An improved synthesis of methyl p-hydroxyphenylalkanoates

Friedel-Crafts reaction of isopropoxybenzene with methyl α-chloro-α-(methylthio)acetate1 afforded methyl α-methylthio-p-isopropoxyphenylacetate2d, which was readily converted into methyl p-isopropoxyphenylacetate3 by reductive desulfurization with zinc dust in acetic acid. Methylation of3 with sodium hydride and methyl iodide gave methyl α-(p-isopropoxyphenyl)propionate5. Methyl p-hydroxyphenylalkanoates (4, 6), useful intermediates for some medicines, were easily prepared by treatment of3 and5 with titanium tetrachloride, respectively.     

Treatment of systemic and renal-limited vasculitic disorders with pooled human intravenous immune globulin

Idiopathic crescentic glomerulonephritis is characterized by an absence of immunohistological evidence of immune deposits, often with evidence of segmental glomerular necrosis. Such pauciimmune crescentic glomerulonephritis is the most common renal manifestation seen in patients with Wegener's granulomatosis, polyarteritis nodosa, and glomerulonephritis associated with other systemic vasculitic disorders (i.e., Churg-Strauss syndrome). Recently, the idiopathic crescentic glomerulonephritides, either in renal-limited form or in association with other systemic vasculitic disorders, were found to have in common a serologic marker, antineutrophil cytoplasmic autoantibodies. These cytoplasmic and perinuclear antineutrophil cytoplasmic autoantibodies are specific for constituents of neutrophil primary granules and monocyte lysosomes. As serologic markers for vasculitic disorders, they are also felt to be directly involved in the pathogenesis of necrotizing vascular injury.In vitro, both perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies are capable of causing cytokineprimed neutrophils to undergo degranulation and respiratory burst, releasing toxic oxygen species and lytic enzymes. Antiidiotype antibodies which inhibit antineutrophil cytoplasmic autoantibodiesin vitro, in a V region-dependent manner, are found in pooled humanγ-globulin preparations. Intravenous immune globulin infusionsin vivo have produced dramatic improvements in the necrotizing vascular injury produced by antineutrophil cytoplasmic autoantibodies, and a rapid reduction in these autoantibody levels is seen post-intravenous immune globulin infusion in most patients. The proposed mechanisms of action of intravenous immune globulin in vasculitic disorders include Fc-dependent mechanisms, and F(ab′)₂-dependent mechanisms are likely important. Intravenous immune globulin infusions appear to have an important place in the management of the necrotizing vascular injury. Blinded, randomized, placebo-controlled trials will be necessary to establish definitively intravenous immune globulin as a therapeutic option in vasculitic disorders.     

Synthesis of a series ofcis-diamminedichloro-platinum (II) complexes linked to uracil and uridine as candidate antitumor agents

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II) (3a), [N-(2-aminoethyl)uracil-6-carboxamide]dichloroplatinum (II) (3b), [5-(2-aminoethyl)carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl) carbamoylu-carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxamide (2a) and N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-carboxy-2′,3′,5′-tri-0-acetyluridine (4a) and 6-carboxy-2′,3′,5′-tri-0-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).     

