Circulating n-3 fatty acids and linoleic acid as indicators of dietary fatty acid intake in post-myocardial infarction patients.

BACKGROUND AND AIMS: Population-based studies often use plasma fatty acids (FAs) as objective indicators of FA intake, especially for n-3 FA and linoleic acid (LA). The relation between dietary and circulating FA in cardiometabolic patients is largely unknown. We examined whether dietary n-3 FA and LA were reflected in plasma lipid pools in post-myocardial infarction (MI) patients. METHODS AND RESULTS: Patients in Alpha Omega Cohort filled out a 203-item food-frequency questionnaire from which eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and LA intake were calculated. Circulating individual FA (% total FA) were assessed in cholesteryl esters (CE; n = 4066), phospholipids (PL; n = 838), and additionally in total plasma for DHA and LA (n = 739). Spearman correlation coefficients (rs) were calculated for dietary vs. circulating FA. Circulating FA were also compared across dietary FA quintiles, overall and in subgroups by sex, obesity, diabetes, statin use, and high alcohol intake. Patients were on average 69 years old and 79% was male. Moderate correlations between dietary and circulating levels were observed for EPA (rs∼0.4 in CE and PL) and DHA (rs ∼0.5 in CE and PL, ∼0.4 in total plasma), but not for ALA (rs ∼0.0). Weak correlations were observed for LA (rs 0.1 to 0.2). Plasma LA was significantly lower in statin users and in patients with a high alcohol intake. CONCLUSIONS: In post-MI patients, dietary EPA and DHA were well reflected in circulating levels. This was not the case for LA, which may partly be influenced by alcohol use and statins.

A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes.

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 µg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

The 2015 Dutch food-based dietary guidelines.

The objective of this study was to derive food-based dietary guidelines for the Dutch population. The dietary guidelines are based on 29 systematic reviews of English language meta-analyses in PubMed summarizing randomized controlled trials and prospective cohort studies on nutrients, foods and food patterns and the risk of 10 major chronic diseases: coronary heart disease, stroke, heart failure, diabetes, breast cancer, colorectal cancer, lung cancer, chronic obstructive pulmonary disease, dementia and depression. The committee also selected three causal risk factors for cardiovascular diseases or diabetes: systolic blood pressure, low-density lipoprotein cholesterol and body weight. Findings were categorized as strong or weak evidence, inconsistent effects, too little evidence or effect unlikely for experimental and observational data separately. Next, the committee selected only findings with a strong level of evidence for deriving the guidelines. Convincing evidence was based on strong evidence from the experimental data either or not in combination with strong evidence from prospective cohort studies. Plausible evidence was based on strong evidence from prospective cohort studies only. A general guideline to eat a more plant food-based dietary pattern and limit consumption of animal-based food and 15 specific guidelines have been formulated. There are 10 new guidelines on legumes, nuts, meat, dairy produce, cereal products, fats and oils, tea, coffee and sugar-containing beverages. Three guidelines on vegetables, fruits, fish and alcoholic beverages have been sharpened, and the 2006 guideline on salt stayed the same. A separate guideline has been formulated on nutrient supplements. Completely food-based dietary guidelines can be derived in a systematic and transparent way.

Testicular microlithiasis in acquired undescended testis after orchidopexy at diagnosis.

The aim of this study was to observe the prevalence of testicular microlithiasis (TM) in surgically corrected acquired undescended testis (UDT). The prevalence of TM was assessed by ultrasound. Boys and young men who had undergone orchidopexy (ORP) for acquired UDT in mid or late childhood were observed to study the long-term testicular volume. During this examination, the presence or absence of TM was also assessed. TM was defined as echogenic foci without shadowing within the testis parenchyma. We included 106 patients who had undergone ORP at the Medical Center Alkmaar (1986-1999) and 155 patients who had undergone ORP at the Juliana Children's Hospital (1996-2009). The majority of patients were white, Caucasian (82%). The median age at follow-up, 25.8 years (range 14.0-31.6 years) was higher in Medical Center Alkmaar than in Juliana Children's Hospital 13.4 years (range 5.1-26.6 years). From 2009 to 2011, these 261 patients (median age 18.9 years) underwent an ultrasound examination. Median follow-up after ORP was 11.3 years (range 1.4-23.5 years); age at ORP ranged from 2.1 to 16.2 years, with a median of 8.5 years. TM was found in 17 (6.5%) patients (median age at follow-up 20.4 years; range 11-28). No significant association was found with the incidence of TM and the operated testis, the age at ORP or the racial variance (p > 0.05). ORP at diagnosis for acquired UDT is associated with a 6.5% prevalence of TM in boys and young adults.

