Bone microarchitecture and strength assessment in adults with osteogenesis imperfecta using HR-pQCT: normative comparison and challenges.

Data on bone microarchitecture in osteogenesis imperfecta (OI) are scarce. The aim of this cross-sectional study was to assess bone microarchitecture and strength in a large cohort of adults with OI using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to evaluate challenges of using HR-pQCT in this cohort. Second-generation HR-pQCT scans were obtained at the distal radius and tibia in 118 men and women with Sillence OI type I, III, or IV using an extremity-length-dependent scan protocol. In total, 102 radius and 105 tibia scans of sufficient quality could be obtained, of which 11 radius scans (11%) and 14 tibia scans (13%) had a deviated axial scan angle as compared with axial angle data of 13 young women. In the scans without a deviated axial angle and compared with normative HR-pQCT data, Z-scores at the radius for trabecular bone mineral density (BMD), number, and separation were -1.6 ± 1.3, -2.5 ± 1.4, and -2.7 (IQR: 2.7), respectively. They were -1.4 ± 1.5 and -1.1 ± 1.2 for stiffness and failure load and between ±1 for trabecular thickness and cortical bone parameters. Z-scores were significantly lower for total and trabecular BMD, stiffness, failure load, and cortical area and thickness at the tibia. Additionally, local microarchitectural inhomogeneities were observed, most pronounced being trabecular void volumes. In the scans with a deviated axial angle, the proportion of Z-scores <-4 or >4 was significantly higher for trabecular BMD and separation (radius) or most total and trabecular bone parameters (tibia). To conclude, especially trabecular bone microarchitecture and bone strength were impaired in adults with OI. HR-pQCT may be used without challenges in most adults with OI, but approximately 12% of the scans may have a deviated axial angle in OI due to bone deformities or scan positioning limitations. Furthermore, standard HR-pQCT parameters may not always be reliable due to microarchitectural inhomogeneities nor fully reflect all inhomogeneities.

OI is a rare condition with large clinical heterogeneity. One of the major characteristics associated with OI is the increased fracture risk due to defects in bone structure and material. Data on the defects in bone structure at the micrometer level (i.e. bone microarchitecture) are scarce. Bone microarchitecture can be assessed noninvasively using HR-pQCT, but its use in OI has not extensively been described. Yet, potential challenges may arise related to among others the occurrence of short extremities and skeletal deformities in OI. We assessed bone microarchitecture and strength in 118 adults with OI types I, III, or IV using HR-pQCT with an extremity-length-dependent scan protocol. Additionally, we evaluated potential challenges of using HR-pQCT in this cohort. Our results demonstrated that predominantly trabecular microarchitecture­especially trabecular number and separation­and overall bone strength were impaired in adults with OI as compared with normative data. Furthermore, we observed various microarchitectural inhomogeneities, most pronounced being trabecular void volumes. Regarding applicability, HR-pQCT could be used without challenges in most adults with OI. However, deviations in scan region may potentially influence HR-pQCT parameters, and standard HR-pQCT analyses may not always give accurate results due to microarchitectural inhomogeneities nor fully reflect all microarchitectural inhomogeneities.

Intraperitoneal versus subcutaneous insulin therapy in the treatment of type 1 diabetes mellitus.

