. Action Learning. The one thing I still have not worked out is when to re-do the courses (especially the mandatory ones) ??? every 3-yrs. Comments welcome.
The Scottish Junior Diabetes Forum, 2005 – Peter Carey
Being of Irish decent, and married to a Scot, I don’t need much persuading to try anything celtic, particularly if it’s derived from a single malt. Having heard Stuart Bennett sing the praises of the Caledonian Society for Endocrinology meeting on numerous occasions, I was intrigued when I received an email inviting Northern region SpRs to attend the Scottish Junior Diabetes Forum. This is a Pfizer sponsored meeting which has been running for over 25 years and is held annually at Dunkeld House Hotel, some twenty odd miles north of Perth.
As you might expect of a SpR meeting, it was relaxed and friendly, with the opening item on the agenda “19.00 - The bar on the right”. Dinner followed an informal talk, and the socialising continued after dinner in the small hours. However, this is no “jolly” and the scientific sessions the following morning were of an exceptionally high standard, on subjects as diverse as anti-platelet therapy in type 2 diabetes, glucose tolerance during long-term analogue therapy for acromegaly, automated grading of diabetic retinopathy, recovery of cognitive function after insulin-induced hypoglycaemia in type 1 diabetes, insulin resistance in the vascular endothelium, insulin signalling and, my personal favourite, effect (or lack thereof) of acute inhibition of lipolysis on postprandial hepatic glucose production.
This year’s meeting is to be held on Nov 17- 18th and invites should be sent out soon. I would recommend this meeting to all SpRs but particularly to those of you who have recently been, or are at present conducting research as it allows an excellent opportunity to present your work to a friendly audience. The meeting has traditionally been open to Northern region SpRs, but we have been noticeable by our absence of late, and the organisers are keen to encourage attendance from just south of the border. Further details can be obtained by contacting Fraser Gibb.
BMJ Learning -Shaz Wahid
I would highly recommend joining this service for CME purposes. It has a wide variety of topics from clinical to non-clinical of interest to Trainees and Consultants. Although the specialty side might be a bit thin and outdated, the General medicine is well covered. I recently benefited from undertaking the modules on AF and PE. The radiology modules are excellent. CPD points are available and topics informing appraisal and revalidation are aplenty. It can be done at ones own pace and is not onerous. Well worth a look in.
ADA WASHINGTON 2006 – Sukesh Chandran
I really enjoyed my trip to ADA Washington. Although I could not travel to Washington with my Newcastle colleagues, we had good time together. Most memorable was the “Newcastle Dinner” when all the Newcastle consultants and SpRs who attended the conference got together. Conference schedule was hectic and there were drug company meetings which started at 5.30 in the morning. Out of the various topics that I attended I liked the talks on GLP-1 analogues used for the treatment of Type 2 DM. It sounds very promising and in the US they have been using in clinical practice.GLP-1 is secreted by L cells of the gut. Its actions are:
1. Enhances glucose dependent insulin secretion by Beta cells.
2. Suppresses inappropriately elevated Glucagon secretion. It does not impair normal Glucagon response to Hypoglycaemia.
3. Restores 1st phase insulin response to Carbohydrates.
4. Reduces weight.
5. Reduces Triglycerides, BNP and PAI-1 activity.
6. Reduces BP.
7. Promotes B cell proliferation and B cell mass.
8. Reduces appetite and food intake.
9. Improves regulation of gastric emptying rate.
Exenatide – GLP-1 analogue is given s/c twice a day within 1 hour before food. Starting dose is 5 mcg which can be increased to 10 mcg. It is usually well tolerated. Adverse effects are nausea and vomiting, diarrhoea, headache and dizziness. Hypoglycaemia is noted especially when combined with SU or SU+Metformin. One of the speakers shared the experience of using Exenatide in PCOS. It sounds like GLP-1 analogues will play an important role in managing patients with Type 2 DM. It might still take a couple of years before it is available in the UK. I enjoyed attending ADA and recommend this to all my SpR colleagues.
SPARROWS 2006 – Arutchelvam Vijayaraman
SPARROWS 2006 took six of us to Washington to attend the Annual scientific sessions of the American Diabetes Association. It was wonderful to go with five other friends including Latika, Ana, Peter, Sukesh and Andrew. As there were so many parallel sessions I made a plan listing the sessions to attend which was very helpful (though the world cup football interfered with the planning a lot!)We presented our experiences on return. I share the ideas I gathered from attending some of the sessions.
Metabolic syndrome and its single traits as risk factors for atherosclerotic vascular disease in type 2 diabetes: DIG(Diabetes In Germany) Study, Carsta Koehler et al, Dresden, Germany
This Population based observational study aimed at investigating the association between metabolic syndrome (MS), its single traits, and their combinations with Atherosclerotic Vascular disease (AVD).
