Evolution of Haemophilia Care in Europe: 10 years of the principles of care.

INTRODUCTION: The European principles of care in haemophilia marked their first decade in 2018. These guiding principles were the beginning of the European Haemophilia Consortium (EHC) review of countries' adherence to these principles in 2009, 2012, 2015 and 2018. The aim of this paper was to examine the implementation of the principles and how they have impacted the evolution of care in the last decade, as well as to identify remaining gaps and proposes future directions. METHODS: In 2018, the EHC distributed a survey to EHC national member organisations in English and Russian and encouraged them to discuss responses with local clinicians for accuracy. Data was also cross-referenced and validated for countries in earlier surveys using additional available resources. RESULTS: The 10-year-old European principles had a significant impact on the development of care for haemophilia and related bleeding disorders in Europe. They set objectives around which multi-stakeholder groups have established recommendations and specific steps for the progressive improvement of care for bleeding disorders. However, some have been promoted and implemented more than others. CONCLUSION: Monitoring adherence to, and impact of, the European Principles of Care significantly assists in tracking developments and highlighting gaps. Countries' inability to report consistent and coherent data remains a challenge and hinders both provision of treatment and care for patients as well as optimal national and European healthcare systems.

Intracellular Hyper-Acidification Potentiated by Hydrogen Sulfide Mediates Invasive and Therapy Resistant Cancer Cell Death.

Slow and continuous release of H2S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active. We characterized and utilized cancer cell line pairs of various organ origins, based on their aggressive behaviors, and assessed their response to GYY4137. We compared glycolytic activity, via lactate production, and intracellular pH of each cancer cell line pair after exposure to H2S. Invasive and therapy resistant cancers, collectively termed aggressive cancers, are receptive to H2S-mediated cytotoxicity, albeit at a higher concentration of GYY4137 donor. While lactate production was enhanced, intracellular pH of aggressive cancers was only modestly decreased. Inherently, the magnitude of intracellular pH decrease is a key determinant for cancer cell sensitivity to H2S. We demonstrated the utility of coupling GYY4137 with either simvastatin, known to inhibit monocarboxylate transporter 4 (MCT4), or metformin, to further boost glycolysis, in bringing about cell death for aggressive cancers. Simvastatin inhibiting lactate extrusion thence contained excess lactate induced by GYY4137 within intracellular compartment. In contrast, the combined exposure to both GYY4137 and metformin overwhelms cancer cells with lactate over-production exceeding its expulsion rate. Together, GYY4137 and simvastatin or metformin synergize to induce intracellular hyper-acidification-mediated cancer cell death.

Haemophilia care in Europe - A survey of 37 countries.

INTRODUCTION: The European Haemophilia Consortium (EHC) is an international non-profit organization representing 45 national patients' organizations in Europe. Every 3 years, the EHC circulates a survey to its national member organizations to assess the state of haemophilia care. AIM: The purpose of this exercise is to ascertain information about the organization of haemophilia care and treatment availability at national levels. Furthermore, the survey provides a basis from which the EHC are able to monitor the unmet need and stability of care/treatment access in the individual member countries. PATIENTS AND METHODS: Surveys are distributed to EHC member organizations in English and Russian. Patient organizations are encouraged to share the survey with local clinicians to ensure accuracy of responses. The data collected are in part consistent to provide a longitudinal overview for treatment access, but topical items are included such as ageing. Subsequently, completed surveys are transposed into a database for analysis and reporting. RESULTS: Thirty-seven responses were received from the 45 countries approached, representing an 82% response rate from members. Findings suggest increased access to treatment and some improvement in certain areas of care. However, access to treatment has declined or remained largely unchanged in some countries. CONCLUSION: The survey has been a successful exercise in enabling a greater understanding of the current Haemophilia care landscape across Europe. However, there remain unmet needs in various aspects of patient care, and specific examples include psychosocial care and general preparedness for an ageing haemophilia population.

Sarcopenia and sarcopenic obesity and their association with dyslipidemia in Korean elderly men: the 2008-2010 Korea National Health and Nutrition Examination Survey.

