Psychosocial, psychiatric and work-related risk factors associated with suicide in Ireland: optimised methodological approach of a case-control psychological autopsy study.

BACKGROUND: Suicide has profound effects on families and communities, but is a statistically rare event. Psychological autopsies using a case-control design allow researchers to examine risk factors for suicide, using a variety of sources to detail the psychological and social characteristics of decedents and to compare them to controls. The Suicide Support and Information System Case Control study (SSIS-ACE) aimed to compare psychosocial, psychiatric and work-related risk factors across three groups of subjects: suicide decedents, patients presenting to hospital with a high-risk self-harm episode, and general practice controls. METHODS: The study design includes two inter-related studies; one main case-control study: comparing suicide cases to general practice (GP) controls, and one comparative study: comparing suicide cases to patients presenting with high-risk self-harm. Consecutive cases of suicide and probable suicide are identified through coroners' registration of deaths in the defined region (Cork City and County, Ireland) and are frequency-matched for age group and gender with GP patient controls recruited from the same GP practice as the deceased. Data sources for suicide cases include coroners' records, interviews with health care professionals and proxy informants; data sources for GP controls and for high-risk self-harm controls include interviews with control, with proxy informants and with health care professionals. Interviews are semi-structured and consist of quantitative and qualitative parts. The quantitative parts include a range of validated questionnaires addressing psychiatric, psychosocial and occupational factors. The study adopts several methodological innovations, including accessing multiple data sources for suicide cases and controls simultaneously, recruiting proxy informants to examine consistency across sources. CONCLUSIONS: The study allows for the investigation of consistency across different data sources and contributes to the methodological advancement of psychological autopsy research. The study will also inform clinical and public health practice. The comparison between suicide cases and controls will allow investigation of risk and protective factors for suicide more generally, while the comparison with high-risk self-harm patients will help to identify the factors associated specifically with a fatal outcome to a self-harm episode. A further enhancement is the particular focus on specific work-related risk factors for suicide.

Intensive care monitoring after total joint replacement.

Patient safety is a critical issue in elective total joint replacement surgery. Identifying risk factors that might predict complications and intensive care unit (ICU) admission proves instrumental in reducing morbidity and mortality. The institution's experience with risk stratification and pre-operative ICU triage has resulted in a reduction in unplanned ICU admissions and post-operative complications after total hip replacement. The application of the prediction tools to total knee replacement has proven less robust so far. This work also reviews areas for future research in patient safety and cost containment.

Tolerance induction by costimulator blockade in 100 cGy treated hosts with varying degrees of genetic disparity.

Long-term multilineage allochimerism can be obtained in H2-mismatched B6.SJL to BALB/c transplants with host irradiation of 100 cGy, donor spleen cell pre-exposure and costimulator blockade with anti-CD40 ligand (CD40L) antibody. We evaluated this allochimerism approach in murine marrow transplants with different degrees of major histocompatibility complexe (MHC) mismatching; these include: (1) H2-mismatched transplant H2Kk to H2Kb, (2) full haplo-identical transplant H2Kbd to H2Kbk, (3) a partial haplo-identical transplant H2Kd to H2Kbd and (4) an MHC class II mismatch. Levels of chimerism increased up to 12 weeks and then stayed relatively stable up to 1 year after transplant. At 18 weeks post-transplant, the H2-mismatched, haplo-identical, partial haplo-identical and class II-mismatch transplants evidenced 17.9+/-4.4, 40.7+/-0.9, 25.1+/-4.19 and 33.7+/-3.5% donor chimerism, respectively. Dropping the anti-CD40 antibody treatment and spleen cells or changing the schedule of antibody to one injection, in haplo-identical or full-mismatched transplants resulted in no donor-derived chimerism. On the other hand, these still resulted in minor chimerism in class II-mismatched transplants. Lineage analysis of peripheral blood at 6 and 12 months post-transplant demonstrated a significant shift toward increased chimeric lymphocytes and decreased chimeric granulocytes in the full H2 as compared with haplo-identical or class II transplants. Transplantation with anti-CD40L antibody eliminated both graft-versus-leukemia and graft-versus-host disease (GVHD) and delayed lymphocyte infusion did not rescue animals from fatal leukemia. In conclusion, under the conditions of our tolerization regimen, a haplo transplant gives higher engraftment levels than a full H2 mismatch, and despite lower engraftment levels, a class II-mismatched transplant can be successfully accomplished with only 100 cGy and no CD40L blockade.

The marrow stem cell: the continuum.

