Amnon Lahad

Chapter 2. European guidelines for prevention in low back pain : November 2004.

Summary of the concepts of prevention in low back pain (LBP): • The general nature and course of commonly experienced LBP means that there is limited scope for preventing its incidence (first-time onset). Prevention, in the context of this guideline, is focused primarily on reduction of the impact and consequences of LBP. • Primary causative mechanisms remain largely undetermined: risk factor modification will not necessarily achieve prevention. • There is considerable scope, in principle, for prevention of the consequences of LBP – e.g. episodes (recurrence), care seeking, disability, and workloss. • Different interventions and outcomes will be appropriate for different target populations (general population, workers, and children) yet inevitably there is overlap. • Interventions that are essentially treatments in the clinical environment, focused on management of current symptoms, are not considered as ‘prevention’ for the purposes of this guideline: they are covered in the accompanying clinical guidelines

A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers

BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5′ untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6–9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3–9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.

Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2

Significance Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose to very high risks of breast and ovarian cancer. For carriers of these mutations, risk-reducing surgery significantly reduces morbidity and mortality. General population screening for BRCA1 and BRCA2 mutations in young adult women could be feasible if accurate estimates of cancer risk for mutation carriers could be obtained. We determined that risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained from the general population are as high as for mutation carriers ascertained through personal or family history of cancer. General screening of BRCA1 and BRCA2 would identify many carriers who are currently not evaluated and could serve as a model for population screening for genetic predisposition to cancer. In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Population-Based Screening for BRCA1 and BRCA2 2014 Lasker Award

The 2014 Lasker-Koshland Special Achievement Award in Medical Science has been presented to Dr Mary-Claire King to recognize and honor her “for bold and imaginative contributions to medical science and society – exemplified by her discovery of a single gene BRCA1 that causes a ... form of hereditary breast cancer ...” This Viewpoint describes the application of that discovery, and suggests that populationbased screening of women for BRCA1 and BRCA2 should become a routine part of clinical practice.

Echocardiographic assessment of pulmonary hypertension in Gaucher's disease

BACKGROUND Enzyme therapy has been shown to decrease the signs and symptoms of Gauchers disease. A few patients, however, develop pulmonary hypertension on such treatment. We investigated the frequency of pulmonary hypertension in Gauchers disease. METHODS We studied 134 adults with type 1 Gauchers disease, including 73 patients on enzyme replacement, with echocardiography. We measured tricuspid incompetence (TI) with continuous-wave doppler. Pulmonary hypertension was indicated by a TI gradient of more than 30 mm Hg. FINDINGS Nine (7%) patients had pulmonary hypertension: all were treated and six had undergone splenectomy. Chest radiographs confirmed the presence of pulmonary hypertension in these patients as well as in most patients with TI gradients of 25-29 mm Hg. INTERPRETATION The confounding effects of disease severity and splenectomy in many treated patients precluded definitive conclusion of cause and effect. Nonetheless, we found an unexpectedly high rate of pulmonary hypertension and recommended routine echocardiographic monitoring of all treated and untreated patients with type 1 Gauchers disease. We also suggest consideration of treatment withdrawal if the TI gradient progresses to more than 30 mm Hg.

Tricuspid Incompetence Following Permanent Pacemaker Implantation

Aim: Severe tricuspid insufficiency (TI) after permanent pacemaker implantation (PPI) has been described in small series of patients, though its incidence is not known.

Use of complementary medicine in children with attention deficit hyperactivity disorder and epilepsy

We retrospectively studied use of complementary medicine in children with Attention Deficit Hyperactivity Disorder, epilepsy, and controls. Parents of patients with Attention Deficit Hyperactivity Disorder (n = 120; mean age 11.0 +/- 3.1 years), epilepsy (n = 115; 10.9 +/- 5.5), and healthy children seen in the emergency room during an acute illness (n = 115; 5.0 +/- 4.9) were individually interviewed regarding past and present use of complementary medicine. We found that 34 children with Attention Deficit Hyperactivity Disorder, 37 with epilepsy, and 24 controls had, at some time during their life, received complementary medicine: diet (n = 50), homeopathy (n = 46), acupuncture (n = 23), and biofeedback (n = 9). Current use was significantly less: Attention Deficit Hyperactivity Disorder- 7.5%, epilepsy-14%, and controls-7%. No differences among groups were found for either past use or method of complementary medicine employed. However, the most significant predictor for current use of complementary medicine was past use (OR 3.2, P < 0.001), followed by level of fathers education (OR = 1.16, P = 0.01). There was a trend for more children with epilepsy (OR = 1.7) and children from religious families (OR = 1.51) to be currently receiving complementary medicine. In summary, only a small minority of patients with either Attention Deficit Hyperactivity Disorder or epilepsy used complementary medicine as part of their current medical regimen, although during their lifetime a third had received complementary medicine. Complementary medicine was more consistently used in children who had previously received complementary medicine, regardless of their medical diagnosis.

