Israel Medical Association Journal

Background: The presence of anti-cyclic citrullinated peptide autoantibody is highly specific for rheumatoid arthritis. Certain HLA-DR4 (HLA-DRB1*04) alleles, also known as the "shared epitope," are associated with increased susceptibility to RA[1]. In addition, these alleles may also have relevance for disease outcome. Anti-CCP[2] antibody positivity has been associated with the presence of HLA-DR4 alleles in patients with RA. However, there is little information available regarding any relationship between quantitative anti-CCP production (serum anti-CCP concentrations) and the shared epitope.

Objectives: To determine the association between anti-CCP antibody production and various HLA-DRB1 alleles.

Methods: Serum anti-CCP, rheumatoid factor and C-reactive protein levels were assessed in 53 RA patients. All these patients underwent HLA-DRB1 genotyping.

Results: Of the 53 patients 33 (62%) were positive for anti-CCP antibody. We found significant correlations between anti-CCP and RF[3] positivity (chi-square = 6.717, P < 0.01), as well as between anti-CCP and HLA-DRB1*04 positivity (chi-square = 5.828, P < 0.01). There was no correlation between RF positivity and serum levels, CRP[4] serum levels and HLA-DRB1*04 positivity. When quantitatively comparing serum anti-CCP levels with shared epitope positivity, patients carrying one or two copies of HLA-DRB1*04 alleles had significantly higher anti-CCP concentrations (530.0 ± 182.6 U/ml) compared to DRB1*04-negative patients (56.8 ± 27.4 U/ml) (P < 0.01). There was no difference in serum anti-CCP antibody concentrations between patients carrying only one HLA-DRB1*01 allele but no HLA-DRB1*04 allele (12.0 ± 8.6 U/ml) in comparison to SE[5]-negative patients (76.8 ± 56.2 U/ml). Regarding non-SE HLA-DRB1 genotypes, all 6 patients (100%) carrying DRB1*15 alleles and 6 of 7 (85%) patients carrying DRB1*13 were anti-CCP positive. In addition, patients with HLA-DRB1*13 (282.5 ± 23.8 U/ml) and DRB1*15 (398.7 ± 76.2 U/ml) produced significantly more anti-CCP than did any other non-SE HLA-DRB1 subtypes (P < 0.01).

Conclusions: There is significant association between anti-CCP and RF, as well as between anti-CCP and SE positivity in RA. In addition, the presence of one or two copies of HLA-DRB1*04 alleles has been associated with higher serum anti-CCP antibody levels. Thus, patients carrying HLA-DRB1*04 alleles exhibited an overall tenfold increase in serum anti-CCP antibody levels in comparison to HLA-DRB1*04-negative subjects. Increased anti-CCP production may also be associated with other non-SE HLA-DRB1 genotypes, such as DRB1*13 or DRB1*15. In reports by other investigators, both anti-CCP concentrations

Background: Non-operative management of blunt splenic trauma is the preferred option in hemodynamically stable patients.

Objectives: To identify predictors for the successful non-operative management of patients with blunt splenic trauma.

Methods: The study group comprised consecutive patients admitted with the diagnosis of blunt splenic trauma to the Department of Surgery, Hadassah-Hebrew University Medical Center in Jerusalem over a 3 year period. Prospectively recorded were hemodynamic status, computed tomography grade of splenic tear, presence and extent of extra-abdominal injury, number of red blood cell units transfused, and outcome. Hemodynamic instability and the severity of associated injuries were used to determine the need for splenectomy. Hemodynamically stable patients without an indication for laparotomy were admitted to the Intensive Care Unit and monitored.

Results: There were 64 adults (45 males, mean age 30.2 years) who met the inclusion criteria. On univariate analysis the 13 patients (20.3%) who underwent immediate splenectomy were more likely to have lower admission systolic blood pressure (P = 0.001), Glasgow Coma Scale < 8 (P = 0.02), and injury to at least three extra-abdominal regions (P = 0.06). Nine of the 52 patients (17.3%) who were successfully treated non-operatively suffered from grade ≥4 splenic tear. Multivariate analysis identified admission systolic BP[1] (odds ratio 1.04) and associated injury to less than three extra-abdominal regions (OD[2] 8.03) as predictors for the success of non-operative management, while the need for blood transfusion was a strong predictor (OR 66.67) for splenectomy.

