LDL cholesterol targets rarely achieved in familial hypercholesterolemia patients: A sex and gender-specific analysis.

BACKGROUND AND AIMS: Despite lipid lowering therapy (LLT), reaching LDL-C targets in patients with familial hypercholesterolemia (FH) remains challenging. Our aim was to determine attainment of LDL-C target levels and reasons for not reaching these in female and male FH patients. METHODS: We performed a cross-sectional study of heterozygous FH patients in five hospitals in the Netherlands and Norway. Clinical characteristics and information about LLT, lipid levels and reasons for not being on LDL-C treatment target were retrospectively collected from electronic medical records. RESULTS: We studied 3178 FH patients (53.9% women), median age 48.0 (IQR 34.0-59.9) years. Median LDL-C before treatment and on-treatment was higher in women compared to men (6.2 (IQR 5.1-7.3) and 6.0 (IQR 4.9-7.2) mmol/l (p=0.005) and 3.0 (IQR 2.4-3.8) and 2.8 (IQR 2.3-3.5) mmol/L (p<0.001)), respectively. A minority of women (26.9%) and men (28.9%) reached LDL-C target. In patients with CVD, 17.2% of women and 25.8% of men reached LDL-C target. Women received less often high-intensity statins and ezetimibe. Most common reported reasons for not achieving the LDL-C target were insufficient effect of maximum LLT (women 17.3%, men 24.3%) and side effects (women 15.2%, men 8.6%). CONCLUSIONS: In routine practice, only a minority of women and men with FH achieved their LDL-C treatment target. Extra efforts have to be made to provide FH patients with reliable information on the safety of statins and their long-term effects on CVD risk reduction. If statin treatment is insufficient, alternative lipid lowering therapies such as ezetimibe or PCSK9-inhibitors should be considered.

Sex-specific temporal evolution of circulating biomarkers in patients with chronic heart failure with reduced ejection fraction.

BACKGROUND: We aimed to assess differences in clinical characteristics, prognosis, and the temporal evolution of circulating biomarkers in male and female patients with HFrEF. METHODS: We included 250 patients (66 women) with chronic heart failure (CHF) between 2011 and 2013 and performed trimonthly blood sampling during a median follow-up of 2.2 years [median (IQR) of 8 (5-10) urine and 9 (5-10) plasma samples per patient]. After completion of follow-up we measured 8 biomarkers. The primary endpoint (PE) was the composite of cardiac death, cardiac transplantation, left ventricular assist device implantation, and hospitalization due to acute or worsened CHF. Joint models were used to determine whether there were differences in the temporal patterns of the biomarkers between men and women as the PE approached. RESULTS: A total of 66 patients reached the PE of which 52 (78.8%) were male and 14 (21.2%) were female. The temporal patterns of all studied biomarkers were associated with the PE, and overall showed disadvantageous changes as the PE approached. For NT-proBNP, HsTnT, and CRP, women showed higher levels over the entire follow-up duration and concomitant numerically higher hazard ratios [NT-proBNP: women: HR(95%CI) 7.57 (3.17-21.93), men: HR(95%CI) 3.14 (2.09-4.79), p for interaction = 0.104, HsTnT: women: HR(95%CI) 6.38 (2.18-22.46), men: HR(95%CI) 4.91 (2.58-9.39), p for interaction = 0.704, CRP: women: HR(95%CI) 7.48 (3.43-19.53), men: HR(95%CI) 3.29 [2.27-5.44], p for interaction = 0.106). In contrast, temporal patterns of glomerular and tubular renal markers showed similar associations with the PE in men and women. CONCLUSION: Although interaction terms are not statistically significant, the associations of temporal patterns of NT-proBNP, HsTnT, and CRP appear more outspoken in women than in men with HFrEF, whereas associations seem similar for temporal patterns of creatinine, eGFR, Cystatin C, KIM-1 and NAG. Larger studies are needed to confirm these potential sex differences.

Reporting of sex-specific outcomes in trials of interventions for cardiovascular disease: Has there been progress?