BACKGROUND: Continuous intraperitoneal insulin infusion (CIPII), a last-resort type 1 diabetes mellitus (T1DM) treatment, has only been investigated in small or controlled studies. We aimed to investigate glycaemia and quality of life (QoL) with CIPII versus subcutaneous (SC) insulin therapy during usual T1DM care. METHODS: A prospective, observational case-control study. CIPII-treated cases were matched to SC controls. The primary endpoint was a non-inferiority assessment (pre-defined margin of -5.5 mmol÷mol) of the baseline adjusted difference in HbA1c between groups during a 26-week follow-up. Secondary outcomes included QoL, clinical and biochemical measurements. RESULTS: In total, 183 patients were analysed (CIPII n = 39 and SC n = 144). The HbA1c difference between treatment groups was -3.0 mmol÷mol (95% CI -5.0, -1.0), being lower in the SC group. Patients using SC insulin therapy spent less percentage of time in hyperglycaemia (-9.3% (95% CI -15.8, -2.8)) and more in euglycaemia (6.9% (95% CI 1.2, 12.5) as compared with CIPII-treated patients. Besides a 3.6 U÷l (95% CI 1.2, 6.0) lower concentration of alanine aminotransferase with CIPII, no biochemical and clinical differences were present. Most QoL scores were lower at baseline among CIPII-treated patients. However, besides lower health status, there were no differences in the baseline-adjusted general and diabetes-specific QoL and treatment satisfaction. CONCLUSION: Although patients using CIPII had a higher glycaemic profile compared with patients using SC insulin therapy, the HbA1c difference was non-inferior. Overall, health status was lower among CIPII-treated patients, although diabetes-specific QoL and treatment satisfaction was similar to subcutaneously treated patients.

Er(3+)/Yb(3+) upconverters for InGaP solar cells under concentrated broadband illumination.

The inability of solar cell materials to convert all incident photon energy into electrical current, provides a fundamental limit to the solar cell efficiency; the so called Shockley-Queisser (SQ) limit. A process termed upconversion provides a pathway to convert otherwise unabsorbed low energy photons passing through the solar cell into higher energy photons, which subsequently can be redirected back to the solar cell. The combination of a semi-transparent InGaP solar cell with lanthanide upconverters, consisting of ytterbium and erbium ions doped in three different host materials (Gd2O2S, Y2O3 and NaYF4) is investigated. Using sub-band gap light of wavelength range 890 nm to 1045 nm with a total accumulated power density of 2.7 kW m(-2), a distinct photocurrent was measured in the solar cell when the upconverters were applied whereas a zero current was measured without upconverter. Furthermore, a time delay between excitation and emission was observed for all upconverter systems which can be explained by energy transfer upconversion. Also, a quadratic dependence on the illumination intensity was observed for the NaYF4 and Y2O3 host material upconverters. The Gd2O2S host material upconverter deviated from the quadratic illumination intensity dependence towards linear behaviour, which can be attributed to saturation effects occurring at higher illumination power densities.

Long-term patient satisfaction after reconstructive upper extremity surgery to improve arm-hand function in tetraplegia.

STUDY DESIGN: There is a paucity of literature about satisfaction after reconstructive surgery to improve upper limb function in persons with tetraplegia. The present literature describes mainly functional outcomes. OBJECTIVES: To evaluate long-term satisfaction after reconstructive upper extremity surgery in persons with tetraplegia. SETTING: Two rehabilitation centers in the Netherlands. METHOD: A three-part questionnaire consisting questions regarding satisfaction, activities, occupation, changes in functional ability and willingness to undergo the surgeries again was used. Internal reliability of the questionnaire was verified by factor analysis and calculation of Cronbach's alpha. RESULTS: In total, 39 out of 55 persons (70.9%) participated in the study. The participants' responses to questions about satisfaction, activities and occupation were positive in 73.5, 67.6 and 35.0%, respectively. Nearly 81% improved their functional ability. Approximately 65% of the participants were willing to undergo elbow extension surgery again and 77.1% expressed their willingness to undergo hand/wrist surgery again. Significant positive correlation was found between willingness to have surgery again and improvement in activities and occupation: Spearman's correlation coefficients: activities-elbow extension 0.63 (P=0.003), activities-hand/wrist 0.57 (P<0.001), occupation-elbow extension 0.53 (P=0.025), occupation-hand/wrist 0.57 (P=0.001). Differences between the subgroups who would have surgery again and those who would refrain were also significant; one-way analysis of variance for activities (F=9.54, P<0.01) and for occupation (F=6.60, P<0.02). CONCLUSION: In the Netherlands, the majority of persons with tetraplegia who underwent reconstructive upper extremity surgery were satisfied with the results. This was related to improvement in activities and occupation.

