Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia.

AIM: To investigate whether genotyping could be used as a cost-effective screening step, preceding next-generation sequencing (NGS), in molecular diagnosis of familial hypercholesterolaemia (FH) in Swedish patients. METHODS AND RESULTS: Three hundred patients of Swedish origin with clinical suspicion of heterozygous FH were analysed using a specific array genotyping panel embedding 112 FH-causing mutations in the LDLR, APOB and PCSK9 genes. The mutations had been selected from previous reports on FH patients in Scandinavia and Finland. Mutation-negative cases were further analysed by NGS. In 181 patients with probable or definite FH using the Dutch lipid clinics network (DLCN) criteria (score ≥ 6), a causative mutation was identified in 116 (64%). Of these, 94 (81%) were detected by genotyping. Ten mutations accounted for more than 50% of the positive cases, with APOB c.10580G>A being the most common. Mutations in LDLR predominated, with (c.2311+1_2312-1)(2514)del (FH Helsinki) and c.259T>G having the highest frequency. Two novel LDLR mutations were identified. In patients with DLCN score < 6, mutation detection rate was significantly higher at younger age. CONCLUSION: A limited number of mutations explain a major fraction of FH cases in Sweden. Combination of selective genotyping and NGS facilitates the clinical challenge of cost-effective genetic screening in suspected FH. The frequency of APOB c.10580G>A was higher than previously reported in Sweden. The lack of demonstrable mutations in the LDLR, APOB and PCSK9 genes in ~1/3 of patients with probable FH strongly suggests that additional genetic mechanisms are to be found in phenotypic FH.

Genetic testing for familial hypercholesterolemia among survivors of acute coronary syndrome.

BACKGROUND: Familial hypercholesterolemia could be prevalent among patients with acute coronary syndrome. OBJECTIVE: To investigate both the frequency of causative mutations for familial hypercholesterolemia (FH) and the optimal selection of patients for genetic testing among patients with an acute coronary syndrome (ACS). METHODS: One hundred and sixteen patients with an ACS during 2009-2015 were identified through the SWEDEHEART registry. Patients who had either a high total cholesterol level ≥7 mmol L-1 combined with a triglyceride level ≤2.6 mmol L-1 , or were treated with lipid-lowering medication and had a total cholesterol level >4.9 mmol L-1 and a triglyceride level ≤2.6 mmol L-1 were included. Genetic testing was performed first with a regionally designed FH mutation panel (118 mutations), followed by testing with a commercially available FH genetic analysis (Progenika Biopharma). RESULTS: A total of 6.9% (8/116) patients had a FH-causative mutation, all in the LDL-receptor. Five patients were detected on the panel, and further testing of the remaining 111 patients detected an additional 3 FH-causative mutations. Baseline characteristics were similar in FH-positive and FH-negative patients with respect to age, gender, prior ACS and diabetes. Patients with a FH-causative mutation had higher Dutch Lipid Clinical Network (DLCN) score (5.5 (5.0-6.5) vs 3.0 (2.0-5.0), P < 0.001) and a higher low-density lipoprotein level (5.7 (4.7-6.5) vs 4.9 (3.5-5.4), P = 0.030). The Dutch Lipid Clinical Network (DLCN) score had a good discrimination with an area under the curve of 0.856 (95% CI 0.763-0.949). CONCLUSION: Genetic testing for FH should be considered in patients with ACS and high DLCN score.

Protective effects of mercaptoethylguanidine, a selective inhibitor of inducible nitric oxide synthase, in ligature-induced periodontitis in the rat.

1. Excessive production of nitric oxide (NO), and the generation of peroxynitrite have been implicated in various proinflammatory conditions. In the present study, using mercaptoethylguanidine (MEG), a selective inhibitor of iNOS and a peroxynitrite scavenger, we investigated the role of iNOS and peroxynitrite in a rat model of periodontitis. 2. Periodontitis was produced in rat by a ligature of 2/0 braided silk placed around the cervix of the lower left 1st molar. Animals were then divided into two groups: one group of rats was treated with MEG (30 mg kg(-1), i.p., 4 times per day for 8 days), animals in the other group received vehicle. At day 8, the gingivomucosal tissue encircling the mandibular 1st molars was removed on both sides from ligated and sham operated animals for inducible nitric oxide synthase (iNOS) activity assay and for immunocytochemistry with anti-iNOS serum. Plasma extravasation was measured with the Evans blue technique. Alveolar bone loss was measured with a videomicroscopy. 3. Ligation caused a significant, more than 3 fold increase in the gingival iNOS activity, whereas it did not affect iNOS activity on the contralateral side, when compared to sham-operated animals. Immunohistochemical analysis revealed iNOS-positive macrophages, lymphocytes and PMNs in the connective tissue and immunoreactive layers of epithelium on side of the ligature, and only a few iNOS reactive connective tissue cells on the contralateral side [corrected]. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone destruction compared to the contralateral side. MEG treatment significantly reduced the plasma extravasation and bone destruction. 4. The present results demonstrated that ligature-induced periodontitis increases local NO production and that MEG treatment protects against the associated extravasation and bone destruction. Based on the present data, we propose that enhanced formation of NO and peroxynitrite plays a significant role in the pathogenesis of periodontitis.