In the past decade, the leading international cardiology societies have released statements that emphasize the importance of sex-specific reporting of the findings of clinical trials in cardiovascular research. To find out whether this has led to improvement, we compared sex-specific reporting of efficacy and safety outcomes for trials of cardiovascular drug interventions presented at the major clinical trials sessions of the European Society of Cardiology (ESC), American Heart Association (AHA) and the American College of Cardiology (ACC) before and after publication of these statements. We found that sex-specific efficacy and safety outcomes of the most influential cardiovascular intervention trials are still not systematically presented.

Supraventricular tachycardia and the menstrual cycle.

•the influence of the menstrual cycle on the occurrence of arrhythmia is still understudied.•Episodes of arrhythmia might occur more frequently in the premenstrual phase.•Taking the menstrual cycle into account when scheduling diagnostic tests might lead to more accurate diagnoses.

REducing STEroids in Relapsing Nephrotic syndrome: the RESTERN study- protocol of a national, double-blind, randomised, placebo-controlled, non-inferiority intervention study.

INTRODUCTION: Oral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable. METHODS AND ANALYSIS: The RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1-18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period. ETHICS AND DISSEMINATION: This non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants. TRIAL REGISTRATION NUMBER: NTR5670, EudraCT no 2016-002430-76.

The effect of rising and sitting trot on back movements and head-neck position of the horse.

REASON FOR PERFORMING STUDY: During trot, the rider can either rise from the saddle during every stride or remain seated. Rising trot is used frequently because it is widely assumed that it decreases the loading of the equine back. This has, however, not been demonstrated in an objective study. OBJECTIVE: To determine the effects of rising and sitting trot on the movements of the horse. HYPOTHESIS: Sitting trot has more extending effect on the horse's back than rising trot and also results in a higher head and neck position. METHODS: Twelve horses and one rider were used. Kinematic data were captured at trot during over ground locomotion under 3 conditions: unloaded, rising trot and sitting trot. Back movements were calculated using a previously described method with a correction for trunk position. Head-neck position was xpressed as extension and flexion of C1, C3 and C6, and vertical displacement of C1 and the bit. RESULTS: Sitting trot had an overall extending effect on the back of horses when compared to the unloaded situation. In rising trot: the maximal flexion of the back was similar to the unloaded situation, while the maximal extension was similar to sitting trot; lateral bending of the back was larger than during the unloaded situation and sitting trot; and the horses held their heads lower than in the other conditions. The angle of C6 was more flexed in rising than in sitting trot. CONCLUSIONS AND CLINICAL RELEVANCE: The back movement during rising trot showed characteristics of both sitting trot and the unloaded condition. As the same maximal extension of the back is reached during rising and sitting trot, there is no reason to believe that rising trot was less challenging for the back.

[An outbreak of measles at an emergency room]. / Een uitbraak van mazelen op de Spoedeisende Hulp.

A small outbreak of measles occurred after a 33-year-old female aircrew (cabin) member presented at an emergency room with fever. Three members of the hospital staff were infected: a 42-year-old man, a 33-year-old woman, and a 26-year-old woman. The first 2 patients had not been immunised, and the third had received 2 immunisations according to the Dutch National Immunisation Programme. Vaccination of the 2 sero-negative patients within 48 h after exposure with the measles-mumps-rubella vaccine (MMR) did not prevent the development of measles. Vaccination was deemed unnecessary in the third patient. No tertiary cases occurred. The same measles virus (genotype D5) was detected by PCR and sequencing in all 4 patients. Measles remains a risk for hospital staff members who have not acquired natural immunity. The current policy of immunising patients within 72 h after exposure to measles may not be sufficient. It also appears that immunisation through the Dutch National Immunisation Programme does not always protect against nosocomial infection. Providing MMR vaccination or boosters to hospital staff in certain departments might be beneficial.

[Pain in the throat due to acute suppurative thyroiditis caused by Salmonella]. / Een pijnlijke hals door acute suppuratieve thyreoïditis veroorzaakt door Salmonella.

A 53-year-old woman presented with fever accompanied by chills and an extremely painful swelling of her right thyroid lobe. She was initially diagnosed as having subacute thyroiditis, but after 14 days her disease appeared to be caused by a destructive suppurative thyroiditis due to Salmonella group C. A pre-existing hyperplastic nodule in the right thyroid lobe was the predisposing factor. Antibiotics were given for several weeks and surgical drainage was performed. Finally a hemithyroidectomy was done to eliminate the predisposing factor.