N-6 and n-3 fatty acid cholesteryl esters in relation to incident stroke in a Dutch adult population: a nested case-control study.

BACKGROUND AND AIMS: There are few prospective studies on fatty acid status in relation to incident stroke, with inconsistent results. We assessed the associations of plasma n-6 and n-3 PUFA in cholesteryl esters with the risk of total stroke and stroke subtypes in Dutch adults. METHODS AND RESULTS: We conducted a nested case-control study using data from a population-based cohort study in adults aged 20-65 years. Blood sampling and data collection took place during 1993-1997 and subjects were followed for 8-13 years. We identified 179 incident cases of stroke and 179 randomly selected controls, matched on age, gender, and enrollment date. Odds ratios (OR) with 95% confidence intervals (95%CI) were calculated per standard deviation (SD) increase of PUFA in cholesteryl esters using multivariable conditional logistic regression. Cases comprised 93 ischemic, 50 hemorrhagic, and 36 unspecified strokes. The n-6 PUFA linoleic acid and arachidonic acid contributed ~55% and ~6.5% respectively to total plasma fatty acids, whereas the n-3 PUFA alpha-linolenic acid contributed ~0.5% and eicosapentaenoic acid plus docosahexaenoic acid (EPA-DHA) ~1.3%. After adjustment for confounders, n-6 and n-3 PUFA were not associated with incident total stroke or stroke subtypes. The OR (95% CI) for total stroke was 0.95 (0.74-1.23) per SD increase in linoleic acid and 1.02 (0.80-1.30) per SD increase in arachidonic acid. ORs (95% CI) for total stroke were 0.94 (0.72-1.21) for alpha-linolenic acid and 1.16 (0.94-1.45) for EPA-DHA. CONCLUSION: In the present study, plasma n-6 or n-3 fatty acids were not related to incident stroke or stroke subtypes.

[Anemia in the elderly]. / Anämie im Alter: Wen, wie, warum abklären?

Anemia is common in the elderly and its impact on various important health outcomes has recently been clearly demonstrated. Although a causal relationship has not yet been demonstrated, adequate diagnosis and treatment are important. Because of ongoing changes in demographics an increasing number of anemic elderly patients is to be expected. Despite this, many issues regarding the aetiology and the management of anemia in older persons remain unresolved. The present review will focus on aspects specific to the causes of anemia in the elderly and suggests an algorithm for the management of this very common condition. Clearly evidence based guidelines on anemia in this highest age group need to be developed. Treatment options for patients with myelodysplastic syndromes are also discussed.

No effects of n-3 fatty acid supplementation on serum total testosterone levels in older men: the Alpha Omega Trial.

The intake of the n-3 fatty acids alpha-linolenic acid (ALA), acid (EPA) and docosahexaenoic acid (DHA) has been related to testosterone levels in epidemiological analyses. The aim of this study was to assess whether the n-3 fatty acids affects testosterone levels in post-myocardial infarction (MI) patients, who are at risk of testosterone deficiency. In a double-blind, placebo-controlled trial of low-dose supplementation of n-3 fatty acids, we included 1850 male post-MI patients aged 60-80 years who participated in the Alpha Omega Trial. Patients were randomly allocated to margarines that provided 400 mg/day of EPA-DHA (n = 453), 2 mg/day of ALA (n = 467), EPA-DHA plus ALA (n = 458), or placebo (n = 472). Serum testosterone levels were assessed at baseline and after 41 months using whole day blood samples obtained at the subjects' home or at the hospital. Subjects were on average age of 68.4 (SD 5.3) years old and had baseline mean serum total testosterone of 14.8 (SD 5.6) nmol/L. The four randomized groups did not differ for baseline characteristics. ALA, EPA-DHA, and EPA-DHA plus ALA supplementation did not affect serum total testosterone compared to placebo. Moreover, n-3 fatty acid supplementation did not affect the risk of incident testosterone deficiency (n = 76 with total testosterone <8.0 nmol/L). We conclude that n-3 fatty acids supplementation did not affect serum total testosterone in men who had had a MI.

