Overcoming resistance to BRAFV600E inhibition in melanoma by deciphering and targeting personalized protein network alterations.

BRAFV600E melanoma patients, despite initially responding to the clinically prescribed anti-BRAFV600E therapy, often relapse, and their tumors develop drug resistance. While it is widely accepted that these tumors are originally driven by the BRAFV600E mutation, they often eventually diverge and become supported by various signaling networks. Therefore, patient-specific altered signaling signatures should be deciphered and treated individually. In this study, we design individualized melanoma combination treatments based on personalized network alterations. Using an information-theoretic approach, we compute high-resolution patient-specific altered signaling signatures. These altered signaling signatures each consist of several co-expressed subnetworks, which should all be targeted to optimally inhibit the entire altered signaling flux. Based on these data, we design smart, personalized drug combinations, often consisting of FDA-approved drugs. We validate our approach in vitro and in vivo showing that individualized drug combinations that are rationally based on patient-specific altered signaling signatures are more efficient than the clinically used anti-BRAFV600E or BRAFV600E/MEK targeted therapy. Furthermore, these drug combinations are highly selective, as a drug combination efficient for one BRAFV600E tumor is significantly less efficient for another, and vice versa. The approach presented herein can be broadly applicable to aid clinicians to rationally design patient-specific anti-melanoma drug combinations.

Water-carbon dioxide solid phase equilibria at pressures above 4 GPa.

A solid phase in the mixed water-carbon dioxide system, previously identified as carbonic acid, was observed in the high-pressure diamond-anvil cell. The pressure-temperature paths of both its melting and peritectic curves were measured, beginning at 4.4 GPa and 165 °C (where it exists in a quadruple equilibrium, together with an aqueous fluid and the ices H2O(VII) and CO2(I)) and proceeding to higher pressures and temperatures. Single-crystal X-ray diffraction revealed a triclinic crystal with unit cell parameters (at 6.5 GPa and 20 °C) of a = 5.88 Å, b = 6.59 Å, c = 6.99 Å, α = 88.7°, ß = 79.7°, and γ = 67.7°. Raman spectra exhibit a major line at ~1080 cm-1 and lattice modes below 300 cm-1.

Risk Factors for Hospitalization of Home Hospice Enrollees Development and Validation of a Predictive Tool.

BACKGROUND: Over 10% of hospice patients experience at least 1 care transition 6 months prior to death. Transitions at the end of life, particularly from hospice to hospital, result in burdensome and fragmented care for patients and families. Little is known about factors that predict hospitalization in this population. OBJECTIVES: To develop and validate a model predictive of hospitalization after enrollment into home hospice using prehospice admission risk factors. DESIGN: Retrospective cohort study using Medicare fee-for-service claims. PARTICIPANTS: Patients enrolled into the Medicare hospice benefit were ≥18 years old in 2012. OUTCOME MEASURED: Hospitalization within 2 days from a hospice discharge. RESULTS: We developed a predictive model using 61 947 hospice enrollments, of which 3347 (5.4%) underwent a hospitalization. Seven variables were associated with hospitalization: age 18 to 55 years old (adjusted odds ratio [95% confidence interval]: 2.94 [2.41-3.59]), black race (2.13 [1.93-2.34]), east region (1.97 [1.73-2.24]), a noncancer diagnosis (1.32 [1.21-1.45]), 4 or more chronic conditions (8.11 [7.19-9.14]), 2 or more prior hospice enrollments (1.75 [1.35-2.26]), and enrollment in a not-for-profit hospice (2.01 [1.86-2.18]). A risk scoring tool ranging from 0 to 29 was developed, and a cutoff score of 18 identified hospitalized patients with a positive predictive value of 22%. CONCLUSIONS: Reasons for hospitalization among home hospice patients are complex. Patients who are younger, belong to a minority group, and have a greater number of chronic conditions are at increased odds of hospitalization. Our newly developed predictive tool identifies patients at risk for hospitalization and can serve as a benchmark for future model development.

Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling.

The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFß; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.

Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling.

It is well known that specific signal transduction inhibitors rarely suffice as anti-cancer agents. In most cases, tumors possess primary drug resistance due to their inherent heterogeneity, or acquire drug resistance due to genomic instability and acquisition of mutations. Here we expand our previous study of the novel compound, NT157, and show that it acts as a dual-targeting agent that invokes the blockage of two signal transduction pathways that are central to the development and maintenance of multiple human cancers. We show that NT157 targets not only IGF1R-IRS1/2, as previously reported, but also the Stat3 signaling pathway and demonstrates remarkable anti-cancer characteristics in A375 human melanoma cells and in a metastatic melanoma model in mice.

Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis.

Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.

Physical influences on right ventricular infarction and cardiogenic shock in acute myocardial infarction.

AIM: To determine if complicated acute myocardial infarction (AMI) is related to specific cosmophysical activities. METHODS: The study group included 1170 patients who had undergone primary percutaneous coronary intervention (PCI) for AMI in 2000-2006. Geomagnetic and cosmic ray (neutron) activity (GMA, CRA) on the day of PCI were derived from international observatories. The findings were compared among patients with right ventricular infarction (RVI), cardiogenic shock, and uncomplicated AMI. RESULTS: Relative to the whole study period, the mean CRA was higher on days on which PCI was performed for RVI (n=123, 10.5%) (p = .0003) and cardiogenic shock (n=102, 8.72%) (p = .018). When the same artery was involved (LAD, RCA, CRX), CRA was significantly higher for complicated than for uncomplicated AMI (RVI group: p = .006, p = .00027, p = .014, c ardiogenic shock: p = .009, p = .029, p = .089, respectively). At the highest levels of GMA, more RVI cases were seen than cases of cardiogenic shock (p = .06). CONCLUSION: RVI and cardiogenic shock were associated with higher CRA than uncomplicated AMI. RVI occurred more often on days of high GMA than cardiogenic shock. Higher CRA may induce more myocardial damage in patients predisposed to AMI.

Influence of dietary fats on Ecstasy-induced hyperthermia.

BACKGROUND AND PURPOSE: Studies were designed to examine the effects of dietary fats on metabolic effects of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). These effects included hyperthermia, expression of uncoupling protein (UCP1 and 3) in brown adipose tissue or skeletal muscle and plasma free fatty acid (FFA) levels. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were fed either a high-fat diet (HFD, 60% kcal) or a lower fat isocaloric controlled diet (LFD, 10% kcal) for 28 days before MDMA challenge. KEY RESULTS: No significant differences were observed between LFD and HFD groups in terms of body weight, plasma thyroxine (T4) levels and expression of brown fat UCP1 or skeletal muscle UCP3 protein. HFD significantly raised levels of circulating FFA and potentiated the thermogenesis induced by MDMA (10 mg kg(-1), s.c.), compared to the effects of the LFD. Moreover, 30 and 60 min after MDMA administration, plasma FFA levels decreased in HFD animals, but were markedly elevated in the LFD group. CONCLUSIONS AND IMPLICATIONS: These results indicate that high-fat feeding regulates MDMA-induced thermogenesis by augmenting the activation of UCP rather than its expression.

Neutrons and sudden cardiac death (SCD) codes 121-125 ICD 10.

