Expert consensus on systemic therapy for plaque psoriasis with limited skin involvement in JAPAN: Results from a DELPHI study.

Our objective was to establish consensus on (1) which patients with plaque psoriasis and limited skin involvement (body surface area [BSA] <10%) are suitable for systemic treatment, and (2) a definition of 'topical therapy failure'. A steering committee refined 13 statements drawn from literature related to the study objectives. An independent panel of 45 clinical experts from Japan indicated their agreement to each statement using a 10-point Likert scale (Round 1; strong consensus, ≥70% of responses = 7-10 and median value ≥8). The steering committee reviewed Round 1 results and refined the statements for Round 2, as necessary. In Round 2, the panel indicated their agreement to each statement using a 3-point scale (strong consensus, ≥70% of responses and median value of 3) and were shown Round 1 responses before voting. Forty-five clinicians participated in Round 1 and 41 of those (91%) participated in Round 2. Consensus was achieved on the criteria of eligibility for systemic treatment among patients with limited skin involvement as disease involvement at special or difficult to treat areas, psoriasis-induced psychological distress, uncontrolled symptoms (e.g., scaling, bleeding, pruritus, insomnia) affecting their social life, psoriatic arthritis, or failure of topical therapy. Consensus on criteria for topical failure were persistent symptoms (e.g., itchiness, pain) and plaques, poor patient satisfaction with treatment, a need to increase medication quantity or application time after treatment with two topicals for 4 weeks; or if the Psoriasis Area Severity Index score of >3 or Physician Global Assessment Score of ≥2 after 8 weeks treatment. Our Delphi panel proposes criteria to help physicians identify patients with psoriasis and limited skin involvement who would benefit from systemic therapy and suggests a definition for topical therapy 'failure' which could indicate a move to systemic treatment is warranted.

C-Reactive protein in adults with chronic spinal cord injury: increased chronic inflammation in tetraplegia vs paraplegia.

STUDY DESIGN: Cross-sectional. OBJECTIVES: In community-dwelling adults with chronic spinal cord injury (SCI), to (1) quantify C-reactive protein (CRP), a marker of inflammation and cardiovascular disease (CVD) risk; (2) determine factors associated with CRP. SETTING: Hamilton, Ontario, Canada. METHODS: We examined CVD risk factors in 69 participants. Measurements included length, weight, waist circumference, blood pressure, percent fat mass (bioelectrical impedance analysis) and fasting blood parameters (high-sensitivity CRP, lipids, insulin, glucose, insulin resistance by homeostasis model assessment (HOMA)). RESULTS: Mean CRP of the group was 3.37+/-2.86 mg-l(-1), consistent with the American Heart Association (AHA) definition of high risk of CVD. CRP was 74% higher in persons with tetraplegia (4.31+/-2.97) than those with paraplegia (2.47+/-2.47 mg l(-1), P=0.002), consistent with high CVD risk. Participants with high CRP (3.1-9.9 mg l(-1)) had greater waist circumference, BMI, percent fat mass and HOMA values than those with lower CRP (< or =3.0 mg l(-1), all P<0.05). LogCRP was independently correlated with waist circumference (r=0.612), logTriglycerides (r=0.342), logInsulin (r=0.309) and logHOMA (r=0.316, all P<0.05). Only level of lesion and waist circumference remained significantly associated with logCRP when variables with significant bivariate correlations were included in multiple regression analysis. CONCLUSION: Mean CRP values in this sample of adults with chronic SCI were consistent with the AHA classification of high CVD risk, especially those of persons with tetraplegia. Level of lesion and waist circumference are independently associated with CRP in this population.

Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.

Substituted guanines and pyrimidines were tested as inhibitors of cyclin B1/CDK1 and cyclin A3/CDK2 and soaked into crystals of monomeric CDK2. O6-Cyclohexylmethylguanine (NU2058) was a competitive inhibitor of CDK1 and CDK2 with respect to ATP (Ki values: CDK1, 5 +/- 1 microM; CDK2, 12 +/- 3 microM) and formed a triplet of hydrogen bonds (i.e., NH-9 to Glu 81, N-3 to Leu 83, and 2-NH2 to Leu 83). The triplet of hydrogen bonding and CDK inhibition was reproduced by 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027, Ki values: CDK1, 2.5 +/- 0.4 microM; CDK2, 1.3 +/- 0.2 microM). Against human tumor cells, NU2058 and NU6027 were growth inhibitory in vitro (mean GI50 values of 13 +/- 7 microM and 10 +/- 6 microM, respectively), with a pattern of sensitivity distinct from flavopiridol and olomoucine. These CDK inhibition and chemosensitivity data indicate that the distinct mode of