Levels and trends in cardiovascular risk factors and drug treatment in 4837 elderly Dutch myocardial infarction patients between 2002 and 2006.

BACKGROUND: It is important to gain insight into opportunities for secondary prevention of cardiovascular disease. Our aim was to investigate levels and trends in cardiovascular risk factors and drug treatment in Dutch post-myocardial infarction (MI) patients between 2002 and 2006 and to make comparisons with the EUROASPIRE surveys (1999-2007). METHODS: We analysed data from 4837 post-MI patients (aged 69 years, 78% men) from 32 Dutch hospitals, using baseline cross-sectional data from the Alpha Omega Trial. RESULTS: Between 2002 and 2006, significant declines were found in the prevalence of smoking (23% to 16%, p < 0.001), hypercholesterolaemia (≥5 mmol/l; 54% to 27%, p < 0.0001) and hypertension (≥140/90 mmHg; 58% to 48%, p < 0.001). The prevalence of antithrombotic drugs was high (97%). The prevalence of lipid-modifying drugs and antihypertensives was high, and increased (74% to 90%, p < 0.0001 and 82% to 93%, p < 0.001, respectively). The prevalence of obesity (27%) was high in 2002 and decreased to 24% in 2006, albeit not significantly. Diabetes prevalence was high and increased between 2002 and 2006 (18% to 22%, p = 0.02). In comparison with EUROASPIRE patients, who were on average 8-10 years younger, our study in 2006 included patients with lower levels of obesity, hypertension, hypercholesterolaemia, diabetes and lower use of antiplatelets and ß-blockers, but similar levels of lipid-modifying drugs. CONCLUSIONS: This study showed that older Dutch post-MI patients were adequately treated with drugs, and that risk factors reached lower levels than in the younger EUROASPIRE patients. However, there is room for improvement in diet and lifestyle, given the high prevalence of smoking, obesity, and diabetes.

Clinical aspects of testicular microlithiasis in boys: a review.

OBJECTIVE: After review of the pediatric literature, we report on the prevalence of testicular microlithiasis and its relation with benign and malign entities. We provide a guideline for the management of boys with testicular microlithiasis. MATERIALS AND METHODS: The databases searched were Medline, Web of Science, Embase and the Cochrane Library. Data on the rates of testicular microlithiasis were collected and from each study information was extracted on the study population according to country, study design, diagnostic method, type of patient, number of patients, age, associated anomalies, additional diagnostic methods and follow-up information. From the 472 articles, we selected 126 articles as potentially relevant, of which 57 were included. RESULTS: In asymptomatic boys, the prevalence of testicular microlithiasis is 4.2% and in symptomatic referrals it is 1.6%. The development of a testicular malignancy is occasionally reported after diagnosis of testicular microlithiasis. The management of boys with testicular microlithiasis varies widely. Most authors recommend regular self-examination, and some perform testicular ultrasound and/or screen tumor markers. CONCLUSION: The prevalence of testicular microlithiasis in boys varies between 1.1% and 4.2%. For follow-up, regular self-examination is advised from the age of 15 years.

Acquired undescended testis: putting the pieces together.

Acquired undescended testis is now a well-recognized disorder. It is seen in 1.5% of pre-pubertal boys and accounts for the 1-2% orchidopexy rate in older boys. Its pathogenesis remains largely unclear, but it may be caused by a fibrous remnant of the processus vaginalis. There is much controversy over its management, and the proper management awaits a randomized-controlled trial. Until now, follow-up data are available only for cases of spontaneous descent or pubertal orchidopexy. It is speculated that acquired undescended testis is in fact congenital and because of a short funiculus at birth, allowing a low-scrotal position early in life. However, as the boy grows, the testis might evolve into an undescended state. When testosterone surges at puberty, spontaneous descent occurs in three of every four cases.

The volume of retractile testes.