Is there a correlation between degree of splenomegaly, symptoms and hypersplenism? A study of 218 patients with Gaucher disease

Despite the prevalence of splenomegaly as a sign in many disorders, there have been no studies that correlate the degree of organomegaly with the symptoms generally ascribed to splenic enlargement. The degree of splenomegaly was compared with five overt symptoms of mechanical displacement, i.e. chronic abdominal pain, abdominal discomfort, early satiety, pain while lying on the side, or attacks of acute (colicky) left upper quadrant pains. We have also employed splenomegaly as seen in Gaucher disease as a paradigm to determine whether there is a correlation between the degree of splenomegaly and the parameters of hypersplenism. Although there was a statistically significant correlation between degree of splenomegaly and blood counts, this proved to be clinically negligible. Surprisingly, there was also no correlation between degree of splenomegaly and any of symptoms investigated.

A controlled randomized study of the effect of training with orthoses on the incidence of weight bearing induced back pain among infantry recruits

Study Design. Randomized controlled trial. Objectives. To determine if the use of custom shoe orthoses can lessen the incidence of weight bearing-induced back pain. Summary of Background Data. The scientific basis for the use of orthoses to prevent back pain is based principally on studies that show that shoe orthoses can attenuate the shock wave generated at heel strike. The repetitive impulsive loading that occurs because of this shock wave can cause wear of the mechanical structures of the back. Previous randomized studies showed mixed results in preventing back pain, were not blinded, and used orthoses for only short periods of time. Methods. A total of 404 eligible new infantry recruits without a history of prior back pain were randomly assigned to received either custom soft, semirigid biomechanical, or simple shoe inserts without supportive or shock absorbing qualities. Recruits were reviewed biweekly by an orthopaedist for back signs and symptoms during the course of 14 weeks of basic training Results. The overall incidence of back pain was 14%. By intention-to treat and per-protocol analyses, there was no statistically significant difference between the incidence of either subjective or objective back pain among the 3 treatment groups. Significantly more recruits who received soft custom orthoses finished training in their assigned orthoses (67.5%) than those who received semirigid biomechanical orthoses (45.5%) or simple shoe inserts (48.6%), P = 0.001. Conclusions. The results of this study do not support the use of orthoses, either custom soft or semirigid biomechanical, as prophylactic treatment for weight bearing-induced back pain. Custom soft orthoses had a higher utilization rate than the semirigid biomechanical or simple shoe inserts. The pretraining physical fitness and sports participation of recruits were not related to the incidence of weight bearing-induced back pain.

Hostility, aggression and the risk of nonfatal myocardial infarction in postmenopausal women

Hostility can predict coronary heart disease (CHD) and total mortality in men. However, in women this association has not been as thoroughly explored. This study examines whether hostile and aggressive attitudes are associated with myocardial infarction (MI) in postmenopausal women. Cases included 277 women who presented with an incident MI. Controls included a random sample of 988 female health maintenance organization enrollees. Women were asked the Hostile-Affect and the Aggressive-Responding factors of the Cook-Medley Hostility Scale. The Hostile-Affect score was linearly associated with increased risk for MI (odds ratio [OR] per point = 1.22; 95% confidence interval [CI95%] = 1.07-1.38), whereas the Aggressive-Responding score had a modest protective effect (OR = 0.92 per point; CI95% = 0.84-1.02); p = 0.009. Adjustment for sociodemographic and MI risk factors altered these results only slightly. These hostility measures are easily administered, and could help to identify women who are at high risk for CHD and who may benefit from preventive measures.