Coronary heart disease mortality among Arab and Jewish residents of Jerusalem

Information on coronary heart disease (CHD) in the Palestinian population is sparse. We compared mortality rates in the largely Palestinian Arab population of Jerusalem with the Jewish population of the district between 1984 and 1997 based on official Israeli statistics. CHD mortality and all-cause mortality rates were significantly higher among Arab residents than among Jewish residents aged 35-74 years. Whether the excess CHD mortality reflects increased incidence of events, higher case fatality, or both remains to be established. Possible explanations include a higher prevalence of conventional risk factors such as diabetes, obesity, and smoking in Palestinians, stress effects related to the complex political situation and socioeconomic inequalities, and suspected differences in medical care.     

The Mortality Risk Among Persons with Psychiatric Hospitalizations

Background: Persons affected by severe mental disorders have a higher mortality risk than the general population. Objectives: To investigate the overall mortality and selected natural and external causes of death by age, gender and mental health-related variables among persons who were ever admitted to psychiatric inpatient services. Methods: This cohort study compared the mortality risk among Israeli Jews aged 18 and over who were ever hospitalized in psychiatric facilities until 2006, as recorded in the Psychiatric Case Register (PCR), with never- hospitalized subjects. The national database on causes of death was linked to the PCR. Analysis: Mortality rates were computed by age, gender and psychiatric diagnosis, while proportions of deaths were computed by time from discharge. Rates were also analyzed by time-periods of date of death to check for possible association with mental health policy decisions. Age-adjusted and age-specific mortality rates and rate ratios (RR) were computed for persons in the PCR compared with those never hospitalized. Results: The age-adjusted mortality rate of hospitalized psychiatric persons was double that of the nonhospitalized, RR = 1.98 (95% CI 1.96-2.00). The rate was higher in both genders and for persons of all age groups, particularly for the young. The highest RRs were found for external causes of death, in particular suicide (RR = 16.34, 95% CI 15.49-17.24). Natural causes also showed higher risk, except for malignancies (RR = 1.13, 95% CI 1.10- 1.16). The risk for death was highest for persons admitted for substance abuse, while it was almost equal for those diagnosed with either schizophrenic or affective disorders. The rate ratios were not observed to change as a result of policy decisions, e.g., dehospitalization and the introduction of the atypical antipsychotics. A third of all deaths and 62% of suicides occurred before discharge or within a year from discharge. Conclusions: This study highlights the importance for advancing programs of both preventative and curative medical care among persons who had psychiatric inpatient care.     

Prospective surveillance of phlebitis associated with peripheral intravenous catheters

BACKGROUND: Guidelines have been published for prevention of phlebitis associated with peripheral intravenous catheters (IVC), but this complication continues to occur. We sought to determine the rate of phlebitis associated with peripheral IVCs to identify predictors for phlebitis and to isolate pathogenic bacteria from phlebitic catheter tips. METHODS: Nine-point prevalence studies were conducted during the years 1996-2003 of all hospitalized patients with a peripheral IVC. During the last 3 surveys, conducted in 2003, phlebitic lines were removed, and, for each line, 1 to 2 nonphlebitic lines, in place for 48 to 72 hours, were removed and cultured as controls. In between these surveys, findings and guidelines for improvement were distributed to the staff. RESULTS: During these surveys, 40% +/- 8% of hospitalized patients had a peripheral IVC. The rate of peripheral IVC-associated phlebitis decreased from 12.7% (20/157) in 1998 to 2.6% (5/189) in 2003 (P < .01). Factors significantly associated with phlebitis included pain (P < .001), presence of the catheter for longer than 3 days (P < .05), and cleanliness of the dressing (P < .01). CONCLUSION: The rate of phlebitis associated with peripheral intravenous catheters decreased significantly throughout the study period. The identification of predictors for phlebitis and the dissemination of this information in an educational drive may have contributed to this improvement.     

Orally administered FTS (salirasib) inhibits human pancreatic tumor growth in nude mice

Background S-trans,trans-farnesylthiosalicylic acid (salirasib, FTS) is a synthetic small molecule that acts as a potent Ras inhibitor. Salirasib inhibits specifically both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. The objectives of this study were to develop a sensitive LC-MS/MS assay for determination of FTS in plasma, to assess the bioavailabilty of FTS after oral administration to mice, and then to examine the efficacy of orally administered FTS for inhibition of tumor growth in a nude mouse model. Methods FTS was isolated from mouse plasma by liquid chromatography on a Columbus 5-μm particle size, 50 × 2 mm id column with a methanol/5 mM ammonium acetate (80/20) mobile phase (isocratic elution) at a flow rate of 0.3 ml/min. MS/MS was performed on a PE Sciex API 365 with Turbo Ion Spray as interface and negative ion ionization; parent ion (m/z): 357.2; daughter ion (m/z) 153.2; retention time 2.3 min. For plasma analysis, the amount of analyte in each sample was calculated by comparing response of the analyte in that sample to a nine-point standard curve linear over the range 3–1000 ng/ml. Pharmacokinetic studies were performed in mice following intraperitoneal dosing (20 mk/kg in PBS) or oral dosing (40 mg/kg in either 0.5% aqueous CMC or corn oil). Panc-1 tumor growth in nude mice was determined following daily oral dosing with FTS in 0.5% CMC (40, 60, or 80 mg/kg), or in combination with weekly gemcitabine (30 mg/kg). Results Salirasib was readily detected in mouse plasma by LC-MS/MS at a detection limit of 3 ng/ml. For each route of administration, t _max was 1 h and t _1/2 ranged from 1.86 to 2.66 h. Compared to IP administration, the oral bioavailabilty of FTS was 69.5% for oral CMC and 55% for oral corn oil suspensions, while clearance and volume of distribution were higher in both oral preparations. The orally administered salirasib inhibited panc-1 tumor growth in a dose dependent manner (67% reduction in tumor weight at the highest dose, P < 0.002 vs. control, n = 10 mice per group) and at a 40 mg/kg daily dose was synergistic with gemcitabine (83% increase in survival rate, n = 8 mice per group). Conclusions Salirasib exhibits good bioavailabilty after oral administration, as determined by a highly sensitive method for quantification in plasma. The orally available Ras inhibitor salirasib inhibited growth in nude mice, and may thus be considered for clinical trials.     