BACKGROUND: Recently, aging has been shown to be associated with sarcopenic obesity (SO), of which decreased muscle mass and increased fat mass are features. Sarcopenia and obesity alone are known to be associated with abnormal lipid metabolism. However, it remains unclear whether SO has greater adverse effects on dyslipidemia than on sarcopenia or obesity alone. AIM: We aimed to investigate the association between SO and dyslipidemia in elderly Koreans. SUBJECTS AND METHODS: This study was based on data collected during the 2008-2010 Korea National Health and Nutrition Examination Survey. We included 1,466 men and 2,017 women aged 65 years and over. Sarcopenia was indicated in participants with height- or weight-adjusted appendicular skeletal muscle that was 1 standard deviation below the sex-specific mean for the young reference group, and obesity was defined as a body mass index ≥ 25 kg/m(2). Dyslipidemia was defined according to the National Cholesterol Education Program-Adult Treatment Panel III. RESULTS: After adjusting for confounding factors, the SO group had a higher risk for dyslipidemia [odds ratio (OR) 2.82 (95 % confidence interval 1.76-4.51)] than the obese group [2.12 (1.11-4.07)] and sarcopenic group [1.46 (1.01-2.11)] (p < 0.001) only in men. Furthermore, the SO group in men had the highest OR for hypercholesterolemia, hypertriglyceridemia, hypo-high-density lipoprotein cholesterolemia, hyper-low-density lipoprotein cholesterolemia, and a high ratio of triglyceride to high-density lipoprotein cholesterol even after further adjustments. CONCLUSIONS: In Korean elderly men, SO was associated with an increased risk for dyslipidemia compared with sarcopenia or obesity alone.

High intraocular pressure is associated with cardiometabolic risk factors in South Korean men: Korean National Health and Nutrition Examination Survey, 2008-2010.

OBJECTIVE: Elevated intraocular pressure (IOP) contributes to the progression of visual defects such as glaucoma. This study determined whether metabolic syndrome (MetS) and cardiovascular risk factors are associated with IOP in South Korean men. METHODS: We analyzed data on 4875 men who participated in the Korean National Health and Nutrition Examination Survey 2008-2010. We recorded the values for age, weight, height, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), insulin, homeostasis model assessment of estimated insulin resistance (HOMA-IR), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), non-HDL-C (NHDL-C), and TG/HDL-C, as well as sociodemographic factors. IOP was measured using Goldmann applanation tonometry. RESULTS: Weight, BMI, WC, SBP, DBP, FBG, insulin, HOMA-IR, TC, LDL-C, TG, NHDL-C, TG/HDL-C, and the prevalence of MetS differed significantly among the three groups with IOP (P<0.05). Mean IOP was higher in subjects who were obese and had hypertension, diabetes mellitus, MetS, abdominal obesity, high TG, high FBG, or high BP compared with normal subjects (P<0.005). Analysis using Pearson's correlation coefficient showed that all cardiometabolic risk factors were significantly associated with IOP (P<0.005), with the exception of WC and HDL-C. A multivariate linear regression analysis showed that IOP was positively correlated with BMI, SBP, DBP, FBG, HOMA-IR, TC, LDL-C, TG, NHDL-C, and TG/HDL-C after adjusting for all covariates (all P<0.05). CONCLUSIONS: Cardiometabolic risk factors, including the components of MetS, are associated with increased IOP.

Eating rate is associated with cardiometabolic risk factors in Korean adults.

BACKGROUND AND AIM: Eating slowly is a crucial concept in behavioural nutrition and is recommended for weight management as it is believed to have an important effect on satiety control. This study aimed to determine whether or not eating rate is associated with cardiometabolic risk factors. METHODS AND RESULTS: This was a cross-sectional study involving 8775 Korean adults, who visited the Center for Health Promotion of Korea University Anam Hospital in Seoul, Korea. In male study participants, weight and body mass index (BMI) were found to depend on eating rate after adjusting for age, alcohol consumption, smoking, exercise and total energy intake. When adjusted for age, alcohol consumption, smoking, exercise and BMI, differences were found between the eating rate groups with respect to high-density lipoprotein (HDL)-cholesterol, alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values, white blood cell (WBC) count and total energy intake. Female participants were found to be different from males in that diastolic blood pressure and low-density lipoprotein (LDL)- and HDL-cholesterol values were significantly different between each eating rate group, while ALT and ALP values, WBC count and total energy intake were not. Compared with the slow eating rate group (>15 min), the fastest eating rate group (<5 min) had significantly increased odds ratios for cardiometabolic risk factors such as high glucose and low HDL-cholesterol levels in males, even after adjusting for BMI. CONCLUSION: Fast eating rates are associated with obesity and other cardiometabolic risk factors, particularly in men. Thus, eating slowly is recommended for weight reduction and to decrease cardiovascular risk factors.

Pulmonary toxicity with oxaliplatin and capecitabine/5-Fluorouracil chemotherapy: a case report and review of the literature.

