To examine national trends in mortality rates for injuries among Canadian children younger than 15 years in 1979–2002.
Data on injury deaths were obtained from the Canadian Vital Statistics system at Statistics Canada. Injuries were classified using the codes for external cause of injury and poisoning (E‐codes) by intent and by mechanism. Mortality rates were age adjusted to the 1990 world standard population. Negative binomial regression was used to estimate the secular trends.
Annual mortality rates for total and unintentional injuries declined substantially (from 23.8 and 21.7 in 1979 to 7.2 and 5.8 in 2002, respectively), whereas suicide deaths among children aged 10–14 showed an increasing trend. All Canadian provinces and territories showed a decreasing trend in mortality rates of total injuries. Motor vehicle related injuries were the most common cause of injury deaths (accounted for an average of 36.4% of total injury deaths), followed by suffocation (14.3%), drowning (13.5%), and burning (11.1%); however, suffocation was the leading cause for infants. The number of potential years of life lost due to injury before age 75 decreased from 89 343 in 1979 to 27 948 in 2002 for children aged 0–14 years.
During the period 1979–2002, there were dramatic decreases in childhood mortality for total injuries and unintentional injuries as well as various degrees of reduction for all causes of injury except suffocation in children aged 10–14 years and drowning in infants. The reason for the reduction in injury mortality might be multifactoral.
childhood injury; trend; unintentional injury; intentional injury; mortality
Background and aims
Probiotic bacteria are being investigated as possible treatments for many intestinal disorders. The present study aimed to explore the effects of live, heat killed, or gamma irradiated Lactobacillus reuteri on cardio‐autonomic response and single fibre unit discharge in dorsal root ganglia to colorectal distension in healthy Sprague‐Dawley rats housed under conventional conditions. The effects of this treatment on somatic pain were also examined.
1×109 bacteria were given by gavage for nine days. Colorectal distension occurred under anaesthesia. Heart rate was measured through continuous electrocardiography. Single fibre unit discharge was recorded from the 6th left lumbar dorsal root ganglion. Somatic pain was evaluated by the tail flick and paw pressure tests.
Colorectal distension caused a pressure dependent bradycardia in the control (native medium) group. Treatment with live, heat killed, or gamma irradiated bacteria as well as their products (conditioned medium) prevented the pain response even during the maximum distension pressure (80 mm Hg). Both viable and non‐viable bacteria significantly decreased dorsal root ganglion single unit activity to distension. No effects on somatic pain were seen with any treatment.
Oral administration of either live or killed probiotic bacteria or conditioned medium inhibited the constitutive cardio‐autonomic response to colorectal distension in rats through effects on enteric nerves. These data may provide a novel explanation for beneficial probiotic effects on visceral pain.
colorectal distension; inflammatory bowel disease; irritable bowel syndrome; Lactobacillus reuteri
Background and aim
Abdominal pain and discomfort are common symptoms in functional disorders and are attributed to visceral hypersensitivity. These symptoms fluctuate over time but the basis for this is unknown. Here we examine the impact of changes in gut flora and gut inflammatory cell activity on visceral sensitivity.
Visceral sensitivity to colorectal distension (CRD) was assessed at intervals in healthy mice for up to 12 weeks, and in mice before and after administration of dexamethasone or non‐absorbable antibiotics with or without supplementation with Lactobacillus paracasei (NCC2461). Tissue was obtained for measurement of myeloperoxidase activity (MPO), histology, microbiota analysis, and substance P (SP) immunolabelling.
Visceral hypersensitivity developed over time in healthy mice maintained without sterile precautions. This was accompanied by a small increase in MPO activity. Dexamethasone treatment normalised MPO and CRD responses. Antibiotic treatment perturbed gut flora, increased MPO and SP immunoreactivity in the colon, and produced visceral hypersensitivity. Administration of Lactobacillus paracasei in spent culture medium normalised visceral sensitivity and SP immunolabelling, but not intestinal microbiota counts.
