Common genetic variants do not associate with CAD in familial hypercholesterolemia

In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49–0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.     

The Secondary School Football Coach's Relationship With the Athletic Trainer and Perspectives on Exertional Heat Stroke

Context:

Prior researchers have examined the first-aid knowledge and decision making among high school coaches, but little is known about their perceived knowledge of exertional heat stroke (EHS) or their relationships with an athletic trainer (AT).

Objective:

To examine secondary school football coaches'' perceived knowledge of EHS and their professional relationship with an AT.

Design:

Qualitative study.

Setting:

Web-based management system.

Patients or Other Participants:

Thirty-eight secondary school head football coaches (37 men, 1 woman) participated in this study. Their average age was 47 ± 10 years old, and they had 12 ± 9 years'' experience as a head football coach.

Data Collection and Analysis:

Participants responded to a series of online questions that were focused on their perceived knowledge of EHS and professional relationships with ATs. Data credibility was established through multiple-analyst triangulation and peer review. We analyzed the data by borrowing from the principles of a general inductive approach.

Results:

Two dominant themes emerged from the data: perceived self-confidence of the secondary school coach and the influence of the AT. The first theme highlighted the perceived confidence, due to basic emergency care training, of the coach regarding management of an emergency situation, despite a lack of knowledge. The second theme illustrated the secondary school coach''s positive professional relationships with ATs regarding patient care and emergency procedures. Of the coaches who participated, 89% (34 out of 38) indicated positive interactions with their ATs.

Conclusions:

These secondary school coaches were unaware of the potential causes of EHS or the symptoms associated with EHS, and they had higher perceived levels of self-confidence in management abilities than indicated by their perceived knowledge level. The secondary school football coaches valued and understood the role of the AT regarding patient and emergency care.Key Words: sudden death in sport, emergency care, heat injuries, coach''s knowledge

Key Points

• Because of the limited knowledge of secondary school head football coaches related to the management and care of exertional heat stroke, state high school athletic associations should require all coaches to undergo continuing education on the recognition and management of emergency situations in sport.
• To ensure the safety of secondary school student–athletes, school administrators are encouraged to employ the services of an athletic trainer.

