Ascertaining the prevalence of childhood disability.

OBJECTIVES: To reapply 1985 Office of Population Census and Surveys (OPCS) disability survey methods, modified as necessary, to a sample of children to ascertain presence of disability. To compare OPCS-based prevalence with prevalence based on carer's views and medical records. DESIGN: Analytical study. Setting Community Child Health Department in UK. PARTICIPANTS: Principal carers of 100 children aged 5-15, selected from a district special needs register. Main outcome measures Comparable information about disability from three sources and diagnosis from carers and medical records. RESULTS: Medical records of 46% contained a diagnosis. Carers were always aware of this, although a single question did not always elicit their knowledge. OPCS-derived threshold disability criteria in categories of Hand function, Personal care, Consciousness and Continence gave prevalence results similar to medical records and carers. OPCS criteria yielded higher prevalence of disability in the areas of Locomotion (8%), Communication (14%) and Hearing (18%). Carers, OPCS and medical records disagreed markedly about prevalence of disabilities of Vision, probably because of the use of differing definitions. OPCS learning criteria were judged unsuitable and standard attainment targets (SATs) were substituted. These provided similar prevalence figures to carers and medical records. OPCS behaviour criteria were also unsuitable and were replaced by the General Health and Behaviour Questionnaire (GHBQ). This found an increased prevalence of problems compared with carers and doctors. CONCLUSIONS: Diagnostic labels have limited use when collecting data about disabled children. Doubt is cast on the validity of some of the 1985 OPCS threshold criteria, and reassessment is suggested before their future use. Further work is needed on the use of SATs and GHBQ in the benchmarking of disability. To collect population data it would be easier and at least equally effective (with caution in the case of Vision) to ask carers directly rather than applying descriptive thresholds and external judgements. Similar information could be obtained from medical records, however, they are likely to be out of date.

Using simulated patients in a multiprofessional communications skills programme: reflections from the programme facilitators.

This paper discusses a multiprofessional, 4-day communication skills programme in which participants explore the challenges of communicating with cancer patients and their families. Effective communication and skilled emotional support are essential prerequisites for high quality care in oncology and palliative care settings. This aspect of care presents major challenges to nurses and other health care professionals. It is acknowledged that health professionals often lack the requisite skills to communicate meaningfully with this patient group and that tangible benefits accrue from training in this area. Using simulated patients, structured feedback and small group discussions, this multiprofessional programme seeks to provide a forum that enables participants to acquire confidence and competence in a safe, comfortable and non-threatening environment. The programme structure presents several challenges in terms of providing a learning experience that addresses the diverse educational of a heterogeneous learning group. Participants' comments and programme facilitators reflections suggest that the programme is successful in addressing these challenges and providing a meaningful learning experience.

Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity.

The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexes of neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor-enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and 54, have IC(50) values vs neuraminidase from influenza A and B of <1 and <10 nM, respectively. These IC(50) values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.

Addition of lithiated 9-deazapurine derivatives to a carbohydrate cyclic imine: convergent synthesis of the aza-C-nucleoside immucillins.

Means have been developed for the synthesis and addition of 9-deaza-9-lithiopurine derivatives to the carbohydrate-derived cyclic imine 6 in facile convergent syntheses of biologically active aza-C-nucleosides.

Purine nucleoside phosphorylase inhibitor BCX-1777 (Immucillin-H)--a novel potent and orally active immunosuppressive agent.

Patients with purine nucleoside phosphorylase (PNP) deficiency present a selective T-cell immunodeficiency. Inhibitors of PNP are, therefore, of interest as potential T-cell selective immunosuppressive agents. BCX-1777 is a potent inhibitor of PNP from various species including human, mouse, rat, monkey and dog, with IC50 values ranging from 0.48 to 1.57 nM. BCX-1777, in the presence of 2'-deoxyguanosine (dGuo, 3-10 microM), inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction (MLR) and phytohemagglutinin (PHA) (IC50 values < 0.1-0.38 microM). BCX-1777 is a 10-100-fold more potent inhibitor of human lymphocyte proliferation than other known PNP inhibitors like PD141955 and BCX-34. Nucleotide analysis of human lymphocytes indicate that inhibition of proliferation by BCX-1777 correlates with dGTP levels in the cells. BCX-1777 has excellent oral bioavailability (63%) in mice. At a single dose of 10 mg/kg in mice, BCX-1777 elevates dGuo to approximately 5 microM. BCX-1777 was not effective in mouse T-cell models such as delayed type hypersensitivity (DTH) and splenomegaly because mouse T-cells do not accumulate dGTP as do human T-cells. However, in the human peripheral blood lymphocyte severe combined immunodeficiency (hu-PBL-SCID) mouse model, BCX-1777 was effective in prolonging the life span 2-fold or more. This is the first known example of a PNP inhibitor that elevates dGuo in mice similar to the levels observed in PNP-deficient patients. Furthermore, these dGuo levels are also required for in vitro T-cell inhibition by BCX-1777. Thus, BCX-1777 represents a novel class of selective immunosuppressive agents that could have therapeutic utility in various T-cell disorders.

Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir.

We have recently reported an influenza virus neuraminidase inhibitor, RWJ-270201 (BCX-1812), a novel cyclopentane derivative discovered through structure-based drug design. In this paper, we compare the potency of three compounds, RWJ-270201, oseltamivir, and zanamivir, against neuraminidase enzymes from various subtypes of influenza. RWJ-270201 effectively inhibited all tested influenza A and influenza B neuraminidases in vitro, with 50% inhibitory concentrations of 0.09 to 1.4 nM for influenza A neuraminidases and 0.6 to 11 nM for influenza B neuraminidases. These values were comparable to or lower than those for oseltamivir carboxylate (GS4071) and zanamivir (GG167). RWJ-270201 demonstrated excellent selectivity (>10,000-fold) for influenza virus neuraminidase over mammalian, bacterial, or other viral neuraminidases. Oral administration of a dosage of 1 mg/kg of body weight/day of RWJ-270201 for 5 days (beginning 4 h preinfection) showed efficacy in the murine model of influenza virus infection as determined by lethality and weight loss protection. RWJ-270201 administered intranasally at 0.01 mg/kg/day in the murine influenza model demonstrated complete protection against lethality, whereas oseltamivir carboxylate and zanamivir at the same dose demonstrated only partial protection. In the delayed-treatment murine influenza model, oral administration of a 10-mg/kg/day dose of RWJ-270201 or oseltamivir (GS4104, a prodrug of GS4071) at 24 h postinfection showed significant protection against lethality (P < 0.001 versus control). However, when the treatment was delayed for 48 h, no significant protection was observed in either drug group. No drug-related toxicity was observed in mice receiving 100 mg/kg/day of RWJ-270201 for 5 days. These efficacy and safety profiles justify further consideration of RWJ-270201 for the treatment and prevention of human influenza.

Stereoselective synthesis of a conformationally defined cyclohexyl carnitine analogue that binds CPT-1 with high affinity.

Carnitine (1, 3-hydroxy-4-trimethylammoniobutyrate) is important in mammalian tissue as a carrier of acyl groups. In order to explore the binding requirements of the carnitine acyltransferases for carnitine, we designed conformationally defined cyclohexyl carnitine analogues. These diastereomers contain the required gauche conformation between the trimethylammonium and hydroxy groups but vary the conformation between the hydroxy and carboxylic acid groups. Here we describe the synthesis and biological activity of the all-trans diastereomer (2), which was prepared by the ring opening of trans-methyl 2,3-epoxycylohexanecarboxylate with NaN3. Racemic 2 was a competitive inhibitor of neonatal rat cardiac myocyte CPT-1 (K(i) 0.5 mM for racemic 2; K(m) 0.2 mM for L-carnitine) and a noncompetitive inhibitor of neonatal rat cardiac myocyte CPT-2 (K(i) 0.67 mM). These results suggest that 2 represents the bound conformation of carnitine for CPT-1.

Pediatric myocardial infarction after racemic epinephrine administration.

Myocardial infarction is a previously unreported complication of treatment with racemic epinephrine that is used commonly in the emergency department for severe respiratory distress in bronchiolitis or croup syndrome. We describe a pediatric patient who presented with the croup syndrome and severe respiratory distress that required multiple doses of nebulized racemic epinephrine in the emergency department. The patient developed ventricular tachycardia and mild chest discomfort during one treatment, which resolved spontaneously on discontinuation of the nebulization. Persistently abnormal electrocardiograms and elevated creatine phosphokinase MB isoenzyme (CPK-MB) levels suggested a myocardial infarction had occurred. Subsequent echocardiography, cardiac catheterization, and angiography revealed an anatomically normal heart with normal coronary circulation; however, a stress nuclear study showed a small myocardial infarct. The significance of this previously unreported complication of racemic epinephrine is discussed, along with recommendations for proper use in the emergency department.