The Burden of Obesity and Its Sequelae

Obesity [body mass index (BMI) ≥30 kg/m²] is common in many parts of the world, especially in the established market economies, formerly socialist economies of Europe and Latin America and the Caribbean, as well as the Middle Eastern Crescent. Worldwide, as many as 250 million people may be obese (7% of the adult population) and 2 to 3 times as many may be considered overweight (BMI 25 to 30 kg/m²). The prevalence of obesity seems to be increasing in most parts of the world, even in areas where obesity used to be rare.A waist circumference greater than 102cm in men and 88cm in women may be a more sensible classification than BMI to identify individuals who are at increased health risk because of obesity, but information on this point is still scarce.Increased fatness measured by a high BMI, large waist circumference or high waist/hip circumference ratio is associated with many chronic diseases as well as poor physical functioning. These all contribute to the costs associated with excess bodyweight. The economic costs of obesity can be broken down into 3 levels Direct costs: costs to the community related to the diversion of resources to the diagnosis and treatment of diseases directly related to obesity as well as the treatment of obesity itself. These costs have been estimated to account for 2 to 8% of total healthcare costs of various countries. Indirect (or societal) costs: these costs are related to the loss of productivity caused by absenteeism and premature death and disability pensions. There is a lack of good economic analysis in this area, although research from Sweden, Finland and The Netherlands has clearly shown that obesity is associated with increased sick leave and the need for disability pensions. Personal costs: obese individuals may earn less than their lean counterparts because of job discrimination (related to the stigma associated with obesity or because of diseases and disabilities caused by obesity). Many insurance companies (particularly life insurance) charge higher premiums with increasing degrees of overweight.In conclusion, there is much indirect information that obesity and overweight are important and growing public health concerns that contribute substantially to healthcare-related costs. Effective strategies for the prevention and management of obesity are needed.     

Case Management

New roles for nurses are emerging as managed-care organisations continue to evolve. Many of these roles are new for nurses; others expand or redefine traditional roles in the diabetes disease management environment in integrated healthcare systems. It is important now to redefine these roles for nurses in a way which supports the organisations’s quality outcomes.Patient education, one of the cornerstones in diabetes disease management programmes, has been an important nursing role for decades. In the diabetes disease management environment, the challenge for nurses is to provide appropriate education to the diabetes population in a way which acknowledges the continuum of care, the course of the disease and the progression of patient learning needs. Much of the outcomes research studying the effectiveness of patient education programmes is related to traditional, hospital-based programmes. Simply adapting traditional diabetes education programmes may not be sufficient to address patient education needs for the entire diabetes population within the integrated healthcare system.Phased diabetes competency for nurses is built on the premise that both patients and nurses acquire diabetes expertise in a phased, progressive manner. This model matches the competency of nurses at each level with parallel competencies for patients with diabetes.     

An Inner-City Asthma Disease Management Initiative

Objectives: The purpose of this study was to evaluate the effects of a recently implemented disease management programme [Asthma Control and Education Program (ACE)] on patient outcomes (clinical and functional) and on resource utilisation in socio-economically disadvantaged (and largely Hispanic) individuals with asthma treated at Hartford Hospital. Design and Setting: Using standardised measures (i.e. the Health Status Questionnaire [HSQ] and the Center for Epidemiologic Studies Depression Scale) and conducting serial assessments the investigators determined: (i) functional status at intake and follow-up; (ii) change in the level of illness severity over time; (iii) patientss’ acquisition of self-management skills; and (iv) the type and frequency of acute care services utilised pre- and post-enrolment in ACE. Patient Population:The study participants consisted of consenting individuals, aged 18 years or older, enrolled in ACE from 1 January 1997 to 30 September 1998. Each individual had a comprehensive intake interview (data collected included clinical and financial status) followed by 3 educational sessions. Results: While only 34.7% (n = 282) of the 813 patients referred from Hartford Hospital to physicians or emergency department services elected to participate in the programme, 60% of participants completed the educational sessions. 73% of these enrollees returned for the 3-month follow-up.On the HSQ, the mean Physical Composite Summary (PCS) scores increased from 33.3 ± 10.01 at baseline to 41.6 ± 11.48 at the 3-month follow up and 45.3 ± 10.30 at the 6-month follow-up. In an analysis using only those patients (n = 50) with HSQ scores at baseline and 3- and 6-month follow-ups, there were statistically significant increases in both the PCS and the Mental Composite Summary scores (p < 0.001).For the 68 patients with severity data at baseline, 3 months and 6 months there was a statistically significant improvement over time (p < 0.001). For example, 4.4% had severe disease at 6 months versus 69.1% at baseline. A subset of 73 patients for whom pre-ACE data were available realised a 37% reduction in emergency department use and a 52% reduction in in-patient visits. Conclusions: The evaluation of disease management programmes requires outcomes data. The results of this study of an asthma disease management programme indicate there was an improvement in overall functioning, illness severity, self-management, and utilisation of inpatient and emergency department services. Although a cause and effect relationship could not be assumed, the results suggest that the disease management model is an effective one for the studied population of inner-city patients, socioeconomically disadvantaged individuals previously identified as high utilisers of healthcare services and as having significant environmental exposures problematic for patients with asthma. As currently designed, however, this programme does not address the healthcare needs of the large number of referred patients who choose not to enrol or the enrollees (40%) who do not complete the education and follow-up sessions.     