Sudden death in sport continues to be a concern for the secondary school athlete and athletic trainer (AT), as evident by the number of deaths reported during the fall 2011.¹ Cardiac conditions, exertional sickling, and exertional heat stroke (EHS) were the most commonly reported causes of these sport-related deaths. Data regarding sudden death indicate the most common causes, in order, are cardiac death, traumatic head injuries, EHS, exertional sickling, and hyponatremia.^2,3 Advancements including screening instruments, rule changes, and guidelines for participation and activity modifications have helped to reduce and prevent sudden death in sport.Death from EHS is preventable when proper precautions are taken during training and conditioning. Educating athletes, coaches, and parents on the importance of proper hydration during activity and implementing an appropriate heat-acclimatization period during training are some examples of ways EHS deaths can be prevented.⁴ From July 21 through August 15, 2011, 17 deaths occurred during participation in sport and physical activity. Of those 17, 7 have been either confirmed or speculated to be the result of EHS.¹ There have been 13 deaths from EHS in the past 2 years alone, which is on pace to surpass the number of EHS deaths during the 5-year block from 2005 to 2009, during which 18 EHS deaths were recorded.³ Exertional heat stroke can occur regardless of the time of year but often spikes during the preseason conditioning months, especially July and August.⁵Precautions for minimizing sudden death due to EHS consist of appropriate management and treatment, including but not limited to properly trained medical personnel, such as an AT available onsite. Colleges and universities provide health care services to their athletes in the form of athletic training services; however, most secondary school athletes do not benefit from the same consistent onsite medical care that collegiate athletes receive. Fewer than 45% of high schools in the United States employ an AT,⁶ potentially leaving the care in the hands of the coach, parent, or bystander.Lack of proper medical coverage has played a role in some recent EHS deaths. In August 2010, Tyler Davenport, a junior football player from Arkansas, collapsed during practice after suffering EHS. He later died due to complications resulting from the EHS he suffered. Unfortunately, as has happened with other secondary school-aged athletes who have died from EHS, the coaching staff, despite the onset of symptoms and subsequent collapse, did not cool Tyler immediately. In addition, no AT was present to diagnose and begin immediate treatment before the arrival of emergency personnel (D. J. Casa, unpublished data, 2011). Another case highlighting the role of the coach in preventing sudden death in sport involved Max Gilpin, who, similar to Tyler, died of EHS during football practice. Medical reports state that, on the day of Max''s death, the head football coach had the team run condition drills in full gear without water breaks for 45 minutes. At the time of Max''s EHS, no medical staff was present to monitor practice, diagnose his condition, or implement appropriate treatment. Max''s case was the first in United States history in which a coach was prosecuted in criminal court for his role in a player''s death (D. J. Casa, unpublished data, 2011).Despite the recommendations of the National Athletic Trainers'' Association regarding appropriate medical coverage for the secondary school,⁷ many schools fail to provide medical coverage. In lieu of having an AT employed at every secondary school, some states have opted to implement policies placing care in the hands of the coach,⁸ as is the case in the state of Kentucky. This policy change was influenced by the Max Gilpin case and requires coaches to receive advanced sports medicine training to help minimize the occurrence of sudden death.⁸ Currently, there are no national regulations regarding coaching certifications, and many states have adopted their own regulations regarding requirements for initial certification as well as maintenance of the coaching credential. Some states require that all coaches receive training in cardiopulmonary resuscitation (CPR), use of the automated external defibrillator, and first aid as a means to address emergency care procedures, whereas other states have no mandates regarding basic emergency care training. According to the National Federation of State High Schools,⁹ only 37 states require that coaches obtain basic first-aid training to be eligible to coach. Only 14 of those 37 states require coaches to obtain CPR and automated external defibrillation training in addition to basic first aid.⁹ However, the curriculum in these 37 states often centers on more basic concepts rather than on causes, signs and symptoms, and treatment of emergency situations such as EHS and concussions, for example. Additionally, these sessions are often conducted in 1 day of training, during which a coach is expected to retain and put into practice what would take an AT years to master. This training most likely leaves coaches unprepared to handle an emergency situation because they do not have the proper knowledge or training.^8,9The impetus for this study stemmed from the realization that the secondary school coach plays a significant role in preventing sudden death in sport, especially EHS. Because many secondary schools continue to rely on their coaches to protect the safety of their players, it is important to understand secondary school coaches'' current perceptions of and knowledge related to EHS. Evidence of the reliance on the coach as an emergency care provider and determinant in the student–athlete''s well-being is the number of lawsuits filed against coaches. Within the last 5 years, several coaches have been prosecuted under both criminal and civil law for their negligent roles in failing to follow safety guidelines or take precautions related to preventing sudden death in sport. Many of the cases of sudden death in sport have involved EHS or exertional sickling during conditioning sessions or preseason practices, when an AT may not have been present to provide medical care. This may indicate a limited understanding by the coach regarding the causes of sudden death, signs and symptoms of those conditions, and effective prevention measures. Due to the limited data regarding the knowledge of the secondary school head football coach as it relates to the recognition and prevention of EHS, our goal was to gain coaches'' perspectives on this matter.Athletic trainers and coaches are both integral members of the sports medicine team and, despite different roles and training, must be able to work together to help protect the health and safety of the student–athlete. We also paid particular attention to the coaches'' relationships with ATs. The limited research that exists regarding the professional relationship between the 2 indicates that communication is essential; however, coaches lack a complete understanding of the role and training of the AT.¹⁰ Moreover, the presence of an AT within the secondary school setting appears to provide the secondary school coach with a reason to not maintain skills and knowledge regarding emergency care procedures.^11–17 Therefore, the purpose of this study was to examine secondary school football coaches'' perceived knowledge of EHS as well as the professional relationship that exists between them and ATs.     

Clinical approaches to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)ranges from simple steatosis to nonalcoholic steatohepatitis(NASH),leading to fibrosis and potentially cirrhosis,and it is one of the most common causes of liver disease worldwide.NAFLD is associated with other medical conditions such as metabolic syndrome,obesity,cardiovascular disease and diabetes.NASH can only be diagnosed through liver biopsy,but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis,reducing the need for liver biopsy and risk to patients.Disease progression varies between individuals and is linked to a number of risk factors.Mechanisms involved in the pathogenesis are associated with diet and lifestyle,influx of free fatty acids to the liver from adipose tissue due to insulin resistance,hepatic oxidative stress,cytokines production,reduced very low-density lipoprotein secretion and intestinal microbiome.Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD.Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial.Omega 3 polyunsaturated fatty acids and statins may offer additional benefits.Bariatric surgery should be considered in morbidly obese patients.More research is needed to assess the impact of these treatments on a long-term basis.The objective of this article is to briefly review the diagnosis,management and treatment of this disease in order to aid clinicians in managing these patients.     

Comparing human and mouse salivary glands: A practice guide for salivary researchers

Mice are a widely utilized in vivo model for translational salivary gland research but must be used with caution. Specifically, mouse salivary glands are similar in many ways to human salivary glands (i.e., in terms of their anatomy, histology, and physiology) and are both readily available and relatively easy and affordable to maintain. However, there are some significant differences between the two organisms, and by extension, the salivary glands derived from them must be taken into account for translational studies. The current review details pertinent similarities and differences between human and mouse salivary glands and offers practical guidelines for using both for research purposes.     