The marrow hematopoietic stem cell is currently being redefined as to all aspects of its phenotype and its total differentiation capacity. This redefinition now includes its plasticity as to production of nonhematopoietic and hematopoietic cell types, the determinants of its in vivo engraftment potential and its expression of stem cell functional characteristics.

Marrow stem cell potential within a continuum.

On the basis of our studies of the fluctuation of the hematopoietic stem cell phenotype with cell cycle trnsit, we hypothesize that the ability of marrow stem cells to convert to nonhematopoietic cells will also vary at different points in the cell cycle. The new biology of stem cells has an impact on many fields including developmental biology and stem cell biology and the clinical potential is enormous.

Host marrow stem cell potential and engraftability at varying times after low-dose whole-body irradiation.

High levels of chimerism in syngeneic BALB/c transplants were reported when hosts were exposed to 1 Gy (100 cGy) whole body irradiation (WBI) and infused with 40 x 10(6) marrow cells. The recovery of host stem cells and alterations of enhanced host engraftability at varying times after 1 Gy WBI have now been evaluated in this study. Male BALB/c marrow (40 x 10(6) cells) was infused into female BALB/c hosts immediately or at 6, 12, and 24 weeks after 1 Gy WBI of host female BALB/c mice; engraftment percentages 8 weeks after cell injection at week 0, 6, 12, or 24 were 68% +/- 12%, 45% +/- 15%, 51% +/- 12%, or 20% +/- 8%, respectively. Eight-week engraftment levels in nonirradiated hosts average 7.7%. Conversely, engraftable stem cells measured at 8 weeks postengraftment in 1 Gy--exposed hosts were reduced to 8.6% +/- 3% of nonirradiated mice at time 0, 35% +/- 12% 6 weeks later, 49% +/- 10% at 3 months, and 21% +/- 7% at 6 months. Engraftment was still increased and stem cell decreased 1 year after 1 Gy. Furthermore, the primary cells transplanted into 1 Gy hosts can be serially transplanted, and the predominant effect of 1 Gy is directly on engrafting stem cells and not through accessory cells. These data show that transplantation in 1 Gy mice may be delayed until recovery of hematopoiesis, suggesting strategies in allogeneic transplantation to avoid the adverse effects of cytokine storm. The incomplete recovery of engraftable stem cells out to 12 months indicates that stem cell expansion, especially in patients previously treated with radiomimetic drugs, may not be feasible. (Blood. 2001;98:1246-1251)

Stem cell engraftment strategies.

The donor stem cell phenotype and host microenvironment determine the outcome of a stem cell transplant. In a series of transplant studies in syngeneic male to female or congenic Ly5.1/Ly5.2 models in which hosts have received no or minimal irradiation (100 cGy), evidence overwhelmingly supports the concept that syngeneic engraftment is determined by stem cell competition. These approaches can be extended to H-2 mismatched allogeneic mouse combination when antigen pre-exposure and CD40-CD40 ligand antibody blockage are employed. A human trial in patients with resistant neoplasia infusing pheresed blood with 10(8) CD3 cells/kg showed that tumor responses and complete chimerism occur with very low levels of CD34+ cells/kg and that the extent of previous treatment is a critical factor in determining chimerism. A major feature of transplants is the phenotype of the donor stem cell. This phenotype shows dramatic reversible plasticity involving differentiation, adhesion protein expression, and engraftment with cytokine-induced cell-cycle transit. Homing is probably also plastic. Marked fluctuations in engraftment capacity are also seen at different points in marrow circadian rhythm.

The fleet feet of haematopoietic stem cells: rapid motility, interaction and proteopodia.

Haematopoietic stem cells (HSCs) have been extensively characterized regarding in vivo engraftment, surface epitopes and genetic regulation. However, little is known about the homing of these rare cells, and their intrinsic motility and membrane deformation capacity. We used high-speed optical-sectioning microscopy and inverted fluorescent videomicroscopy to study highly purified murine lineage-negative, rhodamine-low, Hoechst-low HSCs over time under various in vitro conditions. We discovered extremely rapid motility, directed migration to stromal cells and marked membrane modulation. High resolution images with three-dimensional reconstruction showed the general presence of microspikes. Further, pseudopodia (proteopodia) were observed that were induced by stromal-derived factor-1 and steel factor. Proteopodia were directed towards and were quenched by stromal cells, at times bridged HSCs, and could rapidly retract or detach from cells. Proteopodia were also observed in vivo with homed HSCs in frozen sections of murine spleen, lung and heart. This is the first demonstration that HSCs are both fast and highly malleable in phenotype.