Recent studies have shown that (1) monthly neutron activity (NA) (imp/min) correlates with monthly number of acute myocardial infarction (AMI); (2) NA is higher on days of automatic implantable cardioverter defibrillators (AICD) discharges for VT, VF. Here we checked the level of NA in relation to timing and type of sudden cardiac death (SCD) patients [n=848 (579, 68.28% male)] obtained from the Kaunas registry for the years 2002-2004. All underwent Forensic Medicine post mortem examination and classification according to ICD10 by code 121-125. Daily NA data were obtained from Oulu U-ty, Finland and Moscow Monitoring Station of the Russian Academy of Sciences. No difference in NA was found on days with or without SCD. In men < 65, SCD occurred on days with higher NA than in women of the same age (p = 0.01) or in > 65 y old men (p = 0.045). Days of SCD with myocardial ruptures showed the highest level of NA, significantly higher than on all days (n = 669) of SCD (p = 0.037) and all 1096 days of the study (p = 0.0048). Three groups were accompanied by significantly higher NA: repeated AMI, myocardial ruptures (codes122, 123), and coronary atherothrombosis without AMI, related to electrical heart instability. The mechanism of possible neutron role in pathophysiology needs special studies.

Are neutrons involved in the pathogenesis of life-threatening cardiac arrhythmias?

Geomagnetic fields protect the earth from the adverse effects of cosmic rays, whose activity can be indirectly measured by monitoring the level of neutrons in the environment. The number and days of discharges from automatic implantable cardioverter defibrillators (ICD) in patients with cardiac arrhythmias are inversely correlated with the daily level of geomagnetic activity (GMA). The aim of the present was to determine whether neutron levels on days of AICD discharges are higher than average. Days on which discharges occurred were recorded in 31 patients bearing ICDs for managing ischemic cardiomyopathy. Daily neutron levels obtained from the monitoring data of the Russian Academy of Sciences in Moscow were analyzed using Student's t test. The mean (+/-SD) daily neutron level for the 1096-day period was 8299.29 +/- 294.236 imp/min (median 8252), and for days of ACID discharge, 8423.93 +/- 274.187 imp/min (median 8443) (p = 0.0002). The mean neutron activity on days of AICD discharges in response to ventricular disturbances was significantly higher than the mean level over the 1096-day study period. Whether this relation is a direct result of low GMA or due to an independent role of neutrons in the pathogenesis and timing of cardiac arrhythmias is unknown.

Suicide-homicide temporal interrelationship, links with other fatalities, and environmental physical activity.

UNLABELLED: Homicide and suicide are extremes in human behavior. The aim of this study is to investigate the connection by time between suicide and homicide, between them and other fatalities, and their links with the level of cosmophysical activity. METHODS: Using the national database of Lithuania (1990-2002) we found that 547,875 deaths, 4,638 homicides (3,374 male) and 19,527 (16,019 male) suicides were registered in that period. Their temporal distribution over 156 months was compared with solar and cosmic-ray activity. Pearson correlation coefficients and their probabilities were established. RESULTS: There was a correlation between monthly rates of homicide and male groups. Female suicide rates correlated with male and total homicide numbers. Both homicide and suicide rates were inversely correlated with solar and cosmic-ray activity. Suicide numbers, but not homicides, were inversely related to geomagnetic activity. Suicide rates were inversely correlated with total, cardiovascular, traffic accident, and sudden deaths; homicide with total, traffic accident, and sudden deaths. CONCLUSION: Temporal distribution of homicide and suicide is significantly interrelated. Both are linked to parameters of cosmophysical activity. The influence of cosmic rays deserves special attention.

The shear viscosity of supercritical oxygen at high pressure.

Shear viscosities of supercritical oxygen have been measured up to a pressure of 5.7 GPa at 294 K. A modified free-volume expression fits the data within 6% between the limits of the tenuous gas and 4.8 times the critical density. Nitrogen viscosities were found to correspond to those of oxygen through a simple scaling by critical constants. Viscosities were measured in the high-pressure diamond-anvil cell with a rolling-ball technique. The dynamics of a sphere rolling on an inclined plane were investigated in the context of these experiments. The effect of a second surface, situated above the sphere, was experimentally determined.

Cosmic rays activity and monthly number of deaths: a correlative study.