Perturbations in gut flora and in inflammatory cell activity alter sensory neurotransmitter content in the colon, and result in altered visceral perception. Changes in gut flora may be a basis for the variability of abdominal symptoms observed in functional gastrointestinal disorders and may be prevented by specific probiotic administration.
probiotic therapy; visceral hypersensitivity; gut flora; inflammation; mice
This study reports magnitudes and the orientation of the 13Cα chemical shift anisotropy (CSA) tensors of peptides obtained using quantum chemical calculations. The dependency of the CSA tensor parameters on the energy optimization of hydrogen atom positions and hydrogen bonding effects and the use of zwitterionic peptides in the calculations are examined. Our results indicate that the energy optimization of the hydrogen atom positions in crystal structures is necessary to obtain accurate CSA tensors. The inclusion of intermolecular effects such as hydrogen bonding in the calculations provided better agreement between the calculated and experimental values; however, the use of zwitterionic peptides in calculations, with or without the inclusion of hydrogen bonding, did not improve the results. In addition, our calculated values are in good agreement with tensor values obtained from solid-state NMR experiments on glycine-containing tripeptides. In the case of peptides containing an aromatic residue, calculations on an isolated peptide yielded more accurate isotropic shift values than the calculations on extended structures of the peptide. The calculations also suggested that the presence of an aromatic ring in the extended crystal peptide structure influences the magnitude of the δ22 which the present level of ab initio calculations are unable to reproduce.
breast cancer; histology; prognosis; relative survival rate; TNM stage; treatment
We examined time trends in thyroid cancer incidence in Canada by age, time period and birth cohort between 1970 and 1996. Age-specific incidence rates by time period and birth cohort were calculated and age-period-cohort modelling used to estimate effects underlying the observed trends. Overall age-adjusted incidence rates of thyroid cancer doubled, from 3.3 and 1.1 per 100 000 in 1970–72 to 6.8 and 2.2 per 100 000 in 1994–96, among females and males respectively. Almost all the increase between 1970–72 and 1994–96 was due to papillary carcinoma of the thyroid. Age, birth cohort and period effects significantly improved the fit of the model for females, while age and birth cohort effects were significant determinants of the incidence among males. There were significant differences in the patterns/curvature for age, period and birth cohort effects between women and men. Our results suggest that the increases in thyroid cancer incidence in Canada may be associated with more intensive diagnostic activities and change in radiation exposure in childhood and adolescence. Temporal changes in reproductive factors among young women may explain some of the gender differences observed. © 2001 Cancer Research Campaign
thyroid cancer; incidence; time trends; Poisson regression; Canada
This study examined histology-specific incidence trends of ovarian cancer in Canada, 1969–1993. The impact of age, period and cohort effects on these trends were studied by means of age-period-cohort analysis. Age-standardized incidence rates of serous, endometrioid, clear cell and germ cell tumours increased significantly and the rates of sex cord-stromal and other classified epithelial ovarian tumours decreased considerably. The rates of mucinous and NOS/unclassified tumours remained unchanged. Cohort effect has a major impact on incidence trends of serous, endometrioid, germ cell, sex cord-stromal and other classified epithelial ovarian tumours but no meaningful impact on trends of mucinous, clear cell, or NOS/unclassified ovarian tumours. Various cohort patterns by histology subtypes were observed: the risk of developing serious tumours increased markedly among birth cohorts of 1895–1930, stabilized thereafter and decreased among young cohorts of 1950–1960; the risk of germ cell tumours increased significantly among young cohorts of 1965–1980; and the risk of sex cord-stromal tumours dropped constantly among cohorts 1910–1950. Various period patterns by histology subtypes observed in this study suggested changes in histology classification criteria over the period. Further studies need to consider the various etiologies and the classification criteria changes according to histology subtypes. © 1999 Cancer Research Campaign
ovarian cancer; incidence; histology; period effect; cohort effect; age-period-cohort analysis
OBJECTIVES: To assess the factors affecting the severity of motor vehicles traffic crashes involving young drivers in Ontario. POPULATION: Ontario young drivers, aged 16 to 20, involved in traffic crashes resulting in injury, between 1 January 1988 and 31 December 1993, on public roads in Ontario. METHODS: Population based case-control study. Cases were fatal injury, major injury, and minor injury crashes involving young drivers. Controls were minimal injury crashes involving young drivers. Cases and controls were obtained retrospectively from the Canadian Traffic Accident Information Databank. Unconditional logistic regression was used for data analysis. RESULTS: Factors significantly increasing the risk of fatal injury crashes include: drinking and driving (odds ratio (OR) 2.3), impairment by alcohol (OR 4.8), exceeding speed limits (OR 2.8), not using seat belts (OR 4.7), full ejection from vehicle (OR 21.3), intersection without traffic control (OR 2.2), bridge or tunnel (OR 4.1), road with speed limit 70-90 km/hour (OR 5.6) or 100 km/hour (OR 5.4), bad weather (OR 1.6), head-on collision (OR 80.0), and overtaking (OR 1.9). Results of the same model applied to major and minor injury crashes demonstrated consistent but weaker associations with decreasing levels of crash severity. CONCLUSIONS: A casual relationship between crash severity and the risk factors listed above was proposed. Risk factors recommended for preventive intervention include: alcohol consumption, speeding, and use of seat belts. Head-on collisions are of primary concern.