Crystal engineering of microporous 'Chinese-lantern' compounds to improve their ability to reversibly adsorb sulfur dioxide.

Three new 'Chinese lantern' complexes [XMn(mu-dppO2)4MnX](2+)2X-.4MeOH.Me2CO [X = Cl, Br, I; dppO2 = 1,3-bis(diphenylphosphinoyl)propane], have been structurally characterised using single-crystal X-ray diffraction and shown to have increasing affinity for SO2 across the series Cl < Br < I via thermogravimetric measurements.

Physical and physiological plasticity of hematopoietic stem cells.

Stem cells from a variety of tissues have recently been shown to be capable of differentiating into cells characteristic of a separate tissue, apparently in response to microenvironmental signals. This is hierarchical plasticity. We have shown that both human and murine neurosphere cells with potential for differentiating into neurons, oligodendrocytes, and astrocytes can produce hematopoietic stem cells when engrafted into fetal sheep or murine day 3.5 blastocysts, respectively. We have also demonstrated an alternative form of stem cell plasticity: functional plasticity at different points in cell cycle transit and at different phases of a circadian rhythm. We have shown that long-term engraftment varies reversibly as primitive murine stem cells (lineage-negative rhodamine(low) Hoechst(low)) transit the cell cycle under stimulation by interleukin-3 (IL-3), IL-6, IL-11, and steel factor, with engraftment being defective in late S/early G2. Engraftment also varies markedly with circadian time. Presumptive mechanisms for these phenotypic shifts include alteration in adhesion protein expression with consequent changes in marrow homing. Most recently, we have also demonstrated that stem cell differentiation varies markedly with cell cycle transit. There are other features of the hematopoietic stem cell which suggest that it is a highly plastic cell with the ability to rapidly change its membrane phenotype, while exhibiting extraordinary directed motility. These data suggest that cell cycle and circadian plasticity should be considered additional major features of the hematopoietic stem cell phenotype.

Lymphohematopoietic stem cell engraftment.

Traditional dogma has stated that space needs to be opened by cytoxic myeloablative therapy in order for marrow stem cells to engraft. Recent work in murine transplant models, however, indicates that engraftment is determined by the ratio of donor to host stem cells, i.e., stem cell competition. One hundred centigray whole body irradiation is stem cell toxic and nonmyelotoxic, thus allowing for higher donor chimerism in a murine syngeneic transplant setting. This nontoxic stem cell transplantation can be applied to allogeneic transplant with the addition of a tolerizing step; in this case presensitization with donor spleen cells and administration of CD40 ligand antibody to block costimulation. The stem cells that engraft in the nonmyeloablated are in G0, but are rapidly induced (by 12 hours) to enter the S phase after in vivo engraftment. Exposure of murine marrow to cytokines (IL-3, IL-6, IL-11 and steel factor) expands progenitor clones, induces stem cells into cell cycle, and causes a fluctuating engraftment phenotype tied to phase of cell cycle. These data indicate that the concepts of stem cell competition and fluctuation of stem cell phenotype with cell cycle transit should underlie any new stem cell engraftment strategy.

The synthesis of 191Pt labelled JM216, an orally active platinum anti-tumour agent.

The orally active platinum anti-tumour complex JM216[bis-acetatoamminedichlorocyclohexylamineplatinum(IV)] is at present in stage II clinical trials. A procedure for synthesising the complex labelled with 191Pt or 188Pt at the platinum centre has been developed. The purity (shown by HPLC) is 98% and the specific activity (0.3-0.4 Ci/kg) is enough for in vivo and in vitro studies.

The tissue distribution in BALB/c mice of C-14-labeled JM216, an orally active platinum antitumour compound.

The ammine/amine platinum(IV) dicarboxylates have been developed as orally active platinum antitumor agents, and one of these, [PtCl2(NH3)(C6H11NH2) (OCOCH3)2] (JM216), is undergoing clinical trials at present. A synthesis method was developed to radiolabel JM216 with carbon 14 at the carboxylate carbon. The labeling efficiency was 92%, and the purity as shown by high-performance liquid chromathography (HPLC) was 96% after recrystallisation. The radiolabeled JM216 was given orally to BALB/c mice and detailed tissue-distribution data were obtained (blood plasma, kidney, liver, spleen, brain, lung, muscle and skin) for time points of 2 h and 2, 6 and 10 days. Comparison of these data with previously reported data for distribution of platinum obtained by atomic absorption spectroscopy has shown distinct differences, especially for the liver and the kidney. This clearly indicates a difference in behaviour between the labeled ligand and the platinum centre, suggesting detachment of the ligand in vivo.

New Perfluorophtalate Complexes of Platinum(II) With Chemotherapeutic Potential.

Two new platinum(II) complexes have been synthesized and their anti-tumour and anti-HIV activities have been evaluated.THE NEW COMPLEXES ARE: (i) cis-tetrafluorophthalate-ammine-morpholine-platinum(II) or MMF3 and (ii) cis-tetrafluorophthalate- ammine-piperidine-platinum(II) or MPF4. They were characterized by elemental analysis, IR spectra and (1)H and (13)C NMR spectra.They were tested against five human ovarian carcinoma cell lines, viz., CH1, CH1cisR, A2780, A2780cisR and SKOV-3. They were less active than cis-platin and showed cross-resistance with cis-platin in the CH1cisR and A2780cisR acquired resistance lines.They were also tested for possible anti-HIV activity using the HIV-I IIIB virus and C8166 cells, but they were inactive compared with AZT.

Diet and risk of colorectal adenomas: macronutrients, cholesterol, and fiber.

BACKGROUND: Diet is thought to be important in the etiology of colorectal cancer. Studies suggest that a diet high in red meat and saturated fat and low in dietary fiber and vegetables may increase cancer risk. Diet may also be important in the development of colorectal adenomas that are precursors of most colorectal cancers, but this hypothesis has not been well studied. PURPOSE: This case-control study was designed to examine the effects of dietary consumption of cholesterol, fiber (vegetables, fruits, beans, and grains), and macronutrients (protein, carbohydrate, and fat) on risk for colorectal adenomas. METHODS: Analyses were based on data from 236 subjects (105 men and 131 women) with histologically confirmed adenomas (cases) and 409 adenoma-free control subjects (165 men and 244 women), all of whom had had colonoscopy. Case and control subjects were similar with respect to gender, body mass, race, marital status, education, and indications for colonoscopy. Using a validated quantitative food-frequency questionnaire, an experienced graduate nutritionist interviewed each subject by telephone. Sex-specific analyses were conducted because the ranges of nutrient intake were substantially different for men and women. Odds ratios (ORs) were calculated according to quintiles of nutrient intake. RESULTS: Carbohydrate intake was inversely related to adenoma risk in women (P for trend = .002). Compared with women in the lowest quintile of carbohydrate consumption, those in the highest quintile were 60% less likely to develop adenomas (OR = 0.39; 95% confidence interval [CI] = 0.19-0.80). Intake of fruit (P for trend = .028) and intake of fiber derived from vegetables and fruits (P for trend = .012) were also inversely related to adenomas in women. Total fat showed a positive association in women (P for trend = .004), with an OR of 2.69 for the highest versus the lowest quintile (95% CI = 1.31-5.50). Results were comparable for saturated fat (P for trend = .027). The risks in men were generally similar in direction and magnitude but were not statistically significant. CONCLUSIONS: These data support the hypothesis that a diet high in fat and low in carbohydrates, fruits, and fruit and vegetable fiber increases risk not only for colorectal cancer but also for precursor colorectal adenomas. IMPLICATIONS: These results, which are consistent with findings of other investigators, suggest that environmental factors, influencing risk for colorectal cancer, such as a high-risk diet, may lead to development of the precursor adenomas.

Cigarette smoking, alcohol, and the risk of colorectal adenomas.

BACKGROUND: The present study was designed to further assess the reported association between cigarette smoking, alcohol, and colorectal adenomas. METHODS: A number of environmental and life-style risk factors were examined in 236 patients with histologically proven adenomas and 409 controls with no adenomas. RESULTS: Age, sex, race, and indication for procedure were similar in cases and controls. Those who had ever smoked were not at increased risk for adenomas compared with those who had never smoked. Years of smoking, cigarettes per day, and total pack-years showed no dose-response effect. Results for men and women were similar. Alcohol was a significant risk factor for men but not for women. Men in the highest quartile of daily caloric intake from alcohol were more than four times more likely than nondrinkers to develop adenomas, with a statistically significant trend in risk from the lowest to the highest quartile. These findings persisted after controlling for other potential risk factors for adenomas. The risk for colon and rectal polyps were similar. Men in the highest tertile of beer consumption were nearly six times more likely to develop adenomas than nondrinkers. CONCLUSIONS: Beer drinking is a risk factor for colorectal adenomas in this population.

A comparative binding of platinum anti-tumour compounds to plasma proteins in the rat (in vivo) and mouse (in vitro).

Plasma protein binding of 195mPt-labelled cisplatin, carboplatin and iproplatin has been studied in vivo in rat and in vitro in mouse, using both electrophoresis and trichloroacetic acid precipitation. After intravenous injection plasma clearance rates were biphasic for all 3 compounds, (t1/2 alpha, 13-17 min) but cisplatin was retained thereafter longer than the others. By 5 min, gel electrophoresis showed protein labelling with all 3 drugs but none involved low mol.wt. proteins (< 16 kDa). At 2 h a notable proportion of the protein bound platinum was associated with the latter components. There was a general resemblance between the distribution patterns of cisplatin and carboplatin whereas iproplatin showed a persistent retention of the label with time to higher mol. wt. proteins. From in vitro incubation with mouse plasma, rates of interaction respectively were cisplatin t1/2 alpha, 35 min, beta 8 h, carboplatin t1/2, 44 h and iproplatin t1/2, 104 h. By electrophoresis the protein bound fraction pattern (1 h) was again similar for cisplatin and carboplatin with virtually no binding to low mol. wt. proteins. After 24 h these were now involved to a high degree (40%). Iproplatin showed relatively marked binding to proteins of higher mol. wt. but no transfer with time to the low mol. wt. protein zone. A possible explanation is the need for in vivo metabolism for this compound as manifest in the rat. It is suggested that the significance of interaction with low mol. wt. proteins merits further investigation in relation to the antitumour and toxicological actions of these drugs.

Rectal mucosal ornithine decarboxylase activity is not a useful marker of risk for colorectal neoplasia.

Rectal mucosal ornithine decarboxylase activity has been reported to distinguish patients with adenomas from normal controls. In order to further explore this association, we assayed biopsy samples from 119 unselected individuals undergoing routine colonoscopic examinations. The overall mean ODC activity was 127.4 (+/- 93.1 SD) pmol/mg protein/hr. There were no differences by age, sex, or race. Tissue handling and storage influenced ODC activity. Specimens collected and transported on Dry Ice had higher ODC activity than specimens initially frozen in a -20 degrees C freezer. After adjusting for storage and collection method, the activity was similar in subjects with adenomas (126.3 pmol/mg/hr) compared to those without adenomas (128.8 pmol/mg/hr). We conclude that variations in assay technique make comparisons between laboratories difficult. Patients with large-bowel adenomas do not necessarily have higher ODC activity in uninvolved rectal mucosa. Further study of the environmental and genetic factors that influence rectal mucosal proliferation may improve our understanding of carcinogenesis in the large bowel.

Comparative intraperitoneal pharmacokinetics of three platinum analogues.

The pharmakokinetic profiles of intraperitoneally infused platinum analogues were determined in 13 women exhibiting minimal residual disease following surgery and systemic chemotherapy for epithelial ovarian cancer or fallopian tube carcinoma by following the disposition of tracer doses of 195mPt radiolabel. Six patients received iproplatin, four were given cisplatin and three received carboplatin. The present data demonstrate no difference in the disposition of total platinum between these three analogues, but differences in the kinetics of free platinum may exist.

Synthesis, characterization and anti-tumour testing of some platinum(II) amine complexes containing 1,1- and 1,2-cyclobutanedicarboxylate ligands.

A series of new platinum(II) amine complexes containing 1,1- and 1,2-cyclobutanedicarboxylate ligands, cis-[PtA2(1,1-CBDCA)] (A = RNH2, where R = C2H5, n-C3H7, n-C4H9, n-C5H11, n-C6H13, c-C3H5, c-C5H9, c-C6H11; A2 = ethylenediamine, 1,3-diaminopropane), cis-[PtA2(1,2-CBDCA)] (A = NH3, RNH2 where R = CH3, C2H5, n-C3H7, n-C4H9, c-C3H5) and trans-[Pt(NH3)2(1,1-CBDCAH)2] (CBDCA, CBDCAH = dianion and monoanion of the dicarboxylic acid, respectively) have been synthesized by an improved route. These complexes are stable in aqueous solution and show good aqueous solubility. The [Pt(c-C3H5NH2)2(1,1-CBDCA)] can be isolated in white, grey and blue forms. The grey and blue forms exhibit ESR signals analogous to the so-called platinum blues. The existence of the blue form in aqueous solution is time and temperature dependent. Several of the complexes have been tested against leukaemia L1210 in male BDF mice and activity appears to decrease with the increase in length of the aliphatic chain (or increase in size of the alicyclic ring) of the primary amine. The Yoshida lymphoscarcoma screen, usually insensitive to platinum drugs, was found to respond well to [Pt(n-C4H9NH2)2(1,1-CBDCA)] in 5-day subcutaneously implanted tumours in female Wistar rats.