MS defined by NCEP-III.
AVD –defined- MI /coronary revascularization/ stroke
The study was performed in238 sites with 4020 patients with type 2 DM.
Average duration 8.4 years
HbA1c –average 7.0%
74.4%of DIG population had MS,91% had Hypertension,55% had high TG,50% had obesity,9% reduced HDL
Highest odds ratio for AVD for a single trait was for hypertension
men 4.2(2.1-8.4)
women 7.7 (1.9-31.4)
All combinations with hypertension had OR more than 5.6(significantly higher in women)
IL-1 Receptor Antagonist (IRAP) Therapy for 13 Weeks Improves Glycemic Control and b-Cell Function in Patients with Type 2 Diabetes. Thomas R. Mandrup-Poulsen
Hyperglycaemia induced apoptosis leading to beta cell mass reduction is mediated by IL-1.This is blocked by the acute phase protein IL-1 RA which has a reduced level in type 2 diabetes. This study aimed at demonstrating that use of ILRA in type 2 diabetes to improve glycaemic control. It was a randomized, placebo controlled, parallel group, double masked study using recombinant ,non glycosylated human IL-1Ra -100 mg/day SC or placebo for 13 weeks. Patients were followed for 39 weeks. The results showed statistically significant improvement in HbA1c.Beta cell function and insulin sensitivity improved significantly in the IL-Ra group but deteriorated in the placebo group.
It was great to watch the presentations as we learnt how a research finding should be presented in a forum like ADA. We get to learn new research ideas .It was a great place to develop professional networking. The liaisons developed there helped me to get good guest speakers for our diabetes & endocrine CME. I highly recommend that the registrars use the opportunity and apply for a SPARROWS position when it is called for in next few months, to attend ADA 2007 in Chicago.
Watch this space for further reports from the ADA2006 in the February 2007 issue.
RECENT PUBLICATIONS FROM THE NORTHEAST
Please send us your recent publication for inclusion in the next newsletter.
Owen CJ, Eden JA, Jennings CE, Wilson V, Cheetham TD, Pearce SH. Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population. J Mol Endocrinol. 2006; 37: 97-104.
Arun CS, Young D, Batey D, Shotton M, Mitchie D, Stannard K, Taylor R Establishing an ongoing quality assurance in retinal screening programme. Diabetic Medicine 23: 629-34, 2006.
Taylor R. Digami too? Diabetologia 49:1134-7; 2006.
Taylor R. Handbook of Retinal Screening in Diabetes. Wiley London 2006 (a book and linked web-site primarily for retinal screeners but containing all the info needed for SpR's and consultants about screening for diabetic retinopathy)
Pitteloud N, Meysing A, Quinton R, Acierno JS, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P-MG, Mohammadi M, Crowley WF, Jr. 2004 Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Molecular & Cellular Endocrinology. 2006, 254-255, 60-69.
Aspray TJ, Nesbit K, Cassidy TP, Farrow E, Hawthorne G. Diabetes in British Nursing and residential homes: a pragmatic screening study. Diabetes Care 2006;29:707-708.
Aspray TJ, Stevenson P, Abdy SE, Rawlings DJ, Holland T, Francis RM. Low bone mineral density measurements in care home residents-a treatable cause of fractures. Age Ageing 2006;35:37-41.
Syed AA, Irving JA, Redfern CP, Hall AG, Unwin NC, White M, Bhopal RS, Weaver JU. Association of glucocorticoid receptor polymorphism A3669G in exon 9beta with reduced central adiposity in women. Obesity (Silver Spring). 2006 May;14(5):759-64.
RECENT PUBLICATIONS IN DIABETES & ENDOCRINOLOGY THAT HIT THE NEWS OR THAT MAY HAVE A SIGNIFICANT IMPACT ON MANAGEMENT
Pituitary Adenoma Predisposition Caused by Germline Mutations in the AIP Gene. Outi Vierimaa, Marianthi Georgitsi, et al . Science 2006; 312: 1228-1230.
Pituitary adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with pituitary adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two AIP mutations account for 16% of all patients diagnosed with pituitary adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of pituitary adenoma; thus, AIP is an example of a low-penetrance tumor susceptibility gene (Submitted by Richard Quinton)
High-dose atorvastatin after stroke or transient ischemic attack. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, RudolphAE, et al A; Stroke Prevention byAggressive Reduction in Cholesterol Levels (SPARCL) Investigators. N Engl J Med. 200;355:549-59.