Although screening for cervical cancer has been shown to be effective in reducing the morbidity and mortality associated with this disease, and despite many attempts to encourage the development of provincial programs, as of 1995 no province had a comprehensive screening program for cervical cancer. Participants at the Interchange '95 workshop, held in Ottawa in November 1995, reviewed the recommendations of the 1989 National Workshop on Screening for Cancer of the Cervix and identified factors that have impeded their implementation. Participants discussed the need for comprehensive information systems, quality control and strategies to increase recruitment of unscreened and underscreened women. They concluded that the formation of a Cervical Cancer Prevention Network involving key stakeholders will facilitate the development and implementation of provincial programs to ensure optimal screening. They agreed that, in the interim, recommendations for practising physicians should remain as they were following the 1989 workshop.
In recent years, more attention has been given to the mechanism of disease induction caused by the surface properties of minerals. In this respect, specific research needs to be focused on the biologic interactions of oxygen radicals generated by mineral particles resulting in cell injury and DNA damage leading to fibrogenesis and carcinogenesis. In this investigation, we used electron spin resonance (ESR) and spin trapping to study oxygen radical generation from aqueous suspensions of freshly fractured crystalline silica. Hydroxyl radical (.OH), superoxide radical (O2.-) and singlet oxygen (1O2) were all detected. Superoxide dismutase (SOD) partially inhibited .OH yield, whereas catalase abolished .OH generation. H2O2 enhanced .OH generation while deferoxamine inhibited it, indicating that .OH is generated via a Haber-Weiss type reaction. These spin trapping measurements provide the first evidence that aqueous suspensions of silica particles generate O2.- and 1O2. Oxygen consumption measurements indicate that freshly fractured silica uses molecular oxygen to generate O2.- and 1O2. Electrophoretic assays of in vitro DNA strand breakages showed that freshly fractured silica induced DNA strand breakage, which was inhibited by catalase and enhanced by H2O2. In an argon atmosphere, DNA damage was suppressed, showing that molecular oxygen is required for the silica-induced DNA damage. Incubation of freshly fractured silica with linoleic acid generated linoleic acid-derived free radicals and caused dose-dependent lipid peroxidation as measured by ESR spin trapping and malondialdehyde formation. SOD, catalase, and sodium benzoate inhibited lipid peroxidation by 49, 52, and 75%, respectively, again showing the role of oxygen radicals in silica-induced lipid peroxidation.(ABSTRACT TRUNCATED AT 250 WORDS)
The interaction of DNA with crystalline silica in buffered aqueous solutions at physiologic pH has been investigated by Fourier-transform infrared spectroscopy (FT-IR). In aqueous buffer, significant changes occur in the spectra of DNA and silica upon coincubation, suggesting that a DNA-silica complex forms as silica interacts with DNA. As compared to the spectrum of silica alone, the changes in the FT-IR spectrum of silica in the DNA-silica complex are consistent with an Si-O bond perturbation on the surface of the silica crystal. DNA remains in a B-form conformation in the DNA-silica complex. The most prominent changes in the DNA spectrum occur in the 1225 to 1000 cm-1 region. Upon binding, the PO2- asymmetric stretch at 1225 cm-1 is increased in intensity and slightly shifted to lower frequencies; the PO2- symmetric stretch at 1086 cm-1 is markedly increased in intensity and the band at 1053 cm-1, representing either the phosphodiester or the C-O stretch of DNA backbone, is significantly reduced in intensity. In D2O buffer, the DNA spectrum reveals a marked increase in intensity of the peak at 1086 cm-1 and a progressive decrease in intensity of the peak at 1053 cm-1 when DNA is exposed to increasing concentrations of silica. The carbonyl band at 1688 cm-1 diminishes and shifts to slightly lower frequencies with increasing concentrations of silica. The present study demonstrates that crystalline silica binds to the phosphate-sugar backbone of DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
