Metabolomic associations of impaired awareness of hypoglycaemia in type 1 diabetes.

This study investigates impaired awareness of hypoglycaemia (IAH), a complication of insulin therapy affecting 20-40% of individuals with type 1 diabetes. The exact pathophysiology is unclear, therefore we sought to identify metabolic signatures in IAH to elucidate potential pathophysiological pathways. Plasma samples from 578 individuals of the Dutch type 1 diabetes biomarker cohort, 67 with IAH and 108 without IAH (NAH) were analysed using the targeted metabolomics Biocrates AbsoluteIDQ p180 assay. Eleven metabolites were significantly associated with IAH. Genome-wide association studies of these 11 metabolites identified significant single nucleotide polymorphisms (SNPs) in C22:1-OH and phosphatidylcholine diacyl C36:6. After adjusting for the SNPs, 11 sphingomyelins and phosphatidylcholines were significantly higher in the IAH group in comparison to NAH. These metabolites are important components of the cell membrane and have been implicated to play a role in cell signalling in diabetes. These findings demonstrate the potential role of phosphatidylcholine and sphingomyelins in IAH.

Characteristics associated with polypharmacy in people with type 2 diabetes: the Dutch Diabetes Pearl cohort.

AIM: To describe the prevalence and characteristics of polypharmacy in a Dutch cohort of individuals with type 2 diabetes. METHODS: We included people with type 2 diabetes from the Diabetes Pearl cohort, of whom 3886 were treated in primary care and 2873 in academic care (secondary/tertiary). With multivariable multinomial logistic regression analyses stratified for line of care, we assessed which sociodemographic, lifestyle and cardiometabolic characteristics were associated with moderate (5-9 medications) and severe polypharmacy (≥10 medications) compared with no polypharmacy (0-4 medications). RESULTS: Mean age was 63 ± 10 years, and 40% were women. The median number of daily medications was 5 (IQR 3-7) in primary care and 7 (IQR 5-10) in academic care. The prevalence of moderate and severe polypharmacy was 44% and 10% in primary care, and 53% and 29% in academic care respectively. Glucose-lowering and lipid-modifying medications were most prevalent. People with severe polypharmacy used a relatively large amount of other (i.e. non-cardiovascular and non-glucose-lowering) medication. Moderate and severe polypharmacy across all lines of care were associated with higher age, low educational level, more smoking, longer diabetes duration, higher BMI and more cardiovascular disease. CONCLUSIONS: Severe and moderate polypharmacy are prevalent in over half of people with type 2 diabetes in primary care, and even more in academic care. People with polypharmacy are characterized by poorer cardiometabolic status. These results highlight the significance of polypharmacy in type 2 diabetes.

Association of vitamin B12, methylmalonic acid, and functional parameters.

INTRODUCTION: Diagnosis of vitamin B12 deficiency is difficult, as there is no conclusive single test for this disorder. We evaluated the association of serum B12 and methylmalonic acid (MMA) with haematologic parameters and physical and cognitive functioning in an effort to use such clinical parameters to improve the interpretation of serum values. METHODS: We used data of participants > 19 years of age from NHANES 2011-2012 and 2013-2014, a cross-sectional survey in the United States. Functional status was assessed with questionnaires on current health condition, disability, hospital utilisation, cognitive functioning, mental health and depression, and physical functioning. Muscle strength assessed with a handgrip dynamometer was used as a performance parameter. Results were evaluated both for the entire population and participants of Western European descent. Because renal function influences MMA concentrations and is a proxy for both frailty and comorbidity, all results were additionally stratified for individuals with normal vs impaired renal function (eGFR < 60 ml/min). RESULTS: In total, data of 9645 participants (mean age 49 (SD 17) years, 49.3% males) were included. Out of all participants with serum B12 < 140, 140-300, and 301-1000 pmol/l, 56.2%, 13.5%, and 4.1%, respectively had elevated MMA. MMA concentrations were more strongly associated with poor functional status and physical performance than serum B12. We identified a significant and independent association of MMA concentrations, as well as haemoglobin and co-morbidity with muscle strength. CONCLUSIONS/INTERPRETATIONS: A large proportion of individuals with a decreased serum B12 concentration still has normal MMA concentrations. Elevated MMA concentrations were more strongly associated with poor functional performance than serum B12.