4731 patients who had had a stroke or TIA within one to six months before study entry, had LDL cholesterol levels of 2.6 to 4.9 mmol/L, and had no known coronary heart disease were randomized to double-blind treatment with 80 mg of atorvastatin per day or placebo. The primary end point was a first nonfatal or fatal stroke. The mean LDL cholesterol level during the trial was 1.9 mmol/L among patients receiving atorvastatin and 3.3 mmol/L among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2%) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2%; adjusted hazard ratio, 0.84; 95%confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5% (hazard ratio, 0.80;0.69 to 0.92; P=0.002). The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. In conclusion, in patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke.
Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. Babenko AP, Polak M, et al. N Engl J Med. 2006;355:456-66.
The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. The authors hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin were screened and the electrophysiologic activity of mutant and wild-type K(ATP) channels were assayed. Seven missense mutations in nine patients were identified. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. The authors have shown that dominant mutations in ABCC8 accounted for 12% of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.
Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. Pearson ER, Flechtner I, et al; Neonatal Diabetes International Collaborative Group. N Engl J Med. 2006;355:467-77.
Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. The authors assessed glycaemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90%) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated haemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1% before treatment to 6.4% after 12 weeks of treatment, P<0.001). Improved glycaemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. In conclusion, sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism.
Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. Moll E, Bossuyt PM, et al . BMJ. 2006;332:1485.
This randomized study compared the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in 228 women with newly diagnosed polycystic ovary syndrome in 20 Dutch hospitals. The primary outcome measure was ovulation. Secondary outcome measures were ongoing pregnancy, spontaneous abortion, and clomifene resistance. 111 women were allocated to clomifene citrate plus metformin (metformin group) and 114 women were allocated to clomifene citrate plus placebo (placebo group). The ovulation rate in the metformin group was 64% compared with 72% in the placebo group, a non-significant difference (risk difference - 8%, 95% confidence interval - 20% to 4%). There were no significant differences in either rate of ongoing pregnancy (40% v 46%; - 6%, - 20% to 7%) or rate of spontaneous abortion (12% v 11%; 1%, - 7% to 10%). A significantly larger proportion of women in the metformin group discontinued treatment because of side effects (16% v 5%; 11%, 5% to 16%). In this study metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome.
Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. Graham TE, Yang Q, Bluher M, et al. N Engl J Med. 2006;354:2552-63.
Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. The authors studied whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity, and whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes (an early pathological feature of insulin resistance). Serum RBP4, insulin resistance, and components of the metabolic syndrome were measured in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes. Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased HDL cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated. The authors have shown that RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.
TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. Florez JC, Jablonski KA, et al. Diabetes Prevention Program Research Group. N Engl J Med. 2006;355:241-50.
Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. The authors studied whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo. These variants were genotyped in 3548 participants with Cox regression analysis using genotype, intervention, and their interactions as predictors. The effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year were assessed. Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95% confidence interval, 1.20 to 2.01; P<0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372. In conclusion, common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance.
Osteoporosis. Philip Sambrook & Cyrus Cooper. Lancet 2006;367:2010-2018.
This is an excellent review on osteoporoses and must reading for trainees.
Assessing kidney function-measured and estimated glomerular filtration rate. LA Stevens et al. NEJM 2006;354:2473-2483.
Given the move towards routinely using eGFR this is a very timely review of the subject discussing common pitfalls and tips on interpretation and application of eGFR.
Challenges of training doctors in the new English NHS. Linda Hutchison. BMJ 2006;332:1502-1506.
A reasonable article highlighting the effect of market forces on medical education. MMC should have taken this into account when introducing all this change and the mismatch in numbers is not helping.
Paget’s disease of bone. Michael Whyte. NEJM 2006;355:593-600.
An excellent review for both Trainees and Trainers.
Resistant or difficult-to-control hypertension. Marvin Moser & John Setaro. NEJM 2006;355:385-392.
Although full of the “American” approach I picked up some useful tips for my own clinical practice. Well worth a read.
Structure of the insulin receptor ectodomain reveals a folded-over conformation. McKern NM, Lawrence MC, Streltsov VA, et al. Nature 2006;443:218-221.
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14, grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding (Suggested by Simon Pearce)
NHS reorganisation: Who’s kicking who? Nigel Hawkes. BMJ 2006;333:645-648.
A rather witty account and summary of all the recent new policy shifts in the NHS, however the lack of mention of MMC detracts from the overall message. Also, the interpretation that not much has changed and that the “Trusts” still have the power is confusing from a personal perspective. I can tell you that Primary Care have been doing their fair share of “kicking”.
NEXT NEWSLETTER Due out beginning of February 2007 so keep the gossip coming.
posted by Arutchelvam at 11:31 PM
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