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Intravenous flucloxacillin is one of the most frequently used high-dose penicillin therapies in hospitalized patients, forming the cornerstone treatment of invasive Staphylococcus aureus infection. Being a nonreabsorbable anion, flucloxacillin has been suggested to cause hypokalaemia, although the frequency and magnitude of this unwanted effect is unknown. In a retrospective cohort, we investigated the incidence and extent of hypokalaemia after initiation of intravenous flucloxacillin or ceftriaxone therapy. In total, 77 patients receiving flucloxacillin (62% male, mean age 70.5 years) and 84 patients receiving ceftriaxone (46% male, mean age 70.8 years) were included. Hypokalaemia occurred significantly more often in patients receiving flucloxacillin than ceftriaxone (42% vs 14%, p < 10 -4 ). Moreover, follow-up potassium levels were significantly lower during flucloxacillin therapy. In general, women were more prone to develop hypokalaemia than men. In conclusion, intravenous flucloxacillin use is associated with a striking incidence of hypokalaemia. Therefore, standardized potassium measurements are necessary., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Patients with osteoporosis often have chronic kidney disease (CKD). CKD is associated with bone and mineral disturbances, renal osteodystrophy, which like osteoporosis leads to a higher risk of fractures. Bisphosphonates are first-line therapy for osteoporosis; however, these are contra-indicated in patients with a GFR <30 ml/min. In this article, we have reviewed the diagnosis and treatment of osteoporosis in moderate to severe renal failure from data of clinical trials. Results have shown that osteoporosis patients and severe CKD with no signs of renal osteodystrophy, oral bisphosphonates (risedronate) seem to be a safe choice. Renal function and PTH should subsequently be monitored strictly. Denosumab, with regularly monitoring of calcium and adequate vitamin D levels or raloxifene are a possible second choice. In any case, one should be certain that there is no adynamic bone before treatment can be started. If there is any doubt, bone biopsies should be taken.

Background: A reduced heparan sulphate (HS) expression in the glomerular basement membrane of patients with overt diabetic nephropathy is associated with an increased glomerular heparanase expression. We investigated the possible association of urinary heparanase activity with the development of proteinuria in patients with Type 1 diabetes (T1D), Type 2 diabetes (T2D), or membranous glomerulopathy (MGP) as non-diabetic disease controls., Methods: Heparanase activity, albumin, HS and creatinine were measured in the urine of patients with T1D (n=58) or T2D (n=31), in patients with MGP (n=52) and in healthy controls (n=10). Heparanase messenger RNA (mRNA) expression in leukocytes was determined in a subgroup of patients with T1D (n=19)., Results: Urinary heparanase activity was increased in patients with T1D and T2D, which was more prominent in patients with macroalbuminuria, whereas no activity could be detected in healthy controls. Albuminuria levels were associated with increased urinary heparanase activity in diabetic patients (r=0.20; P<0.05) but not in patients with MGP (r=0.11; P=0.43). A lower urinary heparanase activity was observed in diabetic patients treated with inhibitors of the renin-angiotensin-aldosterone system (RAAS), when compared to diabetic patients treated with other anti-hypertensives. Additionally, urinary heparanase activity was associated with age in T1D and MGP. In MGP, heparanase activity and β2-microglobulin excretion correlated. In patients with T1D, no differences in heparanase mRNA expression in leukocytes could be observed., Conclusions: Urinary heparanase activity is increased in diabetic patients with proteinuria. However, whether increased heparanase activity is a cause or consequence of proteinuria requires additional research.