Conclusions: Admission systolic blood pressure and limited extra-abdominal injury can be used to identify patients with blunt splenic trauma who do not require splenectomy and can be safely monitored outside an ICU[3] environment. 

Background: Depression is a leading cause of morbidity, disability and health care utilization. It is commonly encountered in primary care settings yet is often missed or suboptimally managed.

Objective: To summarize studies conducted in Israel on the prevalence of depression in primary care settings, its correlates, and predictors of treatment and outcome, and to discuss their implications for clinical practice and public health policy.

Methods: An electronic search was conducted using the MEDLINE and PsychINFO databases. The inclusion criteria were original studies that assessed aspects of depression in a population aged 18 or older, were conducted in primary care settings in Israel, and with sufficient detailed description of depression-related measures, study sample and outcome measures. Twelve articles reporting results from 7 studies met these criteria.

Results: The prevalence of current depression in primary care varied considerably across studies: 1.6–5.9% for major depression, 1.1–5.4% for minor depression, 14.3–24% for depressive symptoms. Depression was consistently related to female gender and few years of education, and was associated with disability, decreased quality of life, and increased health-related expenditure. Many cases of depression were undiagnosed and most patients had persistent depression or achieved only partial remission.

Conclusions: Depression represents a serious challenge for the primary health care system in Israel. Greater efforts should be focused on screening and treating depression in primary care. However, the studies reviewed here used different methodologies and assessed different aspects of depression, and, therefore, should be generalized cautiously. Systematic research on the prevalence, correlates and management of depression in primary care, with emphasis on collaborative care models, is strongly needed to inform research, clinicians and health care policy makers.

Background: Left ventricular outflow gradient is associated with increased morbidity and mortality in hypertrophic cardiomyopathy. Alcohol septal ablation is the alternative to surgery in cases refractory to drug therapy. The implication of LVOG[1] measured 1 week post-ASA[2] for prediction of outcome is unknown.

Objective: To observe the pattern of LVOG course and prediction of long-term clinical and hemodynamic outcome of ASA.

Methods: Baseline clinical and echocardiographic parameters were prospectively recorded in 14 consecutive patients with a first ASA, at the time of ASA, 3 and 7 days after ASA (in-hospital) and 3 and ≥ 12 months after ASA (last follow-up).

Results: There was improvement in NYHA class, exercise parameters and LVOG in 11 of 14 patients (P < 0.005 in all). Maximal creatine kinase level was lower than 500 U/L in those without such improvement and 850 U/L or higher in successful cases. LVOG dropped from 79 ± 30 to 19 ± 6 mmHg after the ASA. LVOG was 50 ± 21 mmHg on day 3, 39 ± 26 on day 7, 32 ± 26 at 3 months and 24 ± 20 mmHg at last follow-up. LVOG identified 27% sustained procedural successes on day 3 and 73% on day 7. The overall predictive accuracy of the test for sustained success and failure was 36% on day 3 and 71% on day 7. Combination of maximal CK[3] and LVOG on day 7 showed four distinct outcome patterns: "early success" with low LVOG and high CK (73% of successful cases), "late success" with high LVOG and high CK, and "early failure" and "late failure" with both low CK and high or low LVOG, respectively
Conclusion: LVOG measurement 7 days post-ASA combined with maximal CK levels predicts late procedural outcome in the majority of patients

Background: Recently the Joint National Committee (7th report) introduced the term “pre-hypertension.” Little is known on its prevalence in the general population.

Objectives: To assess the prevalence of pre-hypertension in a large national cohort.

Methods: We analyzed the database of all ≥ 18 year old members of Leumit Health Services, one of the four health management organizations in Israel, from which we retrieved the recorded blood pressure levels. Pre-hypertension was defined according to the JNC-7[1] criteria.