Unfavourable blood pressure and LDL-cholesterol levels in obese non-diabetic individuals.

BACKGROUND: Early diagnosis and treatment of high blood pressure (BP) and cholesterol is important to reduce cardiovascular risk. We compared BP and LDL-cholesterol (LDL-C) as well as the quality of treatment between obese subjects and normal weight and overweight individuals. METHODS: 87,648 participants of the Lifelines study were categorised according to obesity (normal weight/ overweight/obesity) and age. Mean systolic BP and LDL-C were calculated depending on treatment, BMI, age and sex. RESULTS: In all age groups, except those aged 70-80 years, women had a significantly lower BP than men. Use of BP-lowering medication did not result in BP levels comparable with non-users, except in those aged 70-80 years. Despite medication, the BP was insufficiently controlled in 20-50% of participants. BP was significantly higher in obese vs. normal weight and overweight individuals of all ages, but most apparently in men younger than 50 years. Mean LDL-C varied between 2.5- .0 mmol/l. Despite higher statin use, obese participants had a higher LDL-C than those with a normal weight. Statins abolished the age-dependent LDL-C increase. Many participants did not achieve target LDL-C < 2.5 mmol/l. A small percentage of individuals treated with BP-lowering drugs were also using statins (overall 32% in men, 17% in women). CONCLUSION: Obese individuals, especially men younger than 50, have a higher BP and LDL-C compared with those with overweight and a normal weight. Use of BP-lowering drugs did not revert the BP back to levels normal for the specific age and BMI group, whereas statins abolished the age-related increase in LDL-C. These data suggest that more attention is needed for active screening and treatment of cardiovascular risk factors.

Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals.

AIMS/HYPOTHESIS: Genetic pleiotropy may contribute to the clustering of obesity and metabolic conditions. We assessed whether genetic variants that are robustly associated with BMI and waist-to-hip ratio (WHR) also influence metabolic and cardiovascular traits, independently of obesity-related traits, in meta-analyses of up to 37,874 individuals from six European population-based studies. METHODS: We examined associations of 32 BMI and 14 WHR loci, individually and combined in two genetic predisposition scores (GPSs), with glycaemic traits, blood lipids and BP, with and without adjusting for BMI and/or WHR. RESULTS: We observed significant associations of BMI-increasing alleles at five BMI loci with lower levels of 2 h glucose (RBJ [also known as DNAJC27], QPTCL: effect sizes -0.068 and -0.107 SD, respectively), HDL-cholesterol (SLC39A8: -0.065 SD, MTCH2: -0.039 SD), and diastolic BP (SLC39A8: -0.069 SD), and higher and lower levels of LDL- and total cholesterol (QPTCL: 0.041 and 0.042 SDs, respectively, FLJ35779 [also known as POC5]: -0.042 and -0.041 SDs, respectively) (all p < 2.4 × 10(-4)), independent of BMI. The WHR-increasing alleles at two WHR loci were significantly associated with higher proinsulin (GRB14: 0.069 SD) and lower fasting glucose levels (CPEB4: -0.049 SD), independent of BMI and WHR. A higher GPS-BMI was associated with lower systolic BP (-0.005 SD), diastolic BP (-0.006 SD) and 2 h glucose (-0.013 SD), while a higher GPS-WHR was associated with lower HDL-cholesterol (-0.015 SD) and higher triacylglycerol levels (0.014 SD) (all p < 2.9 × 10(-3)), independent of BMI and/or WHR. CONCLUSIONS/INTERPRETATION: These pleiotropic effects of obesity-susceptibility loci provide novel insights into mechanisms that link obesity with metabolic abnormalities.

Intestinal pseudo-obstruction as a complication of paragangliomas: case report and literature review.