The carcinogenic effects of crystalline silica in rat lungs were extensively demonstrated by many experimental long-term studies, showing a marked predominance for adenocarcinomas originating from alveolar type II cells and associated with areas of pulmonary fibrosis (silicosis). In contrast with its effects in rats, silica did not induce alveolar type II hyperplasia and lung tumors in mice and hamsters, pointing to a critical role for host factors. Using these animal models, we are investigating the role of cytokines and other cellular mediators on the proliferation of alveolar type II cells. Immunohistochemical localization of TGF-beta 1 precursor in alveolar type II cells adjacent to silicotic granulomas was shown to occur in rats, but not in mice, and hamsters, suggesting a pathogenetic role for this regulatory growth factor. Recent investigations in our laboratory on the biologic mechanisms of crystalline silica included determination of anionic sites on crystalline silica surfaces by binding of the cationic dye Janus Green B; binding of crystalline silica to DNA, demonstrated by infrared spectrometry; production of oxygen radicals by crystalline silica in aqueous media; induction of DNA strand breakage and base oxidation in vitro and its potentiation by superoxide dismutase and by hydrogen peroxide; and induction by crystalline silica of neoplastic transformation and chromosomal damage in cells in culture. On the basis of these in vitro studies, we propose that DNA binding to crystalline silica surfaces may be important in silica carcinogenesis by anchoring DNA close to sites of oxygen radical production on the silica surface, so that the oxygen radicals are produced within a few A from their target DNA nucleotides.
OBJECTIVES: To analyse trends in the incidence and mortality rates of prostate cancer in Canada according to age distribution, temporal pattern and provincial variation; to determine any association with the rate of prostatectomy; and to determine whether any observed increase in the rate of prostate cancer was due to an increase in the detection rate. DESIGN: Descriptive epidemiologic study based on Canadian population data from 1959 to 1989 and chart review from one Canadian hospital. SETTING: The chart review was conducted at the Ottawa Civic Hospital. SUBJECTS: The data on prostate cancer trends were obtained from the Canadian population. Charts were reviewed for two groups of patients: (a) men discharged from inpatient care during 1976 and 1986-87 with prostate cancer first diagnosed in the same year and (b) men who underwent transurethral resection of the prostate (TURP) during 1976 and 1986. OUTCOME MEASURES: Incidence and mortality rates of prostate cancer, rates of prostatectomy and TURP, and correlations between them. From the hospital data, changes between 1976 and 1986-87 in distribution of cancer stages, distribution of cases detected incidentally after surgery for suspected benign prostatic hypertrophy and average number of slides analysed per gram of tissue obtained from prostatectomy. RESULTS: The epidemiologic data showed that the age-adjusted incidence rates increased by 72% overall, an increase seen in all age groups over 60 years. The mortality rates increased by 29% overall, primarily in men over 85 years old. The prostatectomy rate increased by 55%. There were significant linear correlations between the national and provincial incidence rates of prostate cancer and the TURP rates. The chart review revealed that during 1976, 53% of the cases of prostate cancer diagnosed were localized, as compared with 75% in 1986-87 (p < 0.01). The proportion of tumours diagnosed incidentally in men undergoing TURP increased by 11%, whereas the number of procedures did not increase. Significantly more slides per gram of tissue were analysed in 1986-87 than in 1976 (p < 0.01). CONCLUSIONS: The correlations between the incidence rates of prostate cancer and those of TURP suggest that increased treatment of benign prostatic disease has led to increased detection of prostate cancer. Extrapolation of the data obtained from the chart review indicates that the increase in observed incidence rates can be attributed to an increase in the rate of localized disease and thus primarily to early detection rather than to elevated risk. However, because the rate of death from prostate cancer was elevated in elderly men, increases in exposure to unestablished risk factors cannot be ruled out.