PURPOSE: We used ultrasound to determine the volume of retractile testes in boys and compared these volumes with normative testicular volume values. MATERIALS AND METHODS: A total of 171 boys were enrolled in the study, of whom 14 were excluded from analysis. The 157 boys included (age 0.8 to 11.5 years) were recruited from 2 different populations. The first subgroup comprised 92 boys previously excluded from a study aimed at obtaining normative values of ultrasonographically scanned testes. The second group included 65 boys who had been referred to our outpatient clinic for nonscrotal testis and who were diagnosed with retractile testis. Testicular volume was measured by ultrasound in a scrotal position or in an inguinal position. Three separate transverse and longitudinal images of each testis were recorded. Length, width and height were measured, and the volume was calculated with the formula for an ellipsoid, π/6 × length × width × height. The highest value of the 3 testicular volumes was determined and taken as the volume measurement. RESULTS: The volumes measured by ultrasound for the 157 boys with 276 retractile testes ranged from 0.18 to 1.49 ml (mean 0.50). The volumes of the retractile testes were significantly smaller than normative values (p <0.001). Furthermore, the testicular volumes of retractile testes measured in an inguinal position were significantly smaller than those measured in a scrotal position (p <0.001). CONCLUSIONS: The volumes of retractile testes are significantly smaller than recently determined normative values.

Normative values for testicular volume measured by ultrasonography in a normal population from infancy to adolescence.

BACKGROUND/AIMS: We obtained reference data for testicular volume measured by ultrasound in asymptomatic boys aged 0.5-18 years. In addition, we assessed the validity of the Prader orchidometer per age group by correlating it with the volume measurement by ultrasound. METHODS: The study only included healthy boys with two scrotal testes at birth and at the time of the examination. For each boy the testicular volume of both testes was measured by ultrasound and the Prader orchidometer. Testicular volumes were measured for boys aged from 1 to 18 years. The boys' ages were rounded down to the last birthday if it had occurred less than 6 months previously or rounded up to the next birthday if it was going to be within 6 months. RESULTS: The volume measurement by the Prader orchidometer according to reference curves showed a statistically significant correlation. Moreover, the testicular volumes measured by the Prader orchidometer showed an accurate goodness of fit with US measurements (R(2) = 0.956). CONCLUSION: Normative values are provided for testicular volume measured by ultrasound in boys aged 0.5-18 years. An accurate correlation was found between volume measurements by ultrasound and by the Prader orchidometer (R(2) = 0.956). Therefore, volume measurement by the Prader orchidometer, as generally used in the practice by doctors, can be used as a valid parameter for monitoring testicular growth.

Prevalence of testicular microlithiasis in asymptomatic males 0 to 19 years old.

PURPOSE: We assessed the prevalence of testicular microlithiasis via ultrasound in asymptomatic males 0 to 19 years old. MATERIALS AND METHODS: We studied only patients with 2 scrotal testes at birth and at examination. We excluded boys with a history of undescended testis, hydrocele, varicocele and syndromes associated with testicular microlithiasis. To assess for testicular microlithiasis, we scanned the scrotum ultrasonographically by recording transverse and longitudinal images of each testis. Classic testicular microlithiasis was defined as 5 or more echogenic foci in either or both testes. Boys with fewer than 5 microliths (but with at least 1) were deemed to have limited testicular microlithiasis. RESULTS: We examined 694 asymptomatic boys between October 2007 and July 2008, of whom 670 participated in the study. Classic testicular microlithiasis was present in 16 boys (2.4%) and limited testicular microlithiasis in 12 (1.8%), yielding a total prevalence of 4.2%. Classic testicular microlithiasis was found in 1 patient younger than 6 years, 8 boys 6 to 12 years old and 7 boys older than 12 years. There was a significant difference in prevalence among the 3 age groups (p = 0.032). Testicular malignancies were not found in any patient. Of the 24 boys excluded from the study testicular microlithiasis was seen in 4. CONCLUSIONS: The prevalence of classic testicular microlithiasis in asymptomatic boys is 2.4% and increases with age.

Erythrocyte storage in hypertonic (SAGM) or isotonic (PAGGSM) conservation medium: influence on cell properties.