BACKGROUND: Oxaliplatin in combination with either 5-fluorouracil or capecitabine is commonly used in the treatment of colorectal cancer and is rarely associated with pulmonary toxicity. This is the first reported case of oxaliplatin and capecitabine/5-fluorouracil causing pulmonary toxicity in a patient with pre-existing asymptomatic interstitial lung disease. CASE REPORT: We report a case of a man who was treated with oxaliplatin and capecitabine for 1 cycle, then subsequently with oxaliplatin and 5-fluorouracil following a resected Dukes' C colon carcinoma. His preoperative computed tomography scan incidentally showed mild pulmonary interstitial changes for which he was asymptomatic. He developed pulmonary fibrosis during the course of his chemotherapy, and therefore further chemotherapy was stopped. He was treated with high dose steroids and immunosuppressants which initially stabilized his respiratory symptoms. CONCLUSIONS: Pulmonary fibrosis is a rare complication of oxaliplatin and capecitabine/5-fluorouracil. With the widespread use of oxaliplatin combinations in colorectal cancer, active assessment for interstitial lung disease is recommended and caution in its use should be exercised in those with pre-existing interstitial lung disease.

Ethnic differences in syringomyelia in New Zealand.

OBJECTIVE: To determine the prevalence of syringomyelia in a defined population in New Zealand and measure the prevalence of syringomyelia in the three main ethnic groups (Maori, Pacific people and Caucasians/others) living in this region. METHODS: A retrospective study of all confirmed cases of syringomyelia diagnosed in residents of northern New Zealand from 1961 to 2003. RESULTS: In all, syringomyelia was diagnosed in 137 patients. The mean age at onset of symptoms was 27.5 years and mean age at diagnosis was 32.6 years. The incidence of new cases increased from 0.76/100,000 a year between 1962 and 1971 to 4.70/100,000 a year by 1992-2001. The prevalence of syringomyelia in 2003 was 8.2/100,000 people: 5.4/100,000 in Caucasians or others, 15.4/100,000 in Maori and 18.4/100,000 in Pacific people (chi2 = 37.0, p<0.0001). Syringomyelia was more often associated with an isolated Chiari I malformation in Pacific people (84.4%) as compared with 42.9% of Maori and 38.2% of Caucasians or others (chi2 = 62.3, p<0.0001). CONCLUSION: The prevalence of syringomyelia is higher in northern New Zealand than in studies carried out before the advent of magnetic resonance imaging. The prevalence is particularly high in Maori and Pacific people. The cause of the ethnic differences in the prevalence of syringomyelia identified in this study is unexplained and warrants further investigation.

Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with UW and Euro-Collins.

The aim was to evaluate the effect of HTK compared to UW and Euro-Collins (EC) on the initial graft function and long term graft survival in two prospective randomized studies. Only kidneys from heart-beating, kidney-only or kidney + heart donors were eligible for entry. Initial non-function (INF) was defined as the absence of life-sustaining renal function, requiring dialysis treatment on two or more occasions, during the first week after transplantation. To evaluate the contribution of the preservation solutions on INF in relation to other factors, a multivariate, 2-step logistic regression model was used. Randomization was performed between July 1990 and September 1992. The UW-HTK study comprised 342 donors and 611 transplants (UW: 168 donors and 297 transplants, HTK: 174 donors and 314 transplants). In the EC-HTK study 317 donors and 569 transplants were included (EC: 155 donors and 277 transplants, HTK: 162 donors and 292 transplants). INF occurred in 33% of either HTK-(n = 105) or UW-(n = 99) preserved kidneys (P = NS), and in 29% of the HTK-(n = 85) and in 43% of the EC-(n = 119) preserved kidneys (P = 0.001). Multivariate analysis showed no significant influence of the preservation solution on the incidence of INF in the UW-HTK study, but factors contributing to INF were donor age, cause of death, retransplantation, and cold ischemic period. The EC-HTK study showed a significantly higher risk of INF, using EC as preservation, in addition to cold ischemic period and donor quality. The 3-year graft survival of HTK-preserved kidneys was 73%, compared to 68% for UW-preserved kidneys in the UW-HTK study (P = NS); while the 3-year graft survival of HTK preserved kidneys was 70% compared to 67% for EC-preserved kidneys in the EC-HTK study (P = NS). We can conclude that HTK is comparable to UW in its preservative abilities, using kidneys from heart-beating kidney-only donors, whereas EC as renal preservation solution should be avoided.

Low-grade supratentorial astrocytomas in adults: Management, immunohistochemical analysis and long-term follow-up.

A retrospective review of supratentorial, low-grade astrocytomas in adults over a 10-year period (1983-1993) was performed. All 62 patients had computed tomography and surgery with histological and immunohistochemical analysis of the tumour. Radiotherapy was administered to all patients, regardless of the extent of surgical resection. Multivariate analysis showed that age of the patient at the time of surgery (P=0.008) and female sex (P=0.031) were the most important indicators of improved survival. No significant survival advantage was found with any particular symptom or symptom duration. Neither presence of a tumour cyst nor site of the tumour affected survival. Histological grading (St Anne-Mayo system) found 61 grade II astrocytomas (98%) and one grade I tumour. Six tumours (10%) were protoplasmic astrocytomas and 56 cases (90%) were diffuse fibrillary astrocytomas. Proliferation index derived from Ki-67 antibody staining and the presence of p53 protein expression were not significantly correlated with survival. Most patients underwent biopsy (79%) with 8% undergoing subtotal and 13% total resection. Increased extent of surgical removal showed a trend towards an improved survival (P=0.05). No survival advantage was found with increasing radiotherapy dose. Median survival in the study population was 5.1 years, with survival rates of 70% at 2 years and 53% at 5 years. The follow-up period ranged from 1 to 10.5 years. Younger age, female sex and the extent of surgical resection are important prognostic factors in the management of low-grade astrocytomas, whereas the efficacy of postoperative radiotherapy needs further evaluation. The prognostic significance of Ki-67 and p53 expression in low-grade astrocytomas remains to be determined.