Hypoglycemia unawareness has been linked to desensitization of the beta2-adrenergic receptor. Desensitization of the beta2-adrenergic receptor (ADRB2) is genetically determined by the Arg16Gly variant of this receptor. We tested the hypothesis that hypoglycemia unawareness is more common among patients homozygous for the Gly16 variant. We performed genotyping of the A265G (Arg16Gly) polymorphism in the ADRB2 gene in 85 patients with type 1 diabetes and classified them according to hypoglycemia awareness status. A total of 45 patients (53%) were homozygous for Gly16, 32 patients (38%) were heterozygous and eight patients (9%) were homozygous for Arg16. Hypoglycemia unawareness was 3.4-fold more common among patients homozygous for Gly16 than among patients with other variants of the Arg16Gly polymorphism (P=0.014). We conclude that patients with type 1 diabetes who carry two alleles of the Gly16 variant of ADRB2 are at increased risk of developing hypoglycemia unawareness. Future studies are required to confirm these results in larger, independent populations.

Two adult patients with presumed primary hypertension are presented. In the first patient the diagnosis of coarctation of the aorta was straightforward while in the second patient there was a substantial delay in reaching the correct diagnosis. A 32-year-old patient was analysed for hypertension in the outpatient clinic. At physical examination a systolic cardiac murmur was present and leg blood pressure was not measurable. Magnetic resonance imaging angiography showed a severe coarctation of the thoracic aorta with extensive distended collateral blood vessels. A second patient was a 31-year-old man referred with longstanding hypertension and an unsatisfactory blood pressure response to treatment. Previously, a diagnosis of primary hypertension was made. Renal computed tomography angiography excluded renal artery stenosis as a cause of hypertension but disclosed many distended collateral blood vessels in the musculus rectus abdominis and in the upper abdominal area. Leg blood pressure was measured and further analysis revealed a coarctation of the aorta. Both patients illustrate and emphasise the importance of leg blood pressure measurement at a first analysis of adult hypertensive patients and should always be performed when hypertension is accompanied by murmurs or weak femoral pulsations.

Blood stream infections caused by Candida glabrata are difficult to manage. We describe a patient who underwent an allogeneic peripheral stem cell transplantation for acute myeloid leukaemia. The patient developed C. glabrata fungaemia that was refractory to liposomal amphotericin B therapy. After changing the therapy to caspofungin, blood cultures became sterile within two days and the patient recovered clinically. The patient died shortly after due to graft-versus-host disease and at autopsy there was no evidence of residual or persistent Candida infection. Caspofungin was effective in liposomal amphotericin-B refractory C. glabrata fungaemia and proved to rapidly clear the infection. Treatment options for candidaemia are discussed.

Introduction: Elevated plasma levels of total homocysteine are related to the development of vascular complications. Patients with diabetes mellitus are particularly at risk for the development of these complications. Several factors determine plasma total homocysteine including renal function., Aims: As early Type 1 diabetes is characterized by a relative glomerular hyperfiltration, increased renal clearance could contribute to decreased levels of homocysteine as observed in Type 1 diabetes mellitus. Therefore we investigated the relationship between plasma total homocysteine and the glomerular filtration rate (GFR)., Methods: In 92 Type 1 diabetes patients and 44 control subjects, we measured GFR and effective renal plasma flow (ERPF) by means of continuous infusion of inulin and p-aminohippurate. Fasting plasma total homocysteine was measured using high performance liquid chromatography., Results: GFR (121 +/- 21 resp. 104 +/- 14 ml/min; P < 0.001) and ERPF (563 +/- 127 resp. 516 +/- 121 ml/min; P = 0.05) were significantly higher in Type 1 diabetes patients as compared with control subjects. Plasma total homocysteine was reduced in Type 1 diabetes patients as compared with control subjects (11.0 +/- 4.5 resp. 13.4 +/- 7 micromol/l; P = 0.01). Plasma total homocysteine was strongly correlated with GFR (Type 1 diabetes patients: r = -0.43, P < 0.001; control subjects: r = -0.39, P = 0.01)., Conclusion: GFR is a major determinant of plasma total homocysteine levels in Type 1 diabetes patients as well as control subjects. The reduced plasma total homocysteine levels in diabetes patients can be explained by an increased GFR.