Intestinal pseudo-obstruction is a rare and relatively unknown complication of phaeochromocytoma÷ paraganglioma (PCC÷PGL). Its pathophysiology can be explained by the hypersecretion of catecholamines, which may reduce the peristaltic activity of the gastrointestinal tract. Clinically, this can result in chronic constipation, intestinal pseudo-obstruction or even intestinal perforation. We conducted a comprehensive literature search and retrieved 34 cases of pseudo-obstruction caused by either benign or malignant PCC÷PGL. We also included a case from our centre that has not been described earlier. We conclude that intestinal pseudo-obstruction is a rare but potentially life-threatening complication of PCC÷PGL. Intravenous administration of phentolamine is the most frequently described treatment when surgical resection of the PCC÷PGL is not feasible.

The combination of insulin and GLP-1 analogues in the treatment of type 2 diabetes.

GLP-1 analogues have been proven to be effective in the treatment of type 2 diabetes mellitus. They stimulate insulin production and secretion, and suppress glucagon secretion, depending on the blood glucose level. They also have an effect on the brain, enhancing satiety, and on the gut, where they delay gastric emptying. Theoretically, in type 2 diabetes mellitus patients, the combination of a GLP-1 analogue with insulin seems attractive, because of the weight loss perceived in users of GLP-1 analogues in contrast to the weight gain seen in most patients starting insulin therapy, leading to even more insulin resistance. There are only a few randomised controlled trials which have studied this combination and several uncontrolled studies, which will be reviewed here.

[The natural course of non-functioning pituitary adenomas]. / Het natuurlijke beloop van het niet-functionerende hypofyseadenoom.

3 patients presented with non-functioning pituitary adenomas: a 50-year-old woman who had an adenoma that had not increased in size for 3 years; a 68-year-old man with an adenoma that was undiagnosed for 5 years and led to pituitary insufficiency and bitemporal hemianopsia; and a 64-year-old woman, who had refused therapy and follow-up after diagnosis of the adenoma 20 years earlier. She was admitted with a hydrocephalus, pituitary insufficiency, and severe visual loss. The clinical symptoms of pituitary adenomas are caused by the mass effects of the tumour and may vary considerably between patients. Transsphenoidal surgery is indicated in cases of suprasellar extension with compression or impending compressing of the optic chiasm. A 'wait-and-see' approach can be used for patients with smaller tumours and no visual field defects. The natural course of these adenomas is such that lifelong follow-up is necessary. Postoperative radiotherapy can be effective in reducing recurrence rates without negative effects on quality of life.

[Psychiatric side effects associated with diphosphonate treatment]. / Psychische bijwerkingen van behandeling met bisfosfonaten.

Two women aged 50 and 64 years, respectively, and one man aged 43 years, were treated with cyclic etidronic acid for osteoporosis. After some months/years they developed mood, concentration and memory problems. The complaints diminished within several weeks after withdrawal of the drugs, and reappeared after rechallenge. Two of these patients had similar complaints during the use of another bisphosphonate (pamidronic acid and alendronic acid, respectively). Bisphosphonates are used increasingly frequently for the treatment of osteoporosis. Generally, these drugs are well tolerated. The most frequently reported adverse events are gastrointestinal complaints and oesophageal ulcers. Psychiatric complaints also appear to be a rare side effect.

A population-based case-cohort study of drug-associated agranulocytosis.