We studied the relation between the intensity of cosmic rays, the level of solar/geomagnetic activity, and the monthly numbers of deaths in a large hospital in Israel and in all Lithuania. The Israeli data include 30526 hospital deaths, two groups of fatal suicides (2359, 2763), and 15435 suicidal attempts for two periods of 108 and 236 consecutive months. The national data for the entire Republic of Lithuania include 424925 deaths for the period of 120 consecutive months. Cosmic rays intensity was measured by an Apatity neutron monitor. We obtained the data on solar, geomagnetic radiovawe propagation, ionosphere ionization hours, proton flux of two energy levels (>90 and 60 MeV) from the National Geophysical Data Center at Goddard Space Flight Center, National Space Environment Center at Boulder, Colorado, USA, and from the Institute of Terrestrial Magnetism, Ionosphere and Radio Wave Propagation (IZMIRAN), Russia. We calculated Pearson coefficients and their probabilities for correlation between monthly space activity level and monthly number of male and female deaths from different causes. Cosmic rays activity revealed significant negative correlation with solar/geomagnetic activity indices and related physical phenomena levels. This activity strongly correlated with flux of protons with the energies >90 MeV proton flux and did not exhibit significant correlation with 60 MeV proton fluxes. Cosmic rays intensity correlation with monthly numbers of deaths was strong for noncardiovascular deaths, suicides, and traffic accidents. The correlation was much weaker for deaths caused by ishemic heart disease and strokes.

Distribution of monthly deaths, solar (SA) and geomagnetic (GMA) activity: their interrelationship in the last decade of the second millennium: the Lithuanian study 1990-1999.

Thirty percent of cardiovascular deaths cannot be explained by known risk factors. In this study, we sought links between 1) circannual rhythmicity, solar activity (SA) - sunspot number, solar radioflux and geomagnetic activity (GMA) - Ap., Cp., Am. with monthly number of deaths looking for environmental influence on mortality at the end of the second millennium. The Lithuanian national death data from for 120 consecutive months according to the IDC (1990 - 1999, n = 424925 deaths) was studied: 157189 from IHD (72144 male, 85045 female), 50228 from stroke (19062 male, 31166 female), 33722 from accidents (26193 male, 7529 female), 10655 from road accidents (8127 male, 2528 female) and 14810 from suicide (12137 male, 2673 female), 217508 - non cardiovascular (134308 male, 83200 female). Monthly death numbers (total, < 65y, 65-74, > 74y old for IHD and Stroke, and by gender) were compared with time of year, SA and GMA indices obtained from the National Geophysical Data and National Space Services Center, USA. Circannual rhythmicity indices, Pearson correlation coefficients and their probabilities were obtained and analyzed. The interrelationships of deaths from IHD and stroke and some other pathologies were also studied. In addition a multivariate linear regression analysis was done in order to evaluate the influence of time (month), Solar (S.A.) and Geomagnetic (GMA) activity on the temporal distribution of deaths. The total IHD monthly death number was significantly linked with GMA indices (r = 0.2-0.24, p = 0.03-0.075), but not with SA. IHD correlated with SA (r = 0.25-0.27, p = 0.006-0.0026), only in the 74 year age group. p = 0.0001) In the 65-74 age group, there was an inverse relationship with SA (r = -0.46-0.44) and no significant relationship to GMA. The IHD death number was correlated with GMA only in the < 65 and > 74 year age group (r = 0.30-0.36, p = 0.001-0.001). 2) Stroke-related deaths showed an inverse correlation with SA and GMA only for the 65-74y age group (r = -0.5, p = 0.0001 - SA, r = -0.4, p = 0.0001- GMA) and with GMA at age < 65 only for males (r = 0.20-0.25, p = 0.03-0.04). 3) Both IHD and stroke were strongly circannual rhythmic with acrophase at month 1.27 (IHD) and 1.32 (stroke) - first half of February, (p = 0.0001). 4) The IHD / stroke death ratio was correlated both with SA and GMA (r = 0.35, p 0.0001 - SA, r = 0.40-0.44, p = 0.0001 - GMA). 5) There was a strong inverse monthly deaths correlation between IHD and suicide (n = 14,810, r = -0.53, p = 0.0001). Stroke and suicide were also related, but to a much weaker extent (r = -0.217, p = 0.017). Accidents were inverse related to S.A. (r = -0.286, p = 0.0015), but not to GMA. Road Accidents - with both S.A. (r = 0.427, p < 0.0001) and GMA (r = 0.258, p = 0.004); with acrophases in October for road and November for other fatal accidents. Non cardiovascular deaths were annually rhythmic only for female - acrophase in early February, and for both gender inverse related to S.A. (r = -0.57, p < 0.0001) but not with GMA. Suicide victims had their acrophase in July (p < 0.0001) and were inverse related to S.A. (r = -0.6, p < 0.0001) and GMA (r = -0.27, p = 0.002). At the onset of the third millennium, the temporal distribution of deaths is still related to environmental physical activity. Those links differ for each of the pathologies, and by age and gender.