[A boy with cyclic vomiting and an alleged furosemide allergy on the basis of a subpelvic stenosis]. / Een jongen met cyclisch braken en een vermeende furosemideallergie op basis van een subpelviene stenose.

An 8-year-old boy, known with a Diamond-Blackfan anaemia, was admitted to the hospital because of frequent vomiting since 3 days and loin pain. In previous years, he had been admitted several times for the same complaints but no cause had been identified. Ultrasound examination of the abdomen performed at admittance showed dilatation of the left renal pelvis. A renal scintigraphy was discussed with the mother, and she refused the injection of furosemide, because her son was allegedly allergic to furosemide: previous furosemide treatments during blood transfusions for his anaemia had always resulted in stomach-ache and vomiting, which may be attributed, however, to an acute dilatation of the renal pelvis due to the diuretic effect of furosemide. Scintigraphy without furosemide showed a significant obstruction and asymmetric renal function, so a pyeloplasty was performed after which he has been symptom-free. In patients with cyclic vomiting, an intermittent uretero-pelvic junction obstruction should be considered and can only be ruled out when ultrasound during the complaints and renal scintigraphy under adequate hydration and after furosemide are normal.

Prenatal programming of nephron number and blood pressure.

A low nephron number has been advocated to explain the association between intrauterine growth restriction (IUGR) and hypertension in later life. IUGR not only leads to a low birth weight but is also hypothesized to reprogram nephrogenesis, which results in a low nephron endowment. Several methods are used to estimate the total glomerular number, but only stereological techniques result in accurate (unbiased) and precise (reproducible) data. Several studies, both in humans and animal models that have used these methods indeed revealed that IUGR leads to a low nephron number. According to the hyperfiltration hypothesis, this reduction in renal mass is supposed to lead to glomerular hyperfiltration and hypertension in remnant nephrons with subsequent glomerular injury with proteinuria, systemic hypertension and glomerulosclerosis. Even though IUGR is associated with both a low nephron endowment and an increased risk of hypertension, only circumstantial evidence is available to support the hyperfiltration hypothesis after prenatal programming. A prerequisite for establishment of this association in long-term, prospective follow-up studies is the ability to estimate glomerular numbers in living human beings, for which a further advancement in radiological techniques is necessary. Only then can the association between nephron endowment and blood pressure in humans be studied more conclusively.

Weekend versus working day: differences in telemetric blood pressure in male Wistar rats.

Blood pressure (BP) is a frequently monitored parameter in research. Various methods are used to obtain BP values in animal models, but telemetry is the method of choice because it allows for continuous monitoring in conscious and freely moving animals. However, factors due to the animal facility, like activities and sound, can still influence measurements. We, therefore, retrospectively compared BP values in adult male Wistar rats during working hours with values from non-working days. Telemetry devices were implanted according to standard protocol. Values were obtained at the age of 6 and 12 months during working hours (Friday 10:00-16:00 h, lights on 06:00-18:00 h) and compared with data from the average of Saturday 10:00-16:00 h and Sunday 10:00-16:00 h, representing non-working days. Data were available from 12 and 7 rats at 6 months and 12 months of age respectively. Relative differences in heart rate, spontaneous locomotor activity, systolic and diastolic BP were 2.2% (P<0.001), 32.9% (P<0.05), 3.2% (P<0.05) and 3.7% (P<0.05), respectively, with no differences between the age groups. We have shown a significant and important difference between BP values obtained during working hours and non-working days using telemetry in adult male Wistar rats. This phenomenon has implications for the interpretation of BP measurements in animals.

Influence of intrauterine growth restriction on renal function in the adult rat.

Intrauterine growth restriction (IUGR) has been shown to influence renal development and lead to fewer nephrons. Data on long term renal function after IUGR are limited. We studied the effect on renal function of IUGR in aging rats. IUGR was induced using a model of bilateral uterine artery ligation in pregnant Wistar rats. Renal function was studied at the age of 18 months. In male IUGR rats, estimated glomerular filtration rate was significantly decreased compared to male control rats [1.1 (SD 0.3) 1.7 (SD 0.3) ml x min(-1), p<0.05]. Female IUGR rats showed an increased urinary protein excretion compared with female control rats [84 (SD 73) vs. 12 (SD 13) mg x 24h(-1), p<0.01]. All male rats showed heavy proteinuria (p<0.01 vs. female rats from same experimental group), with no significant differences between the groups. Tubular reabsorption of phosphorus was lower in females, but showed no differences between the experimental groups. In conclusion, IUGR impairs renal function in the rat. It is suggested that a low nephron endowment leads to proteinuria as a sign of glomerular damage, and ends with a decrease in glomerular filtration rate as a sign of glomerular loss.