OBJECTIVE: To update reports of increases in the rates of admission to hospital and death from asthma among children and young adults in Canada during the 1970s by examining data for the 1980s. DESIGN: Age-standardized rates were calculated from data for people less than 35 years of age at the time of death from asthma, bronchitis or other respiratory conditions (from 1980 through 1989) and at the time of admission to hospital for treatment of these diseases (from 1980 through 1988). Standardized mortality ratios were calculated with the death rate for Canada as the expected rate. SETTING: Data for all of Canada were examined by sex, age group and province. RESULTS: In contrast to sharp increases in the rate of death from asthma observed from 1970 through the early 1980s among Canadians less than 35 years of age, the rate showed no net change between 1980 and 1989; on average, there were 58 deaths in this age group annually. During the decade, the rates of death from asthma were three times higher in Saskatchewan and Alberta than in Newfoundland. The national rate of hospital admission/separation for asthma, however, increased greatly, though changes in the rate varied by province. Increases of over 90% were observed in Prince Edward Island and New Brunswick, whereas little overall change occurred in Newfoundland, Manitoba and Saskatchewan. The rate of hospital admission/separation for asthma was highest in Prince Edward Island and lowest in Manitoba and British Columbia. Although the rates of hospital admission/separation for asthma among boys aged less than 15 years of age were consistently 50% higher than those among girls of that age, the rate among people aged 15 through 34 years was twice as high among females as males. A slight decrease in the rates of death from respiratory conditions other than asthma was observed, together with a steady, fairly substantial decline in the rates of hospital admission/separation for these conditions. CONCLUSIONS: Whether there is any relation between increases in rates of admission to hospital for asthma and trends in the rates of death from asthma during the decade will require further study.
OBJECTIVE: To analyse brain cancer patterns in Canada, particularly according to age and sex distributions, temporal patterns and regional variations. Changes in diagnostic techniques, survival rates and trends by tumour type were also examined. DESIGN: Descriptive epidemiologic study based on Canada-wide population data for 1959-88. OUTCOME MEASURES: Rates of death, incidence and admission to hospital because of brain cancer, as well as survival time and methods of diagnosis. SUBJECTS: Incidence and death rates and time trends were examined for Canada as a whole, by province and by census division. RESULTS: The rates of death from brain cancer increased rapidly among Canadians aged 55 years or more from 1959 to 1988. In particular, age-adjusted death rates increased by 117%, 797% and 118% among men 65 to 74 years, 75 to 84 and 85 or more respectively. The corresponding increases among women were 138%, 535% and 400%. The incidence rates also increased substantially. The trends in incidence rates by tumour type indicated that the increase was more pronounced for glioblastomas. The incidence rates of cases detected histologically, radiologically and clinically all increased. CONCLUSIONS: Because glioblastomas are generally easier to diagnose than astrocytomas and because the incidence rates of glioblastomas were found to increase substantially, the increased brain cancer rates among elderly people may not be entirely attributable to improved diagnostic techniques. However, analytic investigations of the impact of changes in diagnostic procedures on brain cancer trends are needed to clarify this issue.
We assessed the mortality rates by age, sex, race, blood type, primary diagnosis, treatment and transplantation history of 8432 patients in Canada for whom end-stage renal disease (ESRD) was diagnosed between 1981 and 1986. Significant differences in the probability of dying were found between those with and without diabetes mellitus, between those who had received a renal transplant and those who had not, between white and nonwhite patients and between various age groups. The mortality rates of the ESRD patients were at least three times higher than those of the general Canadian population. Primary diagnosis and treatment were significantly associated with the risk of dying among the ESRD patients. For those who had received a transplant, the length of time spent waiting for a transplant was positively associated with the risk of death from ESRD. Patients who had received peritoneal dialysis before transplantation had a higher risk of death than those who had received either hemodialysis (risk ratio 1.3) or transplantation (risk ratio 3.2) as the first treatment. No significant differences were found in the cause of death between those who had received peritoneal dialysis and those who had received hemodialysis. Almost half of the deaths among women without diabetes who had received a transplant were due to infection.
We calculated 5-year crude and relative survival rates, by age and sex, for patients in Alberta in whom cancer was diagnosed between 1974 and 1978. Cancers with low overall 5-year relative survival rates (less than 35%) included stomach cancer, cancer of the pancreas, lung cancer, brain cancer, multiple myeloma and myeloid leukemia. Cancers with high overall 5-year relative survival rates (more than 70%) included melanoma, breast cancer, cancer of the uterus, cancer of the bladder and Hodgkin's disease. Five-year relative survival rates were generally lower in the highest age group (75 years or more). A strong inverse relation between age and survival was noted for brain cancer, non-Hodgkin's lymphoma, Hodgkin's disease and myeloid leukemia.