Nitric oxide synthase containing nerves in the cat and dog dental pulp and gingiva.

In a previous study we found that nitric oxide (NO) plays an essential role in the hemodynamic regulation of the feline dental pulp. However, no evidence for the presence of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) containing nerve fibers was found in the rat and cat dental pulps. In the present study, we are first to report the presence of a small number of NADPH-d positive and/or NO synthase immunoreactive perivascular and solitary varicose axons in the dental pulp and abundant number of similar axons in the gingiva of cats and dogs. These fibres may travel within the inferior alveolar nerve and might participate in sensory (i.e. pain) as well as in autonomic (i.e. regulation of blood flow) innervation of the dental pulp and gingiva.

An earthquake disaster in Turkey: assessment of the need for plastic surgery services in a crisis intervention field hospital.

On August 17, 1999, an earthquake of 7.4 magnitude struck Turkey, resulting in the destruction of the cities Golcuk, Izmit, Adapazari, and Yalova. Three days later, the Israel Defense Force Field Hospital arrived at Adapazari, serving as a reinforcement hospital until the rehabilitation of the local medical facilities. Surgical services in the field hospital were supplied by general, orthopedic, and plastic surgeons. The authors evaluated all soft-tissue injuries managed at the hospital and assessed the need for plastic surgery services in a crisis intervention field hospital. Information was gathered regarding soft-tissue injuries throughout the activity of the hospital. In addition, patients' charts, operations' reports, and entry and evacuation logs were reviewed for all patients accepted and treated in the field hospital. Interviews of patients, local physicians, and citizens of Adapazari were performed to evaluate the medical situation in the first 3 days after the earthquake. A total of 1205 patients were treated by the field hospital in Adapazari; 138 (11.45 percent) of these patients sought aid for isolated soft-tissue injuries, 105 of which (76.09 percent) were earthquake-related. Twenty (51.28 percent) of the operations performed in the hospital were to treat soft-tissue injuries; 1.49 percent of all patients underwent minor surgical manipulations by the plastic surgeon on staff. Plastic surgery patients occupied 13.6 percent of the hospital beds. In conclusion, the authors find it beneficial to supply plastic surgery services at a field hospital in an earthquake situation.

Management of varicocele in military obligatory service: Israel Defense Forces Medical Corps policy.

Varicocele is a well-known and highly prevalent medical problem in young obligatory service recruits. Still, there are many questions regarding its management. Is there a clear relation between varicocele and infertility? Can early varicocelectomy in young soldiers prevent future infertility? Is there a role for varicocelectomy in pain relief in physically active soldiers? And finally, what are the pros and cons of the open surgical, laparoscopic, or radiographic techniques in this specific population? Answering these questions should help military physicians in varicocele patients' care. It should also help decision makers to build cost-effective and evidence-based health policy. In this article, we review the literature regarding the controversies in the management of varicocele in young adults and delineate the current policy of the Israel Defense Forces Medical Corps.

Diagnostic medical auxiliary equipment in a field hospital: experience from the Israeli delegation to the site of the Turkish earthquake at Adapazari.

An earthquake striking a highly populated area is likely to cause a mass casualty situation for even the most advanced trauma center. If the local medical teams are injured and the hospitals are damaged beyond immediate repair, external intervention is needed. In the Turkish earthquake crisis, Israel was one of many states to deploy a field hospital to the crisis site. This was set up in Adapazari, the second most severely hit city in terms of the amount of damage. The hospital provided advanced surgical and medical facilities, including laparotomy, cesarean section, and intensive care surveillance. These facilities require sophisticated laboratory and radiology services, including hematology, chemistry, microbiology, and blood bank. The speed with which the hospital must be assembled and transported to be efficient and the basic conditions of a field hospital dictate specific considerations regarding diagnostic auxiliary equipment. Considerations in choosing this equipment, problems encountered during installation, and recommendations for the future are presented.

An earthquake disaster in Turkey: an overview of the experience of the Israeli Defence Forces Field Hospital in Adapazari.

On 17 August 1999 at 3:04 a.m., an earthquake of 7.4 magnitude (Richter scale) struck the Marmara region in Turkey. The city of Adapazari suffered 2,680 fatalities with approximately 5,300 injured. The Israeli Defence Forces (IDF) field hospital arrived at Adapazari, on day four after the quake. The team consisted of 102 personnel. The field hospital acted as a secondary referral centre. A total of 1,205 patients were treated in the field hospital between day four and day 14 of the earthquake. The frequency distribution of the medical problems seen in the field hospital was 32 per cent internal medicine, 13 per cent general surgery including plastic, 21 per cent orthopaedic surgery, 23 per cent paediatric disease, 10 per cent obstetrics and gynaecology and 1 per cent major psychiatric disorders. A mean number of 35 patients per day were hospitalised in the field hospital for between 24 hours to one week. The rapid establishment of the field hospital enabled the local medical facilities to 'buy time' in order to organise and restore surgical and hospitalisation abilities in this disastrous situation.