BACKGROUND: Agranulocytosis is a life-threatening disorder, often caused by drugs. Incidences or risks of drug-induced agranulocytosis are not well known, since it is rare. METHODS: To determine the risk of drug-associated agranulocytosis as a reason for admission to Dutch hospitals, we performed a population-based case-cohort study. Hospital discharge data came from the Dutch Centre for Health Care Information, Utrecht, which contains data on all general and university hospitals in the Netherlands. The reference cohort consisted of all persons in the catchment area of the Pharmaco Morbidity Record Linkage System (PHARMO RLS) in the Netherlands, composing a population of approximately 220 000 to 484 000 persons from 1987 through 1990. All admissions during that period with agranulocytosis or related diagnoses were included in the study (n = 923). The potential causes of agranulocytosis were assessed in all cases classified as probable or possible agranulocytosis. RESULTS: Discharge summaries were received of 753 admissions, of which 678 contained enough information for analysis. Of the 678,108 were classified as "agranulocytosis probable" or as "agranulocytosis possible." In 75 of these 108 cases, agranulocytosis had been the reason for admission. Fifteen patients had used methimazole within 10 days before developing agranulocytosis; 2, carbimazole; 9, sulfasalazine; 8, sulfamethoxazole-trimethoprim; 4, clomipramine hydrochloride; and 2, dipyrone with analgesics, yielding adjusted relative risks of agranulocytosis of 114.8 (for thyroid inhibitors combined) (95% confidence interval [CI], 60.5-218.6), 74.6 (95% CI, 36.3-167.8), 25.1 (95% CI, 11.2-55.0),20.0 (95% CI, 6.1-57.6), and 26.4 (95% CI, 4.4-11.1), respectively. CONCLUSIONS: The highest relative risks were found for thyroid inhibitors, sulfamethoxazole-trimethoprim, sulfasalazine, clomipramine, and dipyrone combined with analgesics.

Anaphylactic reactions associated with trimethoprim.

BACKGROUND: Anaphylactic reactions to cotrimoxazole are often ascribed to the sulphamethoxazole component of this antibacterial drug. OBJECTIVE: To determine whether the trimethoprim component can be the cause of an anaphylactic reaction. METHODS: An analysis was made of reports on anaphylaxis attributed to trimethoprim, as notified to the Drug Safety Unit of the Dutch Inspectorate for Health Care. RESULTS: In the period between September 1981 and November 1995, 13 such reports were received. Nine were classified as probable anaphylaxis. Of these, the causal relationship between exposure to trimethoprim and anaphylaxis was classified as definite in three reports, and as probable in the other six. The remaining four reports were classified as possible anaphylaxis. In one of these, the causal relationship was classified as definite, and in three as probable. CONCLUSION: Although anaphylaxis due to trimethoprim seems to be rare, it may be more common than previously thought. Apparently, anaphylaxis to cotrimoxazole is not always caused by sulphamethoxazole.

Drug-associated agranulocytosis: 20 years of reporting in The Netherlands (1974-1994).

In this descriptive study, all 425 reports were included concerning drug-associated agranulocytosis as registered between 1974 and 1994 in the files of the Drug Safety Unit of the Dutch Inspectorate for Health Care. All reports were analysed as to the probability of agranulocytosis or neutropenia according to previously defined criteria. Subsequently, the causal relationship between exposure and outcome was assessed. It concerned 149 men and 271 women. One hundred and twelve reports were unclassifiable because age, gender, or total number of leukocytes at the time of reaction were unknown. In 100 reports agranulocytosis was probable, in 78 possible, in 8 reports neutropenia was probable, in 20 reports neutropenia was possible, and in 107 reports agranulocytosis or neutropenia were unlikely. In the 13 reports of probable agranulocytosis or neutropenia with a certain causal relationship, causative drugs were cimetidine, dipyrone, sulphasalazine, methyldopa, spironolactone, propylthiouracil (2), thiamazole, sulphamethoxazole with trimethoprim, gentamicin, a combination preparation containing aminophenazone, benzylpenicillin and indomethacin. The individual drugs most often reported to cause agranulocytosis or neutropenia were: dipyrone (19), mianserin (15), sulphasalazine (13), sulphamethoxazole with trimethoprim (11), the group of penicillins (9), cimetidine (8), the thiouracil derivatives (8), phenylbutazone (8), and penicillamine (8). Agranulocytosis is a serious and fairly frequently reported adverse reaction. The reporting system of the Drug Safety Unit can be used very well for signal generation concerning adverse reactions to drugs.

Neuro-psychiatric effects of antimalarials.