BACKGROUND AND OBJECTIVES: Prolonged red blood cell (RBC) storage may be associated with increased post-transfusion morbidity and mortality. A contributing factor is RBC storage lesions. We analysed the role of additive conservation solutions, either hypertonic or isotonic, on such cell properties. MATERIALS AND METHODS: After blood donation in citrate-phosphate-dextrose as an anticoagulant, 10 RBC units were stored with saline-adenine-glucose-mannitol (SAGM; 376 mOsm/l) and 10 units with phosphate-adenine-glucose-guanosin-saline-mannitol (PAGGSM; 285 mOsm/l). Measurements were made on days 1 and 42 of storage. RESULTS: The mean cellular volume measured by centrifuged microhaematocrit increased from 87.6 +/- 3.1 fl to 100.7 +/- 4.3 fl in PAGGSM and to 92.2 +/- 2.5 fl in SAGM (P < 0.001) on day 1, after 42 days it was 95.8 +/- 4.0 fl and 93.8 +/- 3.9 fl, respectively. Spontaneous haemolysis and osmotic fragility were lower after storage in PAGGSM. Both additives showed a similar degree of echinocytosis, decreased RBC aggregability and deformability, and increased RBC suspension viscosity after storage. CONCLUSIONS: The isotonic PAGGSM prevented the initial RBC swelling caused by citrate-phosphate-dextrose less than hypertonic SAGM, but reduced the spontaneous haemolysis rate and osmotic fragility after 42 days of storage. All other parameters, such as echinocytosis, decreased RBC deformability and aggregability, and increased blood viscosity was similar for both additive solutions and remained a major problem of blood banking.

Air classifier technology (ACT) in dry powder inhalation Part 4. Performance of air classifier technology in the Novolizer multi-dose dry powder inhaler.

In this study, the in vitro fine particle deposition from a multi dose dry powder inhaler (Novolizer) with air classifier technology has been investigated. It is shown that different target values for the fine particle fraction (fpf<5 microm) of the same drug can be achieved in a well-controlled way. This is particularly relevant to the application of generic formulations in the inhaler. The well-controlled and predictable fpf is achieved through dispersion of different types of formulations in exactly the same classifier concept. On the other hand, it is shown that air classifier-based inhalers are less sensitive to the carrier surface and bulk properties than competitive inhalers like the Diskus. For 10 randomly selected lactose carriers for inhalation from four different suppliers, the budesonide fpf (at 4 kPa) from the Novolizer varied between 30 and 46% (of the measured dose; R.S.D.=14.2%), whereas the extremes in fpf from the Diskus dpi were 7 and 44% (R.S.D.=56.2%) for the same formulations. The fpf from a classifier-based inhaler appears to be less dependent of the amount of lactose (carrier) fines (<15 microm) in the mixture too. Classifier-based inhalers perform best with coarse carriers that have relatively wide size distributions (e.g. 50-350 microm) and surface discontinuities inside which drug particles can find shelter from press-on forces during mixing. Coarse carrier fractions have good flow properties, which increases the dose measuring accuracy and reproducibility. The fpf from the Novolizer increases with increasing pressure drop across the device. On theoretical grounds, it can be argued that this yields a more reproducible therapy, because it compensates for a shift in deposition to larger airways when the flow rate is increased. Support for this reasoning based on lung deposition modelling studies has been found in a scintigraphic study with the Novolizer. Finally, it is shown that this inhaler produces a finer aerosol than competitor devices, within the fpf<5 microm, subfractions of particles (e.g. <1, 1-2, 2-3, 3-4 and 4-5 microm) are higher.

Air classifier technology (ACT) in dry powder inhalation Part 3. Design and development of an air classifier family for the Novolizer multi-dose dry powder inhaler.

In this study, the design of a multifarious classifier family for different applications is described. The main design and development steps are presented as well as some special techniques that have been applied to achieve preset objectives. It is shown by increasing the number of air supply channels to the classifier chamber (from 2 to 8), that the fine particle losses from adhesion onto the classifier walls can be reduced from 75% to less than 5% of the real dose for soft (spherical) agglomerates. By applying a bypass flow that is arranged as a co-axial sheath of clean air around the aerosol cloud from the classifier, the airflow resistance of the classifier can be controlled over a relatively wide range of values (0.023-0.041 kPa(0.5) min l(-1)). This, without affecting the fine particle dose or increasing the fine particle losses in the inhaler. Moreover, the sheath flow can be modelled to reduce the depositions in the induction port to the cascade impactor or in the patient's mouth, which are the result of back flows in these regions. The principle of powder induced pressure drop reduction across a classifier enables assessment of the amount of powder in the classifier at any moment during inhalation, from which classifier loading (from the dose system) and discharge rates can be derived. This principle has been applied to study the residence time of a dose in the classifier as function of the carrier size fraction and the flow rate. It has been found that this residence time can be controlled in order to obtain an optimal balance between the generated fine particle fraction and the inhalation manoeuvre of the patient. A residence time between 0.5 and 2 s at 60 l/min is considered favourable, as this yields a high fine particle dose (depending on the type of formulation used) and leaves sufficient inhaled volume for particle transport into the deep lung.