Drug-induced hepatitis in an acromegalic patient during combined treatment with pegvisomant and octreotide long-acting repeatable attributed to the use of pegvisomant.

We report on a patient with acromegaly who developed severe drug-induced hepatitis during combined treatment with the long-acting somatostatin-analog octreotide and the GH receptor antagonist pegvisomant. The hepatic enzyme disturbances normalized after discontinuation of pegvisomant. After rechallenge with monotherapy pegvisomant, however, the hepatic enzyme disturbances reappeared within a few weeks, indicating that most likely pegvisomant alone and not the long-acting somatostatin analog or the combination of these two drugs was responsible for this case of drug-induced hepatitis. Clinicians should be aware of this potential severe adverse drug reaction and therefore frequent control of hepatic enzymes is mandatory during treatment with pegvisomant.

Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly.

Pegvisomant monotherapy once daily returns concentrations of insulin-like growth factor I (IGF-I) to normal in most patients with acromegaly, but is very costly. In a 42-week dose-finding study, we assessed the efficacy of the combination of long-acting somatostatin analogues once monthly and pegvisomant once weekly in 26 patients with active acromegaly. Dose of pegvisomant was increased until IGF-I concentration became normal or until a weekly dose of 80 mg was reached. IGF-I reached normal concentrations in 18 of 19 (95%) patients who completed 42 weeks of treatment, with a median weekly dose of 60 mg pegvisomant (range 40-80). No signs of pituitary tumour growth were noted, but mild increases in liver enzymes were observed in ten patients (38%). This combined treatment is effective, might increase compliance, and could greatly reduce the costs of medical treatment for acromegaly in some patients.

Developmental outcome at 18 and 24 months of age in very preterm children: a cohort study from 1996 to 1997.

OBJECTIVE: To determine the effect of prematurity (gestational age (GA) < 32 weeks) on developmental outcome at the corrected age of 18 and 24 months in a regionally defined, prospective cohort study. STUDY DESIGN: The Leiden Follow-Up Project on Prematurity (LFUPP) includes all live-born infants < 32 weeks GA, born in 1996/1997 in three Dutch health regions (n=266). Mental and psychomotor developmental indices (MDI, PDI) were determined with the Bayley Scales of Infant Development I: > or = -1 S.D.: normal, -2 to -1 S.D.: moderate delay and < -2 S.D.: severe delay. RESULTS: At 18 months 168 (71%) and at 24 months, 151 children (64%) of 235 survivors were assessed. Moderate to severely delayed mental and/or psychomotor development occurred in 40% of the children at both ages. Children lost to follow-up were of lower socioeconomic status and more frequently of non-Dutch origin. Since non-Dutch origin negatively affected the outcome at both test ages, availability of the data of these children would probably have worsened the outcome. Postnatal treatment with dexamethasone was associated with an increased risk of delayed development. Other independent predictors of delayed development were bronchopulmonary dysplasia at 18 months and ethnicity, maternal age at birth, birthweight and gender at 24 months. After adjustment for these other predictors of delayed development, the mean PDI of dexamethasone-treated infants was 16.1 points lower than of non-treated infants at 18 months (p=0.03) and 12.7 points lower at 24 months (p=0.04). CONCLUSIONS: At 18 and 24 months corrected age, 40% of the very prematurely born children had both delayed mental and/or psychomotor development. Treatment with dexamethasone postnatally was a major risk factor for delayed (psychomotor) development.

[Drug-induced heart failure]. / Hartfalen door geneesmiddelen.

Although heart failure is predominantly caused by cardiovascular disorders, several classes of drugs may induce heart failure in patients with pre-existing normal left ventricular function or may precipitate the occurrence of heart failure in patients with left ventricular impairment. These drugs are predominantly those belonging to the categories of cytostatics, anti-arrhythmics, beta-blockers, nonsteroidal anti-inflammatory drugs, calcium channel blockers and anaesthetics. Drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes therapeutic alternatives are scarce (e.g. anthracycline-induced cardiomyopathy). Awareness of the possibility of adverse effects on cardiac performance by several classes of drugs, particularly in patients with pre-existing ventricular impairment, may contribute to prevention or timely diagnosis and treatment of drug-induced heart failure.

Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998.

OBJECTIVE: Fluoroquinolone antibiotics have been associated with tendinitis and tendon rupture. In this paper we report on the followup of 42 spontaneous reports of fluoroquinolone-associated tendon disorders. METHODS: This study is based on cases of fluoroquinolone-associated tendon disorders reported to the Netherlands Pharmacovigilance Foundation Lareb and the Drug Safety Unit of the Inspectorate for Health Care between January 1, 1988, and January 1, 1998. By means of a mailed questionnaire, we collected information on the site of injury, onset of symptoms, treatment, and course of the tendon disorder as well as information on possible risk factors and concomitant medication. RESULTS: Of 50 mailed questionnaires, 42 (84%) were returned. The data concerned 32 patients (76%) with tendinitis and 10 patients (24%) with a tendon rupture. Sixteen cases (38%) were attributed to ofloxacin, 13 (31%) to ciprofloxacin, 8 (19%) to norfloxacin, and 5 (12%) to pefloxacin. There was a male predominance, and the median age of the patients was 68 years. Most of the reports concerned the Achilles tendon, and 24 patients (57%) had bilateral tendinitis. The latency period between the start of treatment and the appearance of the first symptoms ranged from 1 to 510 days with a median of 6 days. Most patients recovered within 2 months after cessation of therapy, but 26% had not yet recovered at followup. CONCLUSION: These reports suggest that fluoroquinolone-associated tendon disorders are more common in patients over 60 years of age. Ofloxacin was implicated most frequently relative to the number of filled prescriptions in the Netherlands.

Mesenteric venous thrombosis attributed to docetaxel.

We present a case of a 57-year-old woman with metastatic breast cancer unresponsive to several chemotherapeutic and hormonal regimens. Because of progressive pulmonary metastases and a painful osteolytic metastasis in the sternum, treatment with docetaxel was initiated. She developed mesenteric venous thrombosis within 1 week after the first dose of docetaxel. Although docetaxel may be regarded as an important advancement in the chemotherapeutic treatment of several cancers, ongoing and future trials must assess its position in the standard chemotherapeutic treatment of cancer. Well-documented adverse reactions, either common or rare, may contribute to a balanced risk-benefit profile of docetaxel.

[The need for 'postmarketing surveillance']. / Noodzaak van 'postmarketing surveillance'.

Postmarketing surveillance of medicines includes two activities: pharmacovigilance and pharmaco-epidemiology. Despite the importance of postmarketing surveillance, too few surveillance studies are performed. The studies carried out by the pharmaceutical industry predominantly consist of 'seeding trials': offering prescribing physicians financial rewards if they prescribe a particular product, thus trying to change the prescription habits. The results of such trials are scientifically worthless. These activities cast a shadow on sincere postmarketing surveillance. A recent nationwide cohort study by the Inspectorate for Health Care on mortality in users of ibopamine demonstrates that Dutch medical doctors and pharmacists are very co-operative if further studying of a particular adverse reaction is warranted.

Drug-induced heart failure.

Heart failure is a clinical syndrome that is predominantly caused by cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce heart failure in patients without concurrent cardiovascular disease or may precipitate the occurrence of heart failure in patients with preexisting left ventricular impairment. We reviewed the literature on drug-induced heart failure, using the MEDLINE database and lateral references. Successively, we discuss the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, antidepressants, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, beta-adrenoceptor blocking agents, anesthetics and some miscellaneous agents. Drug-induced heart failure may play a role in only a minority of the patients presenting with heart failure. Nevertheless, drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes other priorities do not offer therapeutic alternatives (e.g., anthracycline-induced cardiomyopathy). The awareness of clinicians of potential adverse effects on cardiac performance by several classes of drugs, particularly in patients with preexisting ventricular dysfunction, may contribute to timely diagnosis and prevention of drug-induced heart failure.