OBJECTIVE: To study the neuro-psychiatric adverse effects of antimalarial drugs. SETTING: Persons who visited a Travel Clinic in Rotterdam over a period of 3 months. DESIGN: Prospective cohort study on 394 persons taking mefloquine, 493 persons taking proguanil and 340 persons not taking antimalarial drugs who visited Africa, South America, Asia, or the Middle East. METHODS: All persons received a structured questionnaire within 14 days of their return to the Netherlands. The questionnaire consisted of questions regarding use of alcohol, smoking, general health, medical history, tropical diseases during the trip, and other medicines, and contained an extensive list of general complaints regarding all body systems at four levels of severity. A modified and validated version of the Profile of Mood States was included. RESULTS: In the study period, 2541 persons visited the Travel Clinic, of whom 1791 (70%) were both eligible and willing to co-operate. Of these 1791, data were obtained from 1501 (84%). Insomnia was most frequently encountered in users of mefloquine and mouth ulcers in proguanil users. After adjustment for gender, age, destination, and alcohol use, the relative risk for insomnia to mefloquine versus non-users of antimalarials was 1.6, and the excess risk was 6 per 100 users over an average period of 2 months. There were no significant differences between groups in depression, anxiety, agitation, and confusion. Stratification by gender demonstrated that insomnia was more common in women on mefloquine, but not in men. Also, women more frequently mentioned palpitations as an adverse event. After adjustment for age, destination, and alcohol use in women, the relative risks for insomnia and palpitations to mefloquine versus non-use of antimalarials were 2.4, and 22.5, respectively. When travellers were specifically asked for the adverse reactions they had experienced, anxiety, vertigo, agitation, and nightmares were significantly more frequently mentioned by mefloquine users. CONCLUSION: Insomnia was more commonly encountered during use of mefloquine than proguanil or during non-use of antimalarials.

Drug-associated anaphylaxis: 20 years of reporting in The Netherlands (1974-1994) and review of the literature.

BACKGROUND: Since 1963, the Drug Safety Unit of the Dutch Inspectorate for Health Care (DSU) holds a voluntary reporting system. OBJECTIVE: To analyse all reports received in the years 1974 to 1994, registered as anaphylaxis or as a diagnosis that could contain cases of anaphylaxis. METHODS: All reports were classified as probable or possible anaphylaxis according to previously described criteria and the causal relationship between exposure and anaphylaxis was assessed. RESULTS: Nine hundred and ninety-two reports possibly concerning anaphylaxis were received between 1974 and 1994. Fifty-six were unclassifiable. The remaining 936 reports concerned 326 men and 610 women. Three hundred and forty-five reports were classified as anaphylaxis probable, 485 as anaphylaxis possible, and 106 as anaphylaxis unlikely by previously specified criteria. Drugs frequently associated with anaphylaxis (causal relationship certain or probable) were: glafenine (326 reports classified as anaphylaxis probable or possible), combination preparations with (propy)phenazone or propyphenazone/phenacetine (39), diclofenac (30), dextran (20), ibuprofen (14), floctafenine (12), allergen extracts (12), sulfamethoxazole with trimethoprim (12), and trimethoprim (11). There is probably substantial under-reporting as well as reporting bias in these data. Furthermore, many reports were classified as possible and not as probable anaphylaxis because the temporal relationship was unknown or not reported. CONCLUSION: Drugs that caused anaphylaxis most frequently were glafenine, NSAID and certain antibiotics. Data from a voluntary reporting system such as the DSU are valuable as an early warning system for drugs that may induce anaphylactic reactions.

Vasculitis attributed to the nicotine patch (Nicotinell).

Nicotine-containing patches are used to facilitate tobacco withdrawal by mitigating abstinence symptoms and diminishing craving. We describe two patients who developed vasculitis in association with the use of a nicotine patch. The first concerns a patient who developed fever, arthritis, a generalized erythema and purpuric lesions, after 3 days use of nicotine patches. Laboratory results and a skin biopsy confirmed the diagnosis of a leucocytoclastic vasculitis. After stopping use of the patch, the patient recovered. On challenge, the symptoms reappeared. The second patient developed purpuric lesions during the use of nicotine patches, and recovered fully after these were stopped. In these patients, nicotine patches seem to be causally related to the development of vasculitis.

[Skin reactions attributed to the use of bromhexine]. / Huidreacties toegeschreven aan het gebruik van broomhexine.