Rationale: L-NMMA is widely used in venous occlusion plethysmography studies to determine baseline NO production. Studies using L-NMMA indicate that endothelial dysfunction is present early in the course of diabetic microvascular complications. However, the optimal dose to maximally inhibit NO-production is unknown., Objective: To determine the L-NMMA-dose that maximally reduces basal forearm blood flow (FBF). To investigate whether there are any differences in the response to L-NMMA between non-complicated type 1 diabetes patients and control subjects., Methods: In eight non-complicated type 1 diabetes patients and nine healthy subjects FBF-responses to intra-arterial infusion of increasing doses of L-NMMA (0.01-1.6 mg/min/dL forearm volume [FAV]) were measured using the perfused forearm technique., Results: Infusion of 0.8 mg/min/dL maximally reduced FBF. The dose of 1.6 mg/min/dL did not additionally reduce FBF. No differences existed between non-complicated type 1 diabetes patients and controls with regard to EC50 (0.017 +/- 0.02 resp. 0.22 +/- 0.02 mg L-NMMA/min/dL) or maximal vasoconstrictive response (Delta FBF: 1.13 +/- 0.4 resp. 0.97 +/- 0.4 mL/min/dL). Throughout the study blood pressure increased significantly in both groups, possibly reflecting a systemic vasoconstrictive effect of L-NMMA., Conclusions: The maximal vasoconstrictive dose was 0.8 mg/min/dL in type 1 diabetes patients as well as the control subjects. There were no significant differences between non-complicated type 1 diabetes subjects and controls with regard to the pharmacodynamics of L-NMMA. At high dosages of L-NMMA a systemic effect can not be ruled out.

A 75-year-old woman presented with angina pectoris and dyspnoea due to critical stenosis of the left main coronary artery with diffuse subendocardial ischaemia.

Type 1 diabetes is a T-cell-mediated chronic disease characterized by the autoimmune destruction of pancreatic insulin-producing beta cells and complete insulin deficiency. It is the result of a complex interrelation of genetic and environmental factors, most of which have yet to be identified. Simultaneous identification of these genetic factors, through use of unphased genotype data, has received increasing attention in the past few years. Several approaches have been described, such as the modified transmission/disequilibrium test procedure, the conditional extended transmission/disequilibrium test, and the stepwise logistic-regression procedure. These approaches are limited either by being restricted to family data or by ignoring so-called "haplotype interactions" between alleles. To overcome this limit, the present study provides a general method to identify, on the basis of unphased genotype data, the haplotype blocks that interact to define the risk for a complex disease. The principle underpinning the proposal is minimal entropy. The performance of our procedure is illustrated for both simulated and real data. In particular, for a set of Dutch type 1 diabetes data, our procedure suggests some novel evidence of the interactions between and within haplotype blocks that are across chromosomes 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 15, 16, 17, 19, and 21. The results demonstrate that, by considering interactions between potential disease haplotype blocks, we may succeed in identifying disease-predisposing genetic variants that might otherwise have remained undetected.

Background: Previously we observed that atrial natriuretic peptide (ANP)-induced albuminuria was accompanied by an increase in urinary excretion of the low-molecular weight protein (LMW protein) beta2-microglobulin (beta2-m), suggesting that the albuminuria may at least partly be the result of blockade of tubular protein reabsorption. However, in our experiments ANP was dissolved in the polygeline Haemaccel (Hoechst, Behring-Werke, Marburg Germany) to prevent adhesion of ANP to the infusion system. Anecdotal reports have shown that high dosages of polygelines such as Haemaccel or Gelofusine (Braun NPBI Oss, the Netherlands) may influence tubular protein handling. In the present study we have evaluated the effect of a low and high doses of the polygeline Haemaccel on proteinuria. In addition, we have reassessed the effects of ANP., Materials and Methods: We measured urinary beta2-microglobulin (beta2-m) and albumin excretion in healthy volunteers after infusion of a high-dose pure Haemaccel (0.04 mL kg(-1) min(-1) for 60 min), a low-dose Haemaccel (0.01 mL kg(-1) min(-1) for 60 min followed by infusion of 0.02 mL kg(-1) min(-1) for 60 min) and a low-dose Gelofusine (dose comparable to the low-dose Haemaccel). In addition we performed similar studies using ANP dissolved in saline and Haemaccel., Results: Infusion of Haemaccel caused a dose-dependent increase in urinary excretion of beta2-m. There were no differences between Haemaccel and Gelofusine. After infusion of ANP dissolved in Haemaccel urinary beta2-m excretion increased from 0.05 +/- 0.03 microg min(-1) to 27 +/- 10 microg min(-1) and urinary albumin excretion increased from 4.5 +/- 1.1 microg min(-1) to 9.7 +/- 6.3 microg min(-1) (P<0.05). During ANP + saline infusion, urinary beta2-m excretion did not change, whereas the urinary albumin excretion increased from 5.3 +/- 1.5 microg min(-1) to 7.9 +/- 2.4 microg min(-1) (P<0.05)., Conclusions: Our study demonstrates that even low doses of the polygelines Haemaccel and Gelofusine profoundly attenuate the tubular reabsorption of the low-molecular weight protein beta2-m. Atrial natriuretic peptide does not affect tubular protein reabsorption. Therefore, the rise in albuminuria during ANP infusion most likely reflects alterations in glomerular permeability.

