The relationship between adiposity, bone density and microarchitecture is maintained in young women irrespective of diabetes status.

BACKGROUND: The relationship between bone health and adiposity and how it may be affected in people with chronic metabolic conditions is complex. METHODS: Seventeen women with type 1 diabetes mellitus (T1DM) and nine age-matched healthy women with a median age of 22.6 years (range, 17.4, 23.8) were studied by 3T MRI and MR spectroscopy to assess abdominal adiposity, tibial bone microarchitecture and vertebral bone marrow adiposity (BMA). Additional measures included DXA-based assessments of total body (TB), femoral neck (FN) and lumbar spine (LS) bone mineral density (BMD) and fat mass (FM). RESULTS: Although women with T1DM had similar BMI and BMA to the controls, they had higher visceral and subcutaneous adiposity on MRI (P<.05) and total body FM by DXA (P=.03). Overall, in the whole cohort, a clear inverse association was evident between BMA and BMD at all sites (P<.05). These associations remained significant after adjusting for age, BMI, FM and abdominal adiposity. In addition, visceral adiposity, but not subcutaneous adiposity, showed a positive association with BMA (r, .4, P=.03), and a negative association with total body BMD (r, .5, P=.02). Apparent trabecular separation as assessed by MRI showed an inverse association to total body BMD by DXA (r, -.4, P=.04). CONCLUSION: Irrespective of the presence of an underlying metabolic condition, young women display a negative relationship between MRI-measured BMA and DXA-based assessment of BMD. Furthermore, an association between BMA and visceral adiposity supports the notion of a common origin of these two fat depots.

Fludrocortisone therapy for persistent hyperkalaemia.

BACKGROUND: Type 4 renal tubular acidosis causes hyperkalaemia, for which diabetes and medications commonly used in this patient group are aetiological factors. Here we describe the novel use of fludrocortisone in this difficult condition. CASE REPORT: A 55-year-old woman with complex co-morbidities, including Type 2 diabetes (HbA1c 37 mmol/mol 5.5%), was admitted with renal failure. Bloods on admission: eGFR 25 ml/min, creatinine 184 ?mol/L, urea 35.9 mmol/L, sodium 128 mmol/L, potassium 5.6 mmol/L, bicarbonate 15 mmol/L, and albumin 30 g/L. Her admission was prolonged, complicated by hospital-acquired sepsis (lower respiratory tract, urinary tract, and infected leg ulcers), poor venous access and severe depression. She had recurrent hyperkalaemia and deteriorating renal function, from presumed Type 4 renal tubular acidosis and excessive fluid losses from leg ulcers. Her renal function recurrently deteriorated, despite conventional treatment methods. After 69 days, she was commenced on fludrocortisone 50 mcg/day. Her renal function and serum potassium stabilized and she was discharged with potassium 4.3 mmol/L, eGFR 42 ml/min, and bicarbonate 23 mmol/L. She has remained stable on this treatment, without requiring further hospital admission for over 6 months, with eGFR 40 ml/min, and potassium 5.5 mmol/L, and albumin 26 g/L. CONCLUSION: This woman was presumed to have Type 4 renal tubular acidosis and recurrent hyperkalaemia due to renal insufficiency, in the context of underlying diabetes and chronic kidney disease, which was poorly responsive to conventional management. There is limited evidence for using fludrocortisone in this setting. Our case suggests that fludrocortisone might offer a novel therapeutic strategy when conventional management is not working.

A "Diabetes Acute Care Day" for medical students increases their knowledge and confidence of diabetes care: a pilot study.