Correlation of two levels of space proton flux with monthly distribution of deaths from cardiovascular disease and suicide.

In our previous studies /1-3/ we described some significant links between monthly number of deaths due to cardiovascular disease and suicide and space proton flux > 90 MeV. The aims of the present study were to compare the relationship of some solar and geomagnetic parameters with space proton fluxes of > 60 and > 90 MeV; to examine the monthly correlation of these two proton groups with the monthly death distribution in two countries, Israel and Lithuania. Physical data were obtained from the National Geophysical Data Center and the SESC in Boulder, CO; NSSDC in Goddard Space Flight Center, USA, and the Izmiran Institute of the Academy of Sciences in Russia. Pearson correlation coefficients and probabilities were compared for 56-180 consecutive months. Proton flux of > 60 MeV significantly correlated with three of the four studied monthly geomagnetic activity indices (Ap, Am, Dst), but not with such solar activity markers as sunspot number and solar flux (2800 MGH, 10.6 cm). There was no significant relationship between proton flux of > 60 MeV and monthly number of deaths from cardiovascular diseases and suicide, in contrast to the results for > 90 MeV. From the data available during the 36 months (1986-1988), there was no correlation between monthly levels of > 60 to > 90 MeV. In conclusion, a monthly space proton flux of > 60 MeV is not significantly correlated with the monthly death distribution from cardiovascular disease and suicide and some solar activity indices, such as proton flux of > 90 MeV. It is possible that the 60-90 MeV fraction in the > 60 MeV proton flux "blunts" the cosmobiological relationship between proton flux of > 90 MeV and monthly death number.

Relationship between deaths from stroke and ischemic heart disease--environmental implications.

We analyzed the ratio of deaths from stroke and ischemic heart disease in Lithuania over a 72-month period (1990-1995) in relation to fluctuations in five physical environmental parameters. Results indicated a highly significant adverse correlation of the stroke/ischemic heart disease death ratio with both solar activity (r = -0.64, p = 0.0001), stronger for women than for men, and the planetary geomagnetic activity index (r = -0.33, p = 0.005). Proton flux > 60 MeV correlated significantly with the death ratio only for the 65-74-year age group (r = -0.36, p = 0.03) (36-month study). The last finding may be a result of different environmental influences on the pathogenesis of ischemic heart disease and cerebral vascular accidents at different ages. We conclude that the monthly ratio of deaths from stroke/ischemic heart disease is related to environmental physical activity.

Relation between QT dispersion and slow intraventricular conduction in patients with acute anterior wall myocardial infarction.