Monitoring gastric lymphoma in peripheral blood by quantitative IgH allele-specific oligonucleotide real-time PCR and API2-MALT1 PCR.

Gastric extranodal marginal zone lymphoma (EMZL) often shows prolonged localised disease, but the present study demonstrated the presence of tumour cells in peripheral blood (PB) of low stage patients. We studied the presence of tumour cells in PB in gastric lymphoma patients harbouring or lacking t(11;18)(q21;q21), by real-time immunoglobulin (Ig)H allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) and API2-MALT1 PCR. Tumour cells were exclusively detected in PB of t(11;18)(q21;q21)+-EMZL patients. The presence of tumour cells in PB and gastric biopsy follow-up samples showed a good correlation in these patients, suggesting clinical relevance for monitoring of tumour cells in PB of gastric t(11;18)(q21;q21)+-EMZL patients.

Triple osteotomy of the pelvis for acetabular dysplasia: results at a mean follow-up of 15 years.

We report the long-term results of 51 pelvic osteotomies in 43 patients with a mean follow-up of 15 years (13 to 20). The mean age of the patients was 28 years (14 to 46). At review three patients were lost to follow-up, and six had received a total hip arthroplasty. Of 48 hips, 42 (88%) were preserved, with good to excellent clinical results in 27 (64%). Pre-operatively, 41 (80%) of the treated hips had shown no sign of osteoarthritis. Thirty-one (65%) hips showed no progression of osteoarthritis after follow-up for 15 years. Significant negative factors for good long-term results were the presence of osteoarthritic changes and a fair or poor clinical score pre-operatively. Pelvic reorientation osteotomy for symptomatic hip dysplasia can give satisfactory and reproducible long-term clinical results.

FISH analysis of MALT lymphoma-specific translocations and aneuploidy in primary cutaneous marginal zone lymphoma.

Primary cutaneous marginal zone lymphomas (PCMZL) share histological and clinical characteristics with mucosa-associated lymphoid tissue (MALT) lymphomas suggesting a common pathogenesis. A number of recurrent structural and numerical chromosomal aberrations have been described in MALT lymphoma, but their incidence in PCMZL is largely unknown, as is their relation with clinical and pathological data. In this study, the incidence of t(11;18)(q21;q21), t(1;14)(p22;q32), two different t(14;18)(q32;q21), involving either IGH/MALT1 or IGH/BCL2, and numerical aberrations of chromosomes 3, 7, 12 and 18 were analysed in 12 patients with PCMZL, with follow-up of up to 10 years. Nuclei were isolated from paraffin wax sections for dual-colour interphase fluorescence in situ hybridization (FISH) using various probe sets either flanking or spanning the involved genes. T(14;18)(q32;q21), with breakpoints in IGH and MALT1, was found in three cases. All three had partly monocytoid histological appearances and lacked blastic transformation. An additional trisomy of chromosome 3 was detected in one of these cases. Trisomy 18 was present in two lymphomas without monocytoid morphology. No definite correlation was seen with any clinical feature, including Borrelia serology. Neither t(11;18)(q21;q21), nor t(1;14)(p22;q32) or any other translocation involving IGH, BCL10, MALT1, BCL2 and API2, amplification or deletion of chromosomal region 11q21, 18q21, 1p22, and 14q32 was detected. These results indicate that a subgroup of PCMZL with partly monocytoid morphology is genetically related to MZL at other extranodal sites.

Modelled influences of non-exchanging trichomes on leaf boundary layers and gas exchange.