Since 1972, the Netherlands Centre for Monitoring of Adverse Reactions to Drugs has received 22 reports of skin reactions attributed to use of bromhexine. The reports concerned II men and II women. The ages ranged between 5 months and 88 years. The skin reactions occurred within one to 30 days after starting the use of bromhexine. Most skin reactions consisted of generalised urticaria. Other reports concerned once an angioedema and once an anaphylactic reaction. Most patients recovered completely after cessation of bromhexine without further treatment.

A case-control study of drugs and other determinants as potential causes of Guillain-Barré syndrome.

The Guillain-Barré syndrome is an inflammatory demyelinating polyneuropathy with an acute or subacute onset. The current case-control study was performed to investigate the possible role of drugs and other determinants in the causation of the Guillain-Barré syndrome. Patients were included as cases if they fulfilled the criteria for acute Guillain-Barré syndrome and were unable to walk 10 m independently and had been admitted to the hospital within 2 weeks of onset of the neuropathy. For every case, two controls without the disease were obtained from the general practitioner (GP) of the patient with Guillain-Barré syndrome. Controls had the same type of health care insurance, were of the same gender and age (within 5 years), and resident in the same area. By telephone, the GPs of the patients with Guillain-Barré syndrome were interviewed. There were 71 female and 75 male cases and 142 female and 149 male controls. Significantly more cases than controls had been prescribed drugs in the 3 months prior to the index date and also diagnoses or symptoms in cases were more common. Case patients used significantly more frequently antipropulsives (loperamide), penicillins (amoxicillin with or without clavulanic acid) and vaccines. Female controls used significantly more often oral contraceptives. More cases than controls suffered from infections of the respiratory, gastrointestinal or urinary tract prior to the onset of neurological symptoms. In a logistic regression analysis, symptoms concerning the gastrointestinal and respiratory system were strongly associated with the Guillain-Barré syndrome. The use of oral contraceptives was significantly lower in female cases which could be compatible with the hypothesis that these drugs are protective.

[Registration of suspected adverse effects by the Bureau Adverse Effects Drugs; research activities in 1993]. / Meldingen van vermoedelijke bijwerkingen bij het Bureau Bijwerkingen Geneesmiddelen; onderzoeksactiviteiten in 1993.

In 1993, the Netherlands Centre for Monitoring of Adverse Reactions to Drugs received 1585 reports of suspected adverse reactions. The most important reports concerned myocardial infarction due to sumatriptan, cholestatic hepatitis due to itraconazole, agranulocytosis due to trazodone and bleeding due to fluoxetine and fluvoxamine. Other published reports concerned cholestatic hepatitis due to amoxicillin/clavulanic acid, hair loss due to beta-blockers, muscle necrosis due to diclofenac, bronchospasm, apnoea and cardiac arrest due to dipyridamole perfusion scintigraphy, interaction of fluvoxamine/fluoxetine and coumarins, liver enzyme elevations due to heparin, skin reactions due to Imedeen, deafness due to neomycin, addiction to nicotine chewing gum, atrial fibrillation and skin reactions due to nicotine patches, interaction between oral contraceptives and terbinafine, neonatal problems caused by psychopharmacological agents, parapemphigus caused by sulfasalazine, taste loss due to terbinafine en intracranial bleeding after use of tranylcypromine and beer. Pharmacoepidemiological studies were performed concerning methods for record linkage, the communication process with respect to the acitretin alert and the adverse events due to sumatriptan.

[Local and generalized skin reactions in the use of nicotine patches]. / Lokale en gegeneraliseerde huidafwijkingen bij gebruik van nicotinepleisters.

Nicotine-containing patches are prescribed to facilitate tobacco withdrawal by mitigating abstinence symptoms and diminishing craving. In clinical trials local skin reactions were often recorded as a reaction to the patches. Systemic skin reactions were described, but only rarely. The Netherlands Centre for Monitoring of Adverse Reactions to Drugs received II reports of local and 5 reports of systemic skin reactions to nicotine patches during the period January 1993 until April 1994. Skin reactions usually occur after about 15 days' use and local reactions tend to become worse when treatment is continued. The mechanism of the reaction and the part of the patch to which the skin reacts are still unclear.