Rationale: The endothelial nitric oxide synthase Glu298Asp polymorphism has been suggested to play a role in the development of hypertension, atherosclerosis and coronary artery disease., Objective: To investigate functional differences between the various genotypes with respect to basal nitric oxide (NO) production, we estimated the response to endothelial NO synthase (ecNOS) inhibition by infusion of increasing doses of N(G)-monomethyl-L-arginine (L-NMMA) into the brachial artery during venous occlusion plethysmography., Methods: In 41 healthy subjects forearm blood flow responses to intra-arterial infusion of increasing doses of L-NMMA (0.05, 0.1 and 0.2 mg/min per dl) and norepinephrine (10, 20 and 40 ng/min per dl) were measured. The genotype of the ecNOS Glu298Asp polymorphism was assessed., Results: Nineteen subjects had the Glu/Glu genotype, 19 subjects had the Glu/Asp genotype and three subjects had the Asp/Asp genotype. Groups were comparable concerning demographic, hemodynamic and possible confounding factors. Subjects with the Asp allele showed a reduced response to infusion of L-NMMA as compared to subjects with the Glu/Glu genotype (ANOVA, = 0.01). There was no significant difference in the response to infusion of the NO-independent vasoconstrictor, norepinephrine, between both groups., Conclusions: The ecNOS Glu298Asp polymorphism is associated with reduced basal NO production and might therefore have functional implications in the development of atherosclerosis or hypertension.

In 3 patients, 2 women aged 16 and 64 years and 1 man aged 64 years, with pain in the left hip region and fever, the diagnosis psoas abscess was made. After antibiotic treatment and drainage they recovered well. The primary from of psoas abscess is presumably caused by haematogenous spread of bacteria, mostly Staphylococcus aureus. The secondary form is caused by spread of infection from surrounding tissue, mostly gastrointestinal micro-organisms with Crohn's disease and diverticulitis. Painful passive extension and endorotation as well as a painful flexion stress-test of the hip joint can indicate a psoas abscess. Echography and blood cultures should be performed if a psoas abscess is suspected. If echography is inconclusive, CT-scan can establish the diagnosis. The psoas abscess should be treated by percutaneous or surgical drainage combined with antibiotic therapy. The underlying cause of a secondary psoas abscess should be treated separately.

Parkinson's disease (PD) is a multifactorial disorder, caused by a combination of age, genetics and environmental factors. Nigral cells are susceptible to multiple causes of derangement of normal cell function, all of which may contribute to the same Parkinson phenotype. Autosomal dominant alpha-synuclein-gene PD represents one of the pure genetic forms, whereas cases of sporadic PD probably depend more on age and environmental factors, MPTP-Parkinsonism being the purest example of an environmentally caused Parkinson phenotype. This review suggests that pesticides-herbicides, smoking and head trauma probably represent the most eligible candidates for environmental factors involved in provoking PD or influencing its natural course.