Results: Of the 426,033 subjects 18.6% had a diagnosis of hypertension or used antihypertensive medications. Only 40.8% of the other 346,799 subjects had had their BP[2] measured in the preceding 2 years. BP recording rates were higher in females than in males (45.1% vs. 36.3%) and higher in elderly subjects than in young subjects (56% aged 66–75 years vs. 32% aged 18–25). Pre-hypertension was observed in 80,625 (23.2%) of the 346,799 while only 56,113 (16.2%) had normal BP records. The prevalence of pre-hypertension increased with age (13.3% aged 18–25 vs. 44.8% aged 66–75), and was more prevalent in men than in women (24.0% vs. 22.5%).

Conclusions: BP levels among young people are low, even though the prevalence of pre-hypertension in this population may be high. Thus, more emphasis should be given to routine BP measurements and confirmation of the findings in all age groups.

Objective: To report our experience with terlipressin treatment for facilitation of transport to distant facilities for diagnostic or therapeutic procedures in septic patients treated with norepinephrine.

Methods:  We conducted a retrospective analysis of the records of our ICU[1], identifying the patients with septic shock who required norepinephrine for hemodynamic support.

Results: Terlipressin was given to 30 septic shock patients (15 females and 15 males) who were on high dose norepinephrine (10 μg/min or more) in order to facilitate their transport outside the ICU. The dose of terlipressin ranged from 1 to 4 mg, with a mean of 2.13 ± 0.68 mg. The dose of norepinephrine needed to maintain systolic blood pressure above 100 mmHg decreased following terlipressin administration, from 21.9 ± 10.4 μg/min (range 5–52 μg/min) to 1.0 ± 1.95 (range 0–10) (P < 0.001). No patients required norepinephrine dose adjustment during transport. No serious complications or overshoot in blood pressure values were observed following terlipressin administration. Acrocyanosis occurred only in eight patients receiving more than 1 mg of the drug. The overall mortality rate was 50%.

Conclusions: Our data suggest that terlipressin is effective in septic shock. Because it is long-acting and necessitates less titration it might be indicated for patient transportation.

Objectives: To identify patients with PPD and to describe their consultation patterns with primary care physicians for themselves and their babies.

Methods: Using a telephone survey and the Edinburgh Postnatal Depression Scale questionnaire we identified PPD in a sample of women who gave birth in HaEmek Medical Center. We also assessed the extent to which the women consulted with family physicians, gynecologists and/or pediatricians.

Results: The survey included 574 women, of whom 9.9% were diagnosed with PPD. There was a higher rate of PPD among Arab compared to Jewish women, among women with a prior history of depression, among women whose pregnancy was unplanned, among those who described the course of pregnancy as “difficult,” and among women who described their general health as “not good.” Women with PPD consulted more with family physicians and pediatricians. The reasons for the consultations are physical and emotional. There were cases of somatization manifested directly by the mother or indirectly through the baby.

Conclusions: Women with PPD have higher consultation rates than those without. By asking a few simple questions it is possible to identify a significant proportion of women with PPD.

The Ink4a-Arf locus, which encodes two distinct tumor suppressor proteins, is inactivated in many cancers. Whereas p16^Ink4a is an inhibitor of cyclin D-dependent kinases, p19^Arf (p14^ARF in humans) antagonizes the E3 ubiquitin protein ligase activity of Mdm2 to activate p53. We now recognize that Arf functions in both p53-dependent and -independent modes to counteract hyper-proliferative signals originating from proto-oncogene activation, but its p53-independent activities remain poorly understood. Arf proteins are highly basic (> 20% arginine content, pI > 12) and predominantly localize within nucleoli in physical association with an abundant acidic protein, nucleophosmin (NPM/B23). When bound to NPM[1], Arf proteins are relatively stable with half-lives of 6–8 hours. Although mouse p19^Arf contains only a single lysine residue and human p14^ARF has none, both proteins are N-terminally ubiquitinated and degraded in proteasomes. Through as yet uncharacterized mechanisms, p19^Arf induces p53-independent sumoylation of a variety of cellular target proteins with which it interacts, including both Mdm2 and NPM. A naturally occurring NPM mutant (NPMc) expressed in myeloid leukemia cells redirects both wild-type NPM and p19^Arf to the cytoplasm, inhibits Arf-induced sumoylation, and attenuates p53 activity. Thus, ubiquitination and sumoylation can each influence Arf tumor suppressor activity.