Heart failure treatments: issues of safety versus issues of quality of life.

Congestive heart failure is an important cause of morbidity and mortality in western countries. The profound impact that congestive heart failure has on life expectancy and quality of life has been a continuous stimulus for the development of new drugs for the treatment of this condition. Despite favourable effects on (aspects of) quality of life in short term studies, several of these new agents have been shown to reduce survival in mortality trials. However, patients with severe congestive heart failure may experience such incapacitating symptoms that the question should be raised as to whether an improvement in quality of life makes the increased risk of mortality associated with these new agents acceptable. Drugs which improve quality of life at the expense of an increased risk of mortality can be of value in the treatment of patients with severe congestive heart failure. However, this is only the case if the probability of improvement in quality of life and prolongation of life expectancy for those using the drug exceeds the probability of improvement in quality of life and prolongation of life expectancy for those not using the drug. Unfortunately, most clinical trials in which both mortality and quality of life are evaluated fail to provide information on this composite probability. Despite disappointing results of some recent mortality trials on new pharmacological treatments of congestive heart failure, sound and well designed clinical trials on innovative heart failure treatments in which these composite probabilities are also assessed should be carried out.

Angioneurotic edema attributed to the use of losartan.

BACKGROUND: Angioedema is a well-known adverse effect of angiotensin-converting enzyme inhibitors. The bradykinin accumulation as a result of the decreased degradation of bradykinin is thought to be the causal mechanism. Angiotensin II antagonists seem to have no effect on the degradation of bradykinin. Therefore, it was expected that angioedema would not occur during treatment with losartan potassium, the first orally active angiotensin II antagonist. METHODS: We reviewed the 13 case reports of angioedema associated with the use of losartan reported to Lareb (Netherlands Pharmacovigilance Foundation, Den Bosch) and to the Drug Safety Unit of the Inspectorate for Health Care, Ryswyh, in the Netherlands since the introduction of losartan in 1995 until May 1997. RESULTS: In all 13 cases, a diagnosis of angioedema attributed to the use of losartan seems to be very plausible. In 7 cases the diagnosis could not be confirmed by a physician because the symptoms had already been resolved, but the signs and symptoms clearly indicated angioedema. The adverse reactions occurred within 24 hours to 16 months after the initiation of losartan therapy. Three patients had previously experienced angioedema during treatment with an angiotensin-converting enzyme inhibitor. Eleven of the patients involved were women and 2 were men. CONCLUSIONS: Our observations strongly suggest that the onset of angioedema was associated with the use of losartan. Physicians and pharmacists should be aware of this potentially life-threatening complication. It may be advisable not to prescribe angiotensin II antagonists to patients with a history of angioedema (of whatever origin).

[Major psychiatric side effects of interferon alpha-2b]. / Ernstige psychiatrische bijwerkingen van interferon alfa-2b.

The Netherlands Pharmacovigilance Foundation Lareb and the Drug Safety Unit of the Inspectorate for Health Care in 1997 received 6 reports of serious psychiatric symptoms during the use of interferon alpha-2b. Of these patients, three men aged 42, 49 and 62 years and three women aged 31, 40 and 33 years, two had had psychic symptoms before. Depression or psychosis developed 12-24 weeks after the start of the use of interferon alpha-2b with 3-10 million IU per week subcutaneously because of chronic hepatitis B or C. After cessation of the medication, four patients recovered after a few days or weeks; the course of one patient was unknown, one patient had committed suicide. Knowledge of these psychiatric adverse drug reactions to interferon alpha-2b can contribute to early recognition by the physician and timely treatment of the symptoms.

Risk factors for mortality in users of ibopamine.