Cytokine activation during attacks of the hyperimmunoglobulinemia D and periodic fever syndrome

The hyperimmunoglobulinemia D and periodic fever (hyper-IgD) syndrome is typified by recurrent febrile attacks with abdominal distress, joint involvement (arthralgias/arthritis), headache, skin lesions, and an elevated serum IgD level (> 100 U/mL). This familial disorder has been diagnosed in 59 patients, mainly from Europe. The pathogenesis of this febrile disorder is unknown, but attacks are joined by an acute-phase response. Because this response is considered to be mediated by cytokines, we measured the acute-phase proteins C-reactive protein (CRP) and soluble type-II phospholipase A2 (PLA2) together with circulating concentrations and ex vivo production of the proinflammatory cytokines interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, and tumor necrosis factor alpha (TNF alpha) and the inhibitory compounds IL-1 receptor antagonist (IL-1ra), IL-10, and the soluble TNF receptors p55 (sTNFr p55) and p75 (sTNFr p75) in 22 patients with the hyper-IgD syndrome during attacks and remission. Serum CRP and PLA2 concentrations were elevated during attacks (mean, 213 mg/L and 1,452 ng/mL, respectively) and decreased between attacks. Plasma concentrations of IL-1 alpha, IL-1 beta, or IL-10 were not increased during attacks. TNF alpha concentrations were slightly, but significantly, higher with attacks (104 v 117 pg/mL). Circulating IL-6 values increased with attacks (19.7 v 147.9 pg/mL) and correlated with CRP and PLA2 values during the febrile attacks. The values of the antiinflammatory compounds IL-1ra, sTNFr p55, and sTNFr p75 were significantly higher with attacks than between attacks, and there was a significant positive correlation between each. The ex-vivo production of TNF alpha, IL-1 beta, and IL-1ra was significantly higher with attacks, suggesting that the monocytes/macrophages were already primed in vivo to produce increased amounts of these cytokines. These findings point to an activation of the cytokine network, and this suggests that these inflammatory mediators may contribute to the symptoms of the hyper-IgD syndrome.     

T cells from patients with Hodgkin's disease have a defective T-cell receptor zeta chain expression that is reversible by T-cell stimulation with CD3 and CD28

To investigate the mechanisms underlying the deficiency of T lymphocytes from patients with Hodgkin's disease, we investigated the expression of the T-cell receptor (TCR) zeta chain in patients with Hodgkin's disease. By flow cytometry using an anti-zeta chain monoclonal antibody, peripheral blood T lymphocytes from patients with untreated Hodgkin's disease were shown to express decreased levels of the TCR zeta chain. After stimulation by combined CD3 and CD28 cross- linking, T cells from Hodgkin's disease patients upregulated zeta chain protein expression to normal values within 48 hours and achieved a cytolytic potential and levels of interleukin (IL)-2 secretion that were not different from T cells obtained from healthy controls. These results show that downregulation of the TCR zeta chain in Hodgkin's T lymphocytes is a reversible event. Costimulation of CD3 and CD28 is a novel approach for overcoming the T-cell deficiency in Hodgkin's disease and might be exploited clinically. As upregulation of the zeta chain can also be achieved using bispecific monoclonal antibodies (BI- MoAbs) with specificity for tumor antigens and CD3 and CD28, respectively, an immunotherapy with CD3/CD30 and CD28/CD30 Bi-MoAbs may overcome and should therefore, not be jeopardized by the inherent T- cell deficiency in patients with Hodgkin's disease.     

High incidence of monoclonal proteins in the serum and urine of chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) is generally considered a nonsecretory B cell immunoproliferative disorder. Conventional electrophoretic and immunoelectrophoretic methods have revealed serum monoclonal proteins in less than 10% of these patients. However, there is increasing experimental evidence from in vitro studies demonstrating that CLL cells may secrete immunoglobulins, particularly free light chains. We examined the serum and urine of 36 consecutive CLL patients for monoclonal proteins using sensitive immunochemical methods (high resolution agarose gel electrophoresis combined with immunofixation). The results obtained were correlated with the Rai stage, quantitative immunoglobulin levels, and lymphocyte membrane immunoglobulin phenotype of the leukemic cells. Twenty-three monoclonal proteins were identified in the serum or urine of 22 patients, an incidence of 61%. Six patients had serum monoclonal proteins, seven had only urinary monoclonal proteins, and nine had monoclonal proteins in serum and urine. In every instance the monoclonal protein was the same light chain type as expressed on the leukemic cells. Our findings suggest that the monoclonal proteins observed in the serum or urine of CLL patients are secretory products of the tumor cells and that their discovery is a function of the sensitivity of the method used for their detection.