Association of benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid (BPDE-DNA) adduct level with aging in male smokers and nonsmokers

We used our new flow cytometric method to measure benzo[a]pyrene-diolepoxide-deoxyribonucleic acid adduct levels in peripheral lymphocytes from healthy male smokers and nonsmokers. Smokers who had pack-years of 20 or more had significantly higher mean benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels than nonsmokers. In smokers, the adduct levels were correlated significantly with age, years of smoking, and pack-years, whereas daily tobacco consumption was not correlated with adduct levels. We also found a positive relationship between age and benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels in nonsmokers. Passive exposure to tobacco smoke was not associated with adduct levels. The results of our study indicate that benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct levels may be closely related to aging and that tobacco smoking-as well as other environmental factors-may play a role in the benzo[a]pyrene-diol-epoxide-deoxyribonucleic acid adduct formation.     

Patient Compliance and its Impact on Treatment Outcomes

Despite an abundance of literature that assesses medication compliance associated with specific diseases, its impact on patient outcomes remains poorly characterised, perhaps due to the complexity associated with its influence and measurement. Much of the previous research includes end-points that were reflective of the duration and pattern of medication use; the value of which is questionable. In fact, the accuracy of compliance data remains highly controversial due to the difficulties associated with its measurement. Monitoring, by itself, may result in minor improvements in medication compliance; monitoring that is coupled to a meaningful clinical outcome that patients can self-measure results in enhanced compliance.Disease management programmes frequently contain interventions to impact compliance. Disease management programme developers interested in positively affecting compliance should incorporate patient self-monitoring methods into their compliance interventions.     

Endoscopic surgery for obstructive hydrocephalus

Endoscopic surgery is popular in the neurosurgical field. The purpose of this study was to determine the role of endoscopy in obstructive hydrocephalus. From 1989 to 1999, we performed 81 endoscopic third ventriculostomies and 10 septostomies. Seventy-one of 81 operations were performed with endoscopic third ventriculostomy alone and 10 patients had endoscopic third ventriculostomy and ventriculoperitoneal shunt simultaneously. Age distribution varied from 2 months to 62 years of age. Our selection criteria included aqueductal stenosis (39 patients) and obstructive hydrocephalus due to tumor or cyst (42 patients). The most common candidate for endoscopic septostomy was atresia of the foramen of Monro (4 patients). Endoscopic septostomy was also performed to simplify shunting in patient; with multiseptated ventricle due to shunt infection, germinoma, thalamic tumor, craniopharyngioma, cyst and brain abscess. Sixty-five of 71 patients who were treated with endoscopic third ventriculostomy alone showed successful results (91.5%). However, 6 patients had unsatisfactory results and they needed a ventriculoperitoneal shunt. With no mortality, transient surgical complications were observed in 7 patients: 2 transient diabetes insipidus from electrical injury to the pituitary stalk, 1 epidural hematoma from sudden drainage of CSF, 1 delayed intraventricular hemorrhage. 2 obstruction of fenestration site and 1 transient memory disturbance from injury to the fornix. Endoscopic septostomy was useful in simplifying shunting in all cases with complicated hydrocephalus. Endoscopic surgery is straightforward and effective in appropriately selected cases with obstructive by drocephalus.