Survey of UK computerised special needs registers.

A postal survey of all computerised children's disability registers in the UK was undertaken in 1996. Information was returned from 155 of 166 districts (93%). The implementation of computerised special needs registers is a continuing nationwide trend. Although there is evidence of successful use of registers both as an individual and as a population service planning tool, a high percentage of existing registers are functioning in a way which is far short of their potential for research, audit, and planning. Registers which work well have been set up with expertise, have staff enthusiastic about data entry, and are well supported for data output and software modification. There should be continued cooperative work towards a national consensus on the categories of disability and definition of severity of disability used in these registers.

Synthesis of 2-[6-(2,4-dinitrophenoxy)hexyl]oxiranecarboxylic acid: a selective carnitine palmitoyltransferase-1 inhibitor.

Carnitine palmitoyltransferases 1 and 2 (CPT-1 and CPT-2) catalyze the transfer of long chain fatty acids between carnitine and coenzyme A. Unlike CPT-2, CPT-1 exists in at least two isoforms with different physical and kinetic properties. Liver and skeletal muscle each contain a different isoform of CPT-1. Cardiac muscle contains both isoforms, and the minor component is identical to the isoform found in the liver. 2-[6-(2,4-Dinitrophenoxy)hexyl]oxiranecarboxylic acid (2) was reported to be a selective inhibitor for the liver isoform of CPT-1. A synthesis of 2 is described here which involves the reaction of diethyl malonate with 1-bromo-6-phenoxyhexane.

Development and satisfaction with individual programme planning in a disability service.

A consumer survey of a preschool disability service identified parents who did not feel their concerns were fully understood by professionals, nor felt involved or in agreement with treatment decisions, nor that services were provided in a coordinated way. A system of individual programme planning (IPP) was introduced in order to address these issues and other shortfalls of the existing service. Information was obtained from 96% of parents and 87% of professionals who attended IPP meetings over a four month period. Overall satisfaction was high (92% of parents: 96% of professionals). Parents now felt fully involved in decision making, 80% felt their views were understood and 100% agreed with treatment goals. Dissatisfaction was expressed with meeting attendance, the marginalisation of parents, and the timing and chairing of meetings. Consumer satisfaction surveys are recommended for use in highlighting areas of service shortfall, to direct and evaluate service change, and to monitor quality.

Arrow wound management in Papua New Guinea.

Arrow injuries sustained during tribal fighting are a common reason for admission to the hospitals of Southern Highlands Province in Papua New Guinea (P.N.G.). The authors, Canadian and American family physicians with an aggregate 12 years' general practice experience in the P.N.G. Highlands, present the findings of a 1-year retrospective study of arrow wound victims admitted to two hospitals. Arrow wound injuries are a consequence of a variety of sociocultural factors that continue to result in their high incidence despite many decades of contact with the outside world. We present the details of the presentation and management of 90 cases including a preponderence of soft-tissue as well as intracranial, thoracic, and abdominal injuries. Illustrative case histories of the more challenging or unusual cases provide insight into the unique opportunity afforded the general practitioner/surgeon in managing a type of injury which has become virtually extinct in North American practice over the last 200 years.

A study of hepatic lesions in broiler chickens at processing plants in Saskatchewan.

A detailed descriptive study was done on broiler chickens with abnormal livers found at processing. Two syndromes were evident: those birds with enlarged, pale, firm livers, designated hepatosis, with Clostridium perfringens type A often isolated; and ascitic birds with cobblestone-appearing livers. Livers with hepatosis had marked proliferation of bile ducts; ascitic livers had normal architecture. Hearts from birds with ascites had elevated right ventricular/total ventricular weight ratios, whereas hearts from normal birds and birds with hepatosis did not. Two isolates of C. perfringens produced necrotic enteritis in experimental birds; an attempt to reproduce hepatosis with these isolates was unsuccessful.