BACKGROUND: QT dispersion has been proposed as a simple, noninvasive measure for identifying patients at risk of postinfarction arrhythmia. It is assumed to reflect nonuniform ventricular repolarization, which, in turn, may result from regional differences in repolarization time as well as from localized activation delay. The aim of this study was to examine the relation between QT dispersion and intraventricular conduction abnormalities in patients with acute anterior wall myocardial infarction. METHODS AND RESULTS: Standard 12-lead electrocardiographic and 12-lead signal-averaged electrocardiographic recordings were performed in 25 patients with a first Q-wave anterior wall myocardial infarction. Measures calculated by using the 6 precordial (V1 through V6) leads for QT dispersion were (1) difference between maximum and minimum QT and QTc intervals and (2) standard deviation of QT and QTc intervals. Measures calculated from the signal-averaged electrocardiogram were (1) maximum filtered QRS duration; (2) mean; and (3) standard deviation of filtered QRS duration. No relation was found between any measure of filtered QRS duration and that of QT dispersion by using linear correlation analysis. Similarly, no significant association was demonstrated between the filtered QRS duration and corresponding QT interval measurements (total 131 leads). CONCLUSIONS: The lack of correlation between signal-averaged electrocardiogram indexes of slow intraventricular conduction and electrocardiogram variables of QT dispersion suggests an independent predictive value for the 2 methods in identifying patients at risk of postinfarction arrhythmia. This suggestion is further supported by the finding that altered activation sequence is an unlikely mechanism of QT dispersion in patients with acute myocardial infarction, as indicated by the lack of association between the filtered QRS duration and corresponding QT interval measurements.

Applications of impulsive stimulated scattering in the Earth and planetary sciences.

The elastic, thermodynamic, and transport properties of crystals and fluids at high temperature and pressure play a central role in the earth and planetary sciences as well as in a variety of technologies. These properties also constitute a principal experimental constraint on the description of intermolecular interactions at short distances. Aspects of "impulsive stimulated scattering," when adapted to measurements in the diamond-anvil high-pressure cell, provide an approach to the determination of a subset of equilibrium and dynamic properties at high density.

Acquired pili torti--a structural hair shaft defect in anorexia nervosa.

The hair of seventeen girls aged 13 to 19 years with anorexia nervosa (AN) was studied and compared with the hair of fifteen healthy girls aged 13 to 18 years with no complaints of hair loss but with similar habits of hairstyling and care. Light microscopic examination of the hair revealed no defect in the control group. In the AN group, fourteen patients (82.3 percent) had pili torti, an acquired hair shaft defect that has not yet been described in association with this disease. We estimate that the hair defect was due to malnutrition combined with ingestion of exaggerated amounts of yellow vegetables and vitamin supplements, causing a significant increase in levels of serum carotene, retinyl esters, retinol, and retinoic acid. We suggest a possible link between excess vitamin A and pili torti in patients with AN.

Distribution of deaths from ischemic heart disease and stroke. Environmental and aging influences in men and women.

UNLABELLED: The goal of this study was to check: 1) links between month of the year (1-12), monthly solar activity (SA) and monthly geomagnetic activity (GMA) with the temporal distribution of deaths from ischemic heart disease (IHD) and stroke in Israel and Lithuania (48 months); 2) related age and gender differences; 3) temporal connection between deaths from IHD and suicide and their relationship to SA and GMA, as was suggested in our previous study in Israel. RESULTS: Total deaths from IHD in Lithuania showed a trend towards a link with SA (r = 0.25, p = 0.09) and a highly significant correlation for females (r = 0.37, p = 0.00096) but not for males. Age < 74 showed no correlation with SA or GMA in females, but a negative correlation with SA in males (r = -0.513, p = 0.0002). At age > 74 both females (r = 0.467, p = 0.0006, n = 20763) and males (r = 0.476, p = 0.0006, n = 14682) showed a highly significant correlation with SA and a negative correlation with 1-12 months of the year, with deaths concentrating at the beginning of the year (r = -0.32, p = 0.002). Number of monthly suicide and IHD deaths were negatively related to each other (r = -0.45, p = 0.0014). CONCLUSIONS: 1) Around age 70 an increasingly positive relationship between the temporal distribution of deaths from IDH and SA is seen. 2) Gender differences in links to SA are partially a consequence of the higher number of deaths in females from IHD at age > 74.3) Monthly number of suicides is inversely related to number of deaths from IHD.