AIMS: In September 1995, the indication for the oral dopamine agonist ibopamine was restricted in the Netherlands and in several other European countries to patients with NYHA-class II heart failure as a result of an interim analysis of the PRIME-II trial. This trial demonstrated an increased risk of mortality in patients with NYHA-class III/IV heart failure on ibopamine. In September 1995, we initiated an assessment of the effects of ibopamine under everyday circumstances in a cohort of users of ibopamine in all NYHA-classes. METHODS: In a nationwide retrospective cohort study all 2147 community pharmacies and drug dispensing general practitioners received a request to list all patients to whom they had dispensed ibopamine in the preceding years. All responding drug dispensing outlets (DDO) received a questionnaire on cardiovascular risk factors and mortality for the general practitioner of a random sample of these patients. DDO were also requested to send an anonymised printout of the complete medication record. On the end-date of follow-up, February 15th 1996, mortality rates were compared across categories of ibopamine use, adjusted for potential confounders. To assess medication use, drug exposure was compared in a 3 months' period before date of death in the deceased, and before a random date in those patients who were still alive. RESULTS: In patients with NYHA-class III/IV heart failure, multivariate analysis indicated that current use of ibopamine was significantly associated with mortality (RR 1.37;95% CI: 1.15-1.64). In patients with NYHA-class I/II heart failure, however, multivariate analysis showed a 2.03 (95% CI: 1.10-3.72) risk of mortality in current users of ibopamine. Apart from current use of ibopamine, male gender and increased serum creatinine were also independent risk factors for mortality in all NYHA-classes. No statistically significant association was found between mortality and current use of amiodarone or use of amiodarone at baseline. CONCLUSIONS: The increased risk of mortality in patients with NYHA-class III and IV heart failure on ibopamine seems to confirm the main finding of the recently published PRIME-II trial. However, our results indicate that also patients with NYHA-class I/II heart failure may be at an increased risk of mortality when using ibopamine. Additional research on the effects of ibopamine in these patients is warranted and the use of ibopamine in NYHA-class II heart failure patients may have to be reconsidered.

[Pill cycle disturbance in simultaneous use of itraconazole and oral contraceptives]. / Verstoring van de pilcyclus tijdens het gelijktijdig gebruik van itraconazol en orale anticonceptiva.

Since the introduction of itraconazole in the Netherlands, the Netherlands Pharmacovigilance Foundation LAREB and the Inspectorate for Health Care received 15 reports of pill cycle disturbances and one of pregnancy occurring during simultaneous use of itraconazole and oral contraceptives. Twelve women used oral contraceptives containing ethinylestradiol and desogestrel. In these women, the withdrawal bleeding was either delayed or did not occur at all; one of these women reported a transiently positive pregnancy test after previous breakthrough bleedings. Three women who used a contraceptive containing ethinylestradiol and levonorgestrel had a breakthrough bleeding. One woman who used an oral contraceptive containing ethinylestradiol and cyproterone acetate became pregnant during the concomitant use of itraconazole. The possible mechanism involved remains to be explained. Although an influence of itraconazole on the reliability of oral contraceptives is uncertain, additional contraceptive measurements might be considered.

[Acute myocardial infarct following sulprostone administration]. / Acuut myocardinfarct na toediening van sulproston.

Because of intrauterine foetal death at 35 weeks, parturition in a woman aged 35 years was induced by intravenous sulprostone. A few hours after its start she sustained a myocardial infarction for which she was treated. Coronary angiography 4 weeks later showed normal coronary arteries and good left ventricular function. Mild cardiovascular reactions such as bradycardia and mild hypotension are frequently observed adverse effects. In some instances, sulprostone can induce myocardial ischaemia. However, the possibility of a myocardial infarction is not mentioned in the product information of sulprostone. As there was an obvious temporal relationship and other causative factors were sufficiently excluded, the causal relation between the administration of sulprostone and the occurrence of myocardial infarction can be regarded as almost certain. Several experimental studies provide support for the hypothesis that coronary spasms play a major role in the pathophysiology of a myocardial infarction during the administration of sulprostone.