BACKGROUND: Evidence suggests that junior doctors lack the confidence and skills to manage acute/inpatient diabetes. We investigated the impact of the introduction of a "Diabetes Acute Care Day" on undergraduate medical students' knowledge and confidence in acute/inpatient diabetes. METHODS: Participants attended four short lectures on the basics of diabetes, diabetic emergencies, inpatient diabetes management and peri-operative/procedure care followed by case-based learning tutorials on diabetic ketoacidosis (DKA), hyperosmolar hyperglycaemic state (HHS) and hypoglycaemia using capillary blood glucose charts to interpret and practice subsequent insulin prescription and adjustment. Participants were asked to complete multiple-choice questions and confidence questionnaires using a visual analogue score pre and post participation. RESULTS: One hundred forty-four students completed the pre-course survey and 196 completed the post-course survey. Mean confidence using a visual analogue score increased in all areas with a mean at baseline of 46.9 mm rising to 71.2 mm post-participation (p < 0.001). The largest increases were in the management of HHS, patients on subcutaneous and intravenous insulin and perioperative/procedure care. The mean mark obtained in the pre-test multiple choice questions (MCQs) was 2.72 (27.2 %) and increased to 4.74 (47.4 %) on the post-score MCQs (p < 0.001). 56.9 % of participants answered all 10 pre-test MCQs with the mean number of questions answered = 4.71 rising to 82.0 % of students answered all ten questions and the mean number of questions answered = 9.56 in the post-test MCQs. CONCLUSIONS: An intensive "Diabetes Acute Care Day" consisting of themed live lectures and case-based learning tutorials is an effective way to increase medical students' knowledge and confidence in acute/inpatient diabetes. Further development and evaluation of this educational intervention is required to assess the impact of on patient care in the clinical setting post graduation.

Spontaneous remission in a case of idiopathic retroperitoneal fibrosis.

A 54-year-old lady being investigated at the medical clinic for back pain and weight loss, was diagnosed with idiopathic retroperitoneal fibrosis on the basis of CT imaging, biopsy findings and absence of known secondary causes. After lengthy discussions with the patient during several clinic visits she declined the use of corticosteroid treatment due to concerns for the potential side effects. Serial monitoring of inflammatory markers and interval imaging suggested a spontaneous remission in the inflammatory process. We describe the case and discuss the management of retroperitoneal fibrosis.

Hypertension in pregnancy: a review of therapeutic options.

Hypertensive disorders in pregnancy are common and can occur as a result of pre-existing hypertension or as new onset hypertension usually in the second half of pregnancy. In either situation there is potential for considerable perinatal and maternal morbidity and mortality. This review article aims to compare therapeutic options outlined in a selection of national guidelines and to look in more detail at the most commonly prescribed drugs - labetalol, methyldopa and nifedipine - with respect to their pharmacology and the evidence for their use in pregnancy. We will also consider the rationale for identifying and treating hypertension in pregnancy and the effect this can have on short- and long-term maternal and neonatal outcomes.

Lack of confidence among trainee doctors in the management of diabetes: the Trainees Own Perception of Delivery of Care (TOPDOC) Diabetes Study.

BACKGROUND: There is an increased prevalence of diabetes. Doctors in training, irrespective of specialty, will have patients with diabetes under their care. AIM: To determine levels of confidence of doctors in training in the management of diabetes and establish their training needs in this area of clinical practice. DESIGN: A national online survey of trainee doctors in the UK using a pre-validated questionnaire. METHODS: A four-point confidence rating scale was used to rate confidence in the management of diabetes and comparators. A six-point scale was used to quantify how often trainees would contribute to the management of patients with diabetes and trainees were asked about their training in managing diabetes. RESULTS: A total of 2149 doctors completed the survey. The percentage 'fully confident' in diagnosing diabetes was 27%, diagnosing and managing hypoglycaemia 55%, diagnosing and managing diabetic ketoacidosis 43%, managing intravenous (IV) insulin 27%, prescribing IV fluids for patients with diabetes 39% and altering diabetes therapy prior to surgery/other procedure 18%. In comparison, 66% and 65% were 'fully confident' in the management of angina and asthma, respectively (P < 0.05). Forty-one percent would take the initiative to optimize glycaemic control for patients under their care >80% of the time. Respectively, 19% and 35% of respondents reported that their undergraduate and postgraduate training had prepared them adequately to optimize treatment of diabetes. The majority (>70%) wanted further training in managing all aspects of diabetes care. CONCLUSIONS: Trainee doctors in the UK lack confidence in the management of diabetes, are unlikely to take the initiative to optimize glycaemic control and report a need for further training.

Metformin action on AMP-activated protein kinase: a translational research approach to understanding a potential new therapeutic target.