Carotid and vertebral artery occlusion after blunt cervical injury: the role of MR angiography in early diagnosis.

The early diagnosis of cervical vascular trauma is critical in the prevention of cerebral ischemia. Traumatic blunt carotid or vertebral artery dissection is rare and frequently associated with other injuries. Diagnosis is often delayed, limiting treatment options and contributing to a poor outcome. The clinical findings and investigation of 14 patients are presented with special reference to the last three who had magnetic resonance imaging angiography. Treatment options are discussed and it is suggested that with modern methods of investigation and management, the prognosis of this condition may be improved.

Rhinogenic subdural empyema in older children and teenagers.

Forty-five patients under the age of 20 years with rhinogenic subdural empyema were treated at Groote Schuur Hospital and Red Cross War Memorial Children's Hospital between 1979 and 1991. Thirty-two were male and 13 female. The majority were between 13 and 19 years of age. Headache was the predominant symptom in 41 patients. Vomiting occurred in 15 and 21 presented with seizures, 2 in status epilepticus. Thirty had swinging pyrexias and 26 neck stiffness while only 14 had focal neurological signs. Swelling of the face or orbit was seen in 24. Twenty-two had depressed levels of consciousness and 7 had Glasgow Coma Scale (GCS) values below 11/15. White cell counts and erythrocyte sedimentation rates were raised in all cases. Twenty-three patients underwent lumbar punctures despite the inherent danger in this procedure. Cerebrospinal fluid analysis showed a pleocytosis in all cases; no organisms were cultured in any of the specimens. The diagnosis in all cases was made by contrast-enhanced computed tomography. Twenty-five patients underwent multiple burrholes, 9 small craniectomies and 11 craniotomies. Thirty-four patients made an excellent recovery. All of the 6 patients who died had GCS values below 11 at the time of their surgery.

Subdural empyema: burr holes or craniotomy? A retrospective computerized tomography-era analysis of treatment in 90 cases.

Ninety patients with subdural empyema were treated in the period after computerized tomography (CT) became available (1979 to 1991). Males predominated by a ratio of 2:1, and 40 patients were between 11 and 20 years old. The site of origin was the paranasal air sinuses in 53 patients, the middle ear in 19, and a superficial infection in eight; the source of infection was not known in 10. The most common clinical presentation was headache, fever, neck stiffness, seizures, or periorbital swelling; only seven patients had status epilepticus. While the erythrocyte sedimentation rate and white blood cell count were invariably elevated, the cerebrospinal fluid showed nonspecific pleocytosis in the 60 patients who underwent lumbar puncture. The definitive preoperative diagnosis was made by contrast-enhanced CT in all cases. Surgical treatment was by multiple burr holes in 37 patients, burr holes and small craniectomies in 33, burr holes with catheter drainage in seven, and a large craniotomy in 12. One patient was treated without surgery. The mortality rate was 7.7%, with 86% making a good recovery. These results compare favorably with those reported in other studies using craniotomy alone, and suggest that burr holes should not be disregarded as a method of treating subdural empyema where contrast-enhanced CT facilities are available.

[Some aspects of the control of atrophic rhinitis (author's transl)]. / Enkele aspecten ten aanzien van de bestrijding van atrofische rhinitis.

The results obtained by a number of methods adopted in the control of atrophic rhinitis in herds in which this disease occurred, are reviewed. The long-term results may be described as disappointing. A number of possible causes of these disappointments are discussed.

[Some features of the control of atrophic rhinitis (author's transl)]. / Enkele aspecten ten aanzien van de bestrijding van atrofische rhinitis

The results obtained by a number of control measures in 152 cases of atrophic rhinitis in the province of North Brabant in 1975 are reviewed. So-called "elimination of piglets" from the herd for a few weeks and treatment of the newborn piglets in accordance with a fixed scheme are the measures stressed in this regard moreover, when this scheme of treatment is adopted in a contaminated environment, i.e. without any taking over by the authorities, it also offers certain prospects. The method of control widely used in the Netherlands so far (elimination of piglets not followed by a scheme of treatment) was not sufficiently successful.