Attributes and outcomes of end stage liver disease as compared with other noncancer patients admitted to a geriatric palliative care unit.

BACKGROUND: End stage liver disease (ESLD) is increasingly more prevalent as a noncancer disease to manage in palliative care. Because of the clear lack of a "terminal phase" in ESLD, palliative care is often initiated only when death is perceived as being imminent. Palliative care units (PCUs) serve as an option for continued care for patients living with ESLD and are a limited resource, often not able to accommodate longer patient admissions. Concerns have been raised that ESLD patients may be admitted late in their disease course, not allowing for equitable access to such a service because of a perceived longer length of stay (LOS). The aim of this study is to better characterize the illness experience of patients with ESLD on a geriatric PCU comparing ESLD patients and other noncancer patients in terms of admission PPS, estimated prognosis and LOS. METHODS: This was a single-center retrospective chart review of all noncancer patients admitted to Baycrest Health Sciences Palliative Care Unit (PCU) in Toronto, Canada over a four-year period. We measured the association between demographic data, estimated prognosis, Palliative Performance Score (PPS), and LOS between patients with ESLD and other noncancer diagnoses. RESULTS: There were 235 patients with noncancer diagnoses admitted to the PCU during the study period, of which 19% had ESLD. Patients with ESLD were both significantly younger (P<0.001) and were admitted with a significantly higher PPS (P<0.001) than patients with other noncancer diagnoses. Estimated prognoses for patients with ESLD compared to other noncancer patients were similar. There were no significant difference in LOS between patients with ESLD and other noncancer patients (P=0.18), although there was a non-significant trend towards a shorter LOS for patients with ESLD. There was no significance in disposition (P=0.30); the vast majority of patients with ESLD and other noncancer diagnoses died on the PCU. CONCLUSIONS: Patients with ESLD were younger and had a higher PPS score with no significant difference in estimated prognosis, LOS, or disposition when compared to other noncancer patients. Our findings suggest that patients with ESLD have a short LOS on the PCU with a unique illness experience compared to other noncancer patients.

Understanding the demographic characteristics and health of medically uninsured patients.

OBJECTIVE: To determine demographic and diagnostic information about the medically uninsured patient population and compare it with that of the medically insured patient population at a primary care centre. DESIGN: Medical chart audit. SETTING: Department of Family and Community Medicine at St Michael's Hospital in Toronto, Ont. PARTICIPANTS: Medically uninsured patients who were treated in the Department of Family and Community Medicine at St Michael's Hospital from 2005 to 2009, as well as randomly selected patients who were insured through the Ontario Health Insurance Program. MAIN OUTCOME MEASURES: The following information was obtained from patients' medical charts: patient's age, sex, and household income; if the patient had a specific diagnosis (ie, hypertension, type 2 diabetes mellitus, HIV, tuberculosis, substance addiction, or mental health disorder); if the patient accessed a specific category of primary care (ie, prenatal care or routine pediatric care); and the reason for the patient's uninsured status. RESULTS: There was no significant difference in the mean age and sex distribution of insured and uninsured patients. The uninsured group had a significantly lower mean household income (P = .02). With the exception of HIV, there was no significant difference in the prevalence of the specific diagnoses studied or in the prevalence of accessing specific categories of primary care between insured and uninsured patients (P > .05). The prevalence of HIV was significantly greater in the uninsured group (24%) than in the insured group (4%) (P = .004). The largest proportion of uninsured patients lacked health insurance owing to the landed immigrant health insurance waiting period (27%), followed by individuals without permanent resident status in Canada (22%). A subgroup analysis of the uninsured, HIV-positive population revealed that the largest proportion of individuals (36%) lacked health insurance because they had no permanent resident status in Canada. CONCLUSION: Uninsured and insured patients at the primary care centre did not differ significantly with respect to age and sex distribution; prevalence of hypertension, type 2 diabetes mellitus, tuberculosis, substance addiction, or mental health disorder; or the proportion who sought prenatal or routine pediatric care. The landed immigrant 3-month waiting period was the most common reason that uninsured patients lacked health insurance. Uninsured patients in this study lived in lower-income areas than insured patients did. This, combined with the increased prevalence of HIV in the uninsured group, might lead to a large number of uninsured, HIV-positive patients delaying seeking treatment and might have negative implications for public health.

A simple DNase model system comprising a dinuclear Zn(II) complex in methanol accelerates the cleavage of a series of methyl aryl phosphate diesters by 10(11)-10(13).