Clinical studies in Type 2 diabetes mellitus have shown that the effects of metformin go beyond improving HbA(1c) and include reductions in cardiovascular endpoints. Metformin therapy has been widely used in the treatment of Type 2 diabetes for many years, yet the precise mode of action remains uncertain. It has recently been proposed that metformin-mediated stimulation of hepatic AMP-activated protein kinase (AMPK) underlies the hypoglycaemic effects of metformin. AMPK is a heterotrimeric enzyme that is expressed in many tissues and plays a central role in the regulation of energy homoeostasis. Furthermore, there is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. The generation of more specific and potent activators of AMPK, however, could have additional metabolic and vascular benefits for patients with Type 2 diabetes.

Diabetes, colorectal cancer and cyclooxygenase 2 inhibition.

Diabetes is a risk factor for cancer and specifically colorectal cancer. It is also associated with increased cancer mortality. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase 2 (Cox-2) inhibitors have been shown to decrease the incidence of colorectal cancer. This effect may be mediated by inhibiting prostaglandin synthesis. Long-term use of high-dose aspirin and NSAIDs is associated with significant gastrointestinal side effects. Unfortunately, the use of Cox-2 inhibitors is associated with an increased incidence of acute myocardial infarction and death from cardiovascular disease. The increased risk of cardiovascular disease in patients with diabetes results in the loss of the potential to use Cox-2 inhibitors for cancer chemoprophylaxis. Until a safer type of Cox-2 inhibitor is available, or low-dose aspirin is evaluated for chemoprophylaxis, a more intense screening programme for colorectal cancer may be appropriate for patients with diabetes, especially men. Healthcare professionals managing patients with diabetes should be aware of the increased risk of this type of cancer.

Comparison of the effects of thioridazine and mesoridazine on the QT interval in healthy adults after single oral doses.

We compared the effects of single doses of thioridazine and mesoridazine on the heart rate-corrected QT (QTc) interval in healthy adult volunteers. QTc intervals and plasma concentrations of thioridazine, mesoridazine, and metabolites were measured after single oral doses of thioridazine hydrochloride 50 mg, mesoridazine besylate 50 mg, or placebo in a double-blind, crossover study. Mean maximum increases in the QTc interval following thioridazine (37.3+/-4.1 ms, P=0.023) and mesoridazine (46.6+/-7.4 ms, P=0.021) were similar and significantly greater than following placebo (12.9+/-8.1 ms). The area under the effect-time curve over 8 h following drug administration was similar between the two drugs (129.3+/-22.1 vs 148.3+/-43.0 ms h). In conclusion, thioridazine and mesoridazine are associated with similar effects on the QTc interval.

Aminoglycoside antibiotic phosphotransferases are also serine protein kinases.

BACKGROUND: Bacterial resistance to aminoglycoside antibiotics occurs primarily through the expression of modifying enzymes that covalently alter the drugs by O-phosphorylation, O-adenylation or N-acetylation. Aminoglycoside phosphotransferases (APHs) catalyze the ATP-dependent phosphorylation of these antibiotics. Two particular enzymes in this class, APH(3')-IIIa and AAC(6')-APH(2"), are produced in gram-positive cocci and have been shown to phosphorylate aminoglycosides on their 3' and 2" hydroxyl groups, respectively. The three-dimensional structure of APH (3')-IIIa is strikingly similar to those of eukaryotic protein kinases (EPKs), and the observation, reported previously, that APH(3')-IIIa and AAC(6')-APH(2") are effectively inhibited by EPK inhibitors suggested the possibility that these aminoglycoside kinases might phosphorylate EPK substrates. RESULTS: Our data demonstrate unequivocally that APHs can phosphorylate several EPK substrates and that this phosphorylation occurs exclusively on serine residues. Phosphorylation of Ser/Thr protein kinase substrates by APHs was considerably slower than phosphorylation of aminoglycosides under identical assay conditions, which is consistent with the primary biological roles of the enzymes. CONCLUSIONS: These results demonstrate a functional relationship between aminoglycoside and protein kinases, expanding on our previous observations of similarities in protein structure, enzyme mechanism and sensitivity to inhibitors, and suggest an evolutionary link between APHs and EPKs.

Inhibition of aminoglycoside antibiotic resistance enzymes by protein kinase inhibitors.