The Ras inhibitor S-trans,trans-farnesylthiosalicylic acid chemosensitizes human tumor cells without causing resistance.

Ras transformation requires Ras membrane anchorage, which is promoted by a farnesylcysteine carboxymethyl ester and by additional sequences specific to each Ras isoform. We showed previously that S-trans,trans-farnesylthiosalicylic acid (FTS) disrupts Ras membrane anchorage and that this disturbance contributes to inhibition of cell transformation and tumor growth. Most tumor cells develop resistance to anticancer agents. Here we examined whether tumor cells develop resistance to FTS and evaluated the therapeutic potential of FTS combined with cytotoxic drugs, because oncogenic Ras promotes antiapoptotic signals in tumors of epithelial origin. We showed that Panc-1 pancreatic cancer cells, SW480 colon cancer cells, and H-ras (EJ)-transformed Rat-1 fibroblasts exposed to FTS for prolonged periods (>6 months) do not escape FTS-induced growth inhibition and do not develop drug resistance. These cells continued to express reduced amounts of Ras, exhibit a reversed phenotype, and show an altered response to the cytotoxic drugs doxorubicin and gemcitabine. FTS-treated Panc-1 or SW480 cells acquired sensitivity to the cytotoxic drugs, whereas FTS-treated EJ cells lost sensitivity to doxorubicin, reflecting the opposite effects of oncogenic Ras on the survival of epithelial cells and fibroblasts. Treatment with FTS led to a marked increase in sensitivity to gemcitabine of the formerly resistant SW480 cells and a 100-fold increase in sensitivity to gemcitabine of Panc-1 cells. Such treatment in mice with preexisting Panc-1 tumors provided a synergistic effect of FTS and gemcitabine, leading to enhanced inhibition of tumor growth and a 65% increase in survival rate.     

Hypertension in late adolescence and cardiovascular mortality in midlife: a cohort study of 2.3 million 16- to 19-year-old examinees

Background

The effect of early hypertension on midlife cardiovascular (CV) mortality remains controversial. We assessed the association of established hypertension in late adolescence with subsequent CV mortality.

Methods

Of 2,298,130 Israeli adolescents (60 % males; age 17.4?±?0.3 years) who underwent a compulsory medical examination prior to military service between 1967 and 2010, 8720 teenagers (0.4 %) were formally diagnosed with persistent hypertension. Using Cox proportional hazards modeling, we compared the hypertensive group to the large normotensive group with regard to time to event analysis of midlife mortality due to cerebrovascular accidents (CVA), coronary heart disease (CHD), sudden death (SD) and their summation as cardiovascular disease (CVD).

Results

During 45,729,521 person-years of follow-up, we identified 2918 CV deaths—2879 and 39 among the 2,289,410 normotensive and 8720 hypertensive adolescents, respectively. Hypertension at a young age was associated with a threefold elevation of stroke mortality compared to normotension when adjusted for sex, age at examination, birth year, country of origin, socioeconomic status, education, body mass index (BMI) and height [hazard ratio (HR) 3.12; 95 % confidence interval (CI)?1.76–5.54; p?<?0.001]. There was no significant association of hypertension with CHD mortality or SD. An increased risk for overall CVD mortality among hypertensive youngsters (HR 1.51; 95 % CI 1.10–2.07) was attenuated after adjusting for BMI and other covariates (HR 1.24; 95 % CI 0.90–1.72).

Conclusions

Established hypertension at a young age was independently associated with elevated stroke mortality in midlife. This finding warrants confirmatory large-scale long-term follow-up studies to address the distant effects of adolescent hypertension.

     

Infant mortality in Israel during 1950-2000: rates, causes, demographic characteristics and trends

We evaluated the trends and risk factors in infant mortality in Israel over five decades (1950-2000), based on data obtained from the official notifications of live births, and death certificates. Until the 1960s the main cause of infant mortality was infectious disease; this was replaced by congenital anomalies in Moslems and Druzes, and preterm birth in Jews and Christians. In 2000, there were 746 infant deaths, and the national infant mortality rate (IMR) was 5.4 per 1000 live births (Jews 3.9; [95% CI 3.5, 4.3]; Moslems 9.2 [8.3, 10.3]; Christians 3.6 [1.4, 5.8]; Druzes 6.3 [3.6, 9.0]). Between 1955 and 2000 the overall IMR declined sevenfold (absolute declines of 56.8, 56.3, 45.0 and 28.3 per 1000 live births, in Moslems, Druzes, Christians and Jews, respectively). The reduction in IMRs between 1990 and 2000 in all religious groups (>45%) exceeded the goal set by the World Summit for Children in 1990 of 33%. In 2000, the main risk factors were birthweight < 1500 g [relative risk (RR) = 69], major congenital malformations (RR = 22.0 [18.8, 25.7], and multiple births (RR of 9.3 and 4.2 in triplets and twins respectively). We conclude that the marked decline in IMRs in Israel over five decades reflects a major improvement in population health. Today, infant mortality in Israel represents a unique combination of high rate of congenital malformations among Moslems, where consanguineous marriages are common, and medical termination of pregnancy of malformed fetuses are infrequent; and relatively high IMRs from preterm birth in Jews, associated with high rates of assisted reproduction.