The two main resistances in the exchange of gases between plants and the atmosphere are stomatal and boundary layer resistances. We modeled boundary layer dynamics over glabrous and pubescent leaves (assuming non-exchanging trichomes) with leaf lengths varying from 0.01 to 0.2 m, and windspeeds of 0.1-5.0 m x s(-1). Results from theoretical and semi-empirical formulae were compared. As expected, boundary layer thickness decreased with decreasing leaf length and increasing windspeed. The presence of trichomes increased leaf surface roughness, resulting in lowered Reynolds numbers at which the boundary layer became turbulent. This effect is especially important at low windspeeds and over small leaves, where the Reynolds number over glabrous surfaces would be low. We derived a new simple dimensionless number, the trip factor, to distinguish field conditions that would lead to a turbulent boundary layer based on the influence of trichomes. Because modeled rates of CO2 and H2O(v) exchange over turbulent boundary layers are one or more orders of magnitude faster than over laminar boundary layers, a turbulent boundary layer may lead to increased carbon uptake by plants. The biological trade-off is potentially increased transpirational water loss. However, in understory habitats characterized by low windspeeds, even a few trichomes may increase turbulence in the boundary layer, thus facilitating photosynthetic gas exchange. Preliminary field data show that critical trip factors are exceeded for several plant species, both in understory and open habitats.

Genetic dissection of blue-light sensing in tomato using mutants deficient in cryptochrome 1 and phytochromes A, B1 and B2.

Several novel allelic groups of tomato (Solanum lycopersicum L.) mutants with impaired photomorphogenesis have been identified after gamma-ray mutagenesis of phyA phyB1 double-mutant seed. Recessive mutants in one allelic group are characterized by retarded hook opening, increased hypocotyl elongation and reduced hypocotyl chlorophyll content under white light (WL). These mutants showed a specific impairment in response to blue light (BL) resulting from lesions in the gene encoding the BL receptor cryptochrome 1 (cry1). Phytochrome A and cry1 are identified as the major photoreceptors mediating BL-induced de-etiolation in tomato, and act under low and high irradiances, respectively. Phytochromes B1 and B2 also contribute to BL sensing, and the relative contribution of each of these four photoreceptors differs according to the light conditions and the specific process examined. Development of the phyA phyB1 phyB2 cry1 quadruple mutant under WL is severely impaired, and seedlings die before flowering. The quadruple mutant is essentially blind to BL, but experiments employing simultaneous irradiation with BL and red light suggest that an additional non-phytochrome photoreceptor may be active under short daily BL exposures. In addition to effects on de-etiolation, cry1 is active in older, WL-grown plants, and influences stem elongation, apical dominance, and the chlorophyll content of leaves and fruit. These results provide the first mutant-based characterization of cry1 in a plant species other than Arabidopsis.

Physiological interactions of phytochromes A, B1 and B2 in the control of development in tomato.

The role of phytochrome B2 (phyB2) in the control of photomorphogenesis in tomato (Solanum lycopersicum L.) has been investigated using recently isolated mutants carrying lesions in the PHYB2 gene. The physiological interactions of phytochrome A (phyA), phytochrome B1 (phyB1) and phyB2 have also been explored, using an isogenic series of all possible mutant combinations and several different phenotypic characteristics. The loss of phyB2 had a negligible effect on the development of white-light-grown wild-type or phyA-deficient plants, but substantially enhanced the elongated pale phenotype of the phyB1 mutant. This redundancy was also seen in the control of de-etiolation under continuous red light (R), where the loss of phyB2 had no detectable effect in the presence of phyB1. Under continuous R, phyA action was largely independent of phyB1 and phyB2 in terms of the control of hypocotyl elongation, but antagonized the effects of phyB1 in the control of anthocyanin synthesis, indicating that photoreceptors may interact differently to control different traits. Irradiance response curves for anthocyanin synthesis revealed that phyB1 and phyB2 together mediate all the detectable response to high-irradiance R, and, surprisingly, that the phyA-dependent low-irradiance component is also strongly reduced in the phyB1 phyB2 double mutant. This is not associated with a reduction in phyA protein content or responsiveness to continuous far-red light (FR), suggesting that phyB1 and phyB2 specifically influence phyA activity under low-irradiance R. Finally, the phyA phyB1 phyB2 triple mutant showed strong residual responsiveness to supplementary daytime FR, indicating that at least one of the two remaining phytochromes plays a significant role in tomato photomorphogenesis.