The di-Zn(II) complex of 1,3-bis[ N1, N1'-(1,5,9-triazacyclododecyl)]propane with an associated methoxide ( 3:Zn(II) 2: (-)OCH 3) was prepared and its catalysis of the methanolysis of a series of fourteen methyl aryl phosphate diesters ( 6) was studied at s (s)pH 9.8 in methanol at 25.0 +/- 0.1 degrees C. Plots of k obs vs [ 3:Zn(II) 2: (-)OCH 3] free for all members of 6 show saturation behavior from which K(M) and kcat (max) were determined. The second order rate constants for the catalyzed reactions (kcat (max)/K(M)) for each substrate are larger than the corresponding methoxide catalyzed reaction (k 2 (-OMe)) by 1.4 x 10(8) to 3 x 10 (9)-fold. The values of k cat (max) for all members of 6 are between 4 x 10(11) and 3 x 10(13) times larger than the solution reaction at s (s)pH 9.8, with the largest accelerations being given for substrates where the departing aryloxy unit contains ortho-NO 2 or C(O)OCH 3 groups. Based on the linear Brønsted plots of k cat (max) vs s (s)pKa of the phenol, beta lg values of -0.57 and -0.34 are determined respectively for the catalyzed methanolysis of "regular" substrates that do not contain the ortho-NO 2 or C(O)OCH 3 groups, and those substrates that do. The data are consistent with a two step mechanism for the catalyzed reaction with rate limiting formation of a catalyst-coordinated phosphorane intermediate, followed by fast loss of the aryloxy leaving group. A detailed energetics calculation indicates that the catalyst binds the transition state comprising [CH 3O (-): 6], giving a hypothetical [ 3:Zn(II) 2:CH 3O (-): 6] complex, by -21.4 to -24.5 kcal/mol, with the strongest binding being for those substrates having the ortho-NO 2 or C(O)OCH 3 groups.

The dinuclear Zn(II) complex catalyzed cyclization of a series of 2-hydroxypropyl aryl phosphate RNA models: progressive change in mechanism from rate-limiting P-O bond cleavage to substrate binding.

A methoxide-bridged dinuclear Zn(II) complex of 1,3-[N,N'-bis(1,5,9-triazacyclododecane)]propane (1-Zn(II)2:(-OCH3)) was prepared, and its catalysis of the cyclization of a series of 2-hydroxypropyl aryl phosphates (4a-g) was investigated in methanol at pH 9.8, T = 25degreesC by stopped-flow spectrophotometry. An X-ray diffraction structure of the hydroxide analogue of 1-Zn(II)2:(-OCH3), namely 1-Zn(II)2:(-OH), reveals that each of the Zn(II) ions is coordinated by the three N's of the triazacyclododecane units and a bridging hydroxide. The cyclizations of substrates 4a-g reveal a progressive change in the observed kinetics from Michaelis-Menten saturation kinetics for the poorer substrates (4-OCH3 (4g); 4-H (4f); 3-OCH3 (4e); 4-Cl (4d); 3-NO2, (4c)) to second-order kinetics (linear in 1-Zn(II)2:(-OCH3)) for the better substrates (4-NO2,3-CH3 (4b); 4-NO2, (4a)). The data are analyzed in terms of a multistep process whereby a first formed complex rearranges to a reactive complex with a doubly activated phosphate coordinated to both metal ions. The kinetic behavior of the series is analyzed in terms of change in rate-limiting step for the catalyzed reaction whereby the rate-limiting step for the poorer substrates (4g-c) is the chemical step of cyclization of the substrate, while for the better substrates (4b,a) the rate-limiting step is binding. The catalysis of the cyclization of these substrates is extremely efficient. The kcat/KM values for the catalyzed reactions range from 2.75 x 10(5) to 2.3 x 10(4) M-1 s-1, providing an acceleration of 1 x 10(8) to 4 x 10(9) relative to the methoxide reaction (k2OCH3, which ranges from 2.6 x 10(-3) to 5.9 x 10(-6) M-1 s-1 for 4a-g). At a pH of 9.8 where the catalyst is maximally active, the acceleration for the substrates ranges from (1 - 4) x 10(12) relative to the background reaction at the same pH. Detailed energetics calculations show that the transition state for the catalyzed reaction comprising 1-Zn(II)2, methoxide, and 4 is stabilized by about -21 to -23 kcal/mol relative to the transition state for the methoxide reaction. The pronounced catalytic activity is attributed to a synergism between a positively charged catalyst that has high affinity for the substrate and for the transition state for cyclization, and a medium effect involving a reduced polarity/dielectric constant that complements a reaction where an oppositely charged reactant and catalyst experience charge dispersal in the transition state.

Mechanistic studies on norcoclaurine synthase of benzylisoquinoline alkaloid biosynthesis: an enzymatic Pictet-Spengler reaction.

Norcoclaurine synthase catalyzes an asymmetric Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde to give (S)-norcoclaurine. This is the first committed step in the biosynthesis of the benzylisoquinoline alkaloids that include morphine and codeine. In this work, the gene encoding for the Thalictrum flavum norcoclaurine synthase is highly overexpressed in Escherichia coli and the resulting His-tagged recombinant enzyme is purified for the first time. A continuous assay based on circular dichroism spectroscopy is developed and used to monitor the kinetics of the enzymatic reaction. Dopamine analogues bearing a methoxy or hydrogen substituent in place of the C-1 phenolic group were readily accepted by the enzyme whereas those bearing the same substituents at C-2 were not. This supports a mechanism involving a two-step cyclization of the putative iminium ion intermediate that does not proceed via a spirocyclic intermediate. The reaction of [3,5,6-2H]dopamine was found to be slowed by a kinetic isotope effect of 1.7 +/- 0.1 on the value of kcat/KM. This is interpreted as showing that the deprotonation step causing rearomatization is partially rate determining in the overall reaction.