A critical evaluation of the relevant parameters for drug redispersion from adhesive mixtures during inhalation.

In this paper, the parameters that are relevant to the drug redispersion from adhesive mixtures during inhalation are discussed and evaluated. The results obtained with air classifier technology give strong evidence for a dominating influence of carrier surface properties on the fraction of drug detached during inhalation at a low carrier payload (< or =1%, w/w), versus a dominating effect of carrier bulk properties at higher payloads. Furthermore, the results indicate that there is a fundamental difference between so-called active carrier sites and large surface discontinuities. The difference refers to the saturation concentrations, the rates of saturation and their effects on drug detachment during inhalation. The degree of saturation of the active sites appears to be proportional with the square root of the carrier surface payload (after 10 min mixing time in a Turbula mixer at 90 rpm). The storage volume of the discontinuities seems largely independent of the carrier diameter for particles derived from the same batch of crystalline lactose. Saturation of these discontinuities is completed at a much lower carrier surface payload than saturation of the active sites. Relatively large discontinuities are beneficial to de-agglomeration principles that make use of inertial separation forces during inhalation, as they provide shelter from inertial and frictional press-on forces during mixing which increase the strength of the interparticulate bonds in the powder mixture. For de-agglomeration principles generating frictional, drag or lift forces, carrier surface depressions and projections are disadvantageous however, as they also provide shelter from these removal forces.

Pulmonary delivery of therapeutic peptides via dry powder inhalation: effects of micronisation and manufacturing.

Pulmonary drug delivery is increasingly appreciated as a route of administration for systemically acting proteins and peptides. A respirable particle size of the drug is a key requirement, but the fragile nature of many proteins may be a limitation for the application of conventional production processes. The aim of this study was to examine the effect of different micronisation processes on the degradation and aerodynamic properties of the GnRH-antagonist cetrorelix in order to enable its application by a dry powder inhaler (Novolizer). A modified pearl mill was used for milling in fluid propellant. Furthermore, a spray drying procedure was established using a novel process of atomisation and drying. Adhesive mixtures of lactose and 5-20% of micronised cetrorelix-acetate were prepared. Analysis by laser light scattering, HPLC, Karl Fischer, cascade impactor and scanning electron microscopy were performed to characterise the manufactured powders. Both micronisation procedures succeeded in producing small range particle size distributions, suitable for deep lung deposition (D50 = 1.6 microm for milling and 3.3 microm for spray drying). The pearl milled cetrorelix showed promising results when delivered by the Novolizer: a reproducible and highly efficient dispersion of the drug was achieved (around 60% of aerosolised drug < 5 microm). The spray dried drug was not suitable when processed as adhesive mixture.

The value of white blood cell count in patients with swollen discs.

BACKGROUND: A broad differential diagnosis has to be considered in a patient with swollen discs. Myeloproliferative disorders such as leukemia and lymphoma can in rare cases cause infiltrative optic neuropathy. HISTORY AND SIGNS: Two patients initially presented with slowly progressive severe visual loss. History was unremarkable except for previously noted slightly elevated white blood cell count for which - according to their general physicians - no treatment or work-up was required. At presentation, bilateral disc swelling was present. Magnetic resonance imaging showed enhancement of the entire optic nerves sparing the chiasm. No other intracranial lesion was found. Cerebrospinal fluid contained no malignant cells. THERAPY AND OUTCOME: After bone marrow aspiration the diagnosis of non-Hodgkin's lymphoma and granulocytic leukemia, respectively, was made. Treatment resulted in visual recovery. CONCLUSION: Work-up in a patient with swollen discs should always include white blood cell count. If the result is abnormal further exploration should be pursued. Elevated white blood cell count may be the only hint of optic nerve infiltration caused by a myeloproliferative disorder and its treatment can result in remarkable recovery.