Bacterial resistance to the aminoglycoside antibiotics is manifested primarily through the expression of enzymes which covalently modify these drugs. One important mechanism of aminoglycoside modification is through ATP-dependent O-phosphorylation, catalyzed by a family of aminoglycoside kinases. The structure of one of these kinases, APH(3')-IIIa has recently been determined by x-ray crystallography, and the general fold is strikingly similar to eukaryotic protein kinases (Hon, W. C., McKay, G. A., Thompson, P. R., Sweet, R. M., Yang, D. S. C., Wright, G. D., and Berghuis, A. M. (1997) Cell 89, 887-895). Based on this similarity, we have examined the effect of known inhibitors of eukaryotic protein kinases on two aminoglycoside kinases, APH(3')-IIIa and the enzyme AAC(6')-APH(2") which also exhibits acetyl-CoA-dependent aminoglycoside modification activity. We report that several known protein kinase inhibitors are also good inhibitors of aminoglycoside kinases. Compounds belonging to the isoquinolinesulfonamide group are especially effective in this regard, giving competitive inhibition in the micromolar range with respect to ATP and noncompetitive inhibition versus the aminoglycoside substrate. This study provides the basis for future aminoglycoside kinase inhibitor design and for the development of compounds which could reverse antibiotic resistance in the clinic.

Structure of an enzyme required for aminoglycoside antibiotic resistance reveals homology to eukaryotic protein kinases.

Bacterial resistance to aminoglycoside antibiotics is almost exclusively accomplished through either phosphorylation, adenylylation, or acetylation of the antibacterial agent. The aminoglycoside kinase, APH(3')-IIIa, catalyzes the phosphorylation of a broad spectrum of aminoglycoside antibiotics. The crystal structure of this enzyme complexed with ADP was determined at 2.2 A. resolution. The three-dimensional fold of APH(3')-IIIa reveals a striking similarity to eukaryotic protein kinases despite a virtually complete lack of sequence homology. Nearly half of the APH(3')-IIIa sequence adopts a conformation identical to that seen in these kinases. Substantial differences are found in the location and conformation of residues presumably responsible for second-substrate specificity. These results indicate that APH(3') enzymes and eukaryotic-type protein kinases share a common ancestor.

Recognition of aminoglycoside antibiotics by enterococcal-staphylococcal aminoglycoside 3'-phosphotransferase type IIIa: role of substrate amino groups.

The interactions of the aminoglycoside 3'-phosphotransferase IIIa with aminoglycoside antibiotics lacking specific amino groups were examined by steady-state kinetic analyses. The results demonstrate that an amino group on C-1 and either an amino or a hydroxyl group at the 2' and 6' positions are important for detoxification of aminoglycosides by this enzyme.

Catalytic mechanism of enterococcal kanamycin kinase (APH(3')-IIIa): viscosity, thio, and solvent isotope effects support a Theorell-Chance mechanism.

Bacterial resistance to the aminoglycoside antibiotics is manifested primarily through the production of enzymes which covalently modify these drugs. The Enterococci and Staphylococci produce an ATP-dependent kinase, APH(3')-IIIa, which phosphorylates such antibiotics as kanamycin, amikacin, and neomycin, and this enzyme shows a Theorell-Chance kinetic mechanism by traditional product and analogue inhibitor analysis and by the alternative substrate diagnostic [McKay, G. A., & Wright, G. D. (1995) J. Biol. Chem. 270, 24686-24692]. We report that the APH(3')-IIIa exhibits small solvent (VH/VD approximately equal to 1.50) and thio effects (VATP/VATP gamma S = 2) indicating hydroxyl group deprotonation and nucleophilic attack on ATP do not significantly contribute to the overall steady-state rate. The enzymatic rates were determined with the viscogens PEG 8000, glycerol, and sucrose, and these experiments demonstrate that ATP binding and ADP release are diffusion controlled and that ADP release is solely rate limiting for APH(3')-IIIa. In addition, the slope of V/K for ATP vs relative viscosity is greater than the theoretical limit of 1, suggesting a possible enzyme conformational change upon binding of ATP. This new experimental evidence supports a Theorell-Chance mechanism for APH(3')-IIIa.