Recent rates of illness and death from asthma in Canada and rates of hospital admission/separation for asthma were examined by age group and region. The death rates were higher in 1982-84 than in 1970-72, especially among those aged 15 to 34 years. Increases were also noted in hospital admission/separation rates, especially among those less than 15 years of age. Hospital admission/separation rates were highest in the Maritime provinces and Saskatchewan, whereas death rates were highest in Alberta and Saskatchewan. Examination of death certificates for coding errors and recoding of certificates to a single (8th) revision of the International Classification of Diseases indicated that changes in disease coding and errors in coding did not account for the significant increase in rates of death from asthma for those aged 15 to 34 years. These increases in rates of illness and death from asthma are unexplained and warrant further investigation.
Recently published evidence indicates that involuntary smoking causes an increased risk of lung cancer among nonsmokers. Information was compiled on the proportion of people who had never smoked among victims of lung cancer, the risk of lung cancer for nonsmokers married to smokers and the prevalence of such exposure. On the basis of these data we estimate that 50 to 60 of the deaths from lung cancer in Canada in 1985 among people who had never smoked were caused by spousal smoking; about 90% occurred in women. The total number of deaths from lung cancer attributable to exposure to tobacco smoke from spouses and other sources (mainly the workplace) was derived by applying estimated age- and sex-specific rates of death from lung cancer attributable to such exposure to the population of Canadians who have never smoked; about 330 deaths from lung cancer annually are attributable to such exposure.
Data on mortality among over 8000 Canadians aged 35 to 79 years who participated in the Nutrition Canada survey are presented. The effects of various risk factors on mortality were assessed with a multivariate Poisson regression analysis. Factors associated with a significantly increased risk of death over a 10-year follow-up period ending in 1981 included cigarette smoking, hypertension and diabetes mellitus. A shallow U-shaped mortality pattern was observed for body mass index and for serum cholesterol level. No statistically significant increases in risk were associated with alcohol consumption. The population attributable risks for smoking, hypertension and diabetes were 39%, 8% and 6% respectively for men and 21%, 12% and 7% respectively for women.
Cancer is diagnosed in about 70 000 Canadians each year and is the leading cause of the loss of potential years of life before age 75 among women. Life-threatening forms of cancer will develop in at least one of every three Canadian newborns during their lifetimes if current cancer risks are not reduced. Lung and breast cancers are, respectively, the leading causes of premature death due to cancer among men and women. Compared with other countries Canada has low death rates for stomach cancer but high rates for certain smoking-related cancers (those of the lung and of the mouth and throat), leukemia and cancers of the colon, breast and lymphatic tissues. Newfoundland has the highest rates of death from stomach cancer and the lowest rates of death from prostatic cancer, whereas the western provinces have the opposite pattern. The rates of death from lung cancer among men are highest in Quebec, the province with the highest prevalence of smoking. In Canada the overall rates of death from cancer increased by 32% among men from 1951 to 1983. However, among women they declined by 12% from 1951 to 1976 and increased from 1976 to 1983, particularly among those aged 55 to 74. The rising rates of death due to lung cancer were primarily responsible for these increases. Lung cancer will likely displace breast cancer as the leading cancer killer of Canadian women by 1990. Given the relatively low survival rates for cancers caused by smoking and the lack of substantial improvement in rates for the most frequent types of cancer, preventive strategies that include effective measures to reduce tobacco consumption are urgently required.
Bet1p is a type II membrane protein that is required for vesicular transport between the endoplasmic reticulum and Golgi complex in the yeast Saccharomyces cerevisiae. A domain of Bet1p, that shows potential to be involved in a coiled-coil interaction, is homologous to a region of the neuronal protein SNAP-25. Here, we used in vitro binding studies to demonstrate that Bet1p plays a role in potentiating soluble NSF attachment protein receptor (SNARE) interactions. Mutational analysis points to the coiled-coil region as necessary for Bet1p function, and circular dichroism experiments support this theory. In vitro binding studies were also used to demonstrate that a direct interaction between Bet1p and Bos1p is required for the efficient interaction of the vesicle SNARE with its SNARE target. Genetic studies suggest that the interactions of Bet1p with Bos1p are regulated by the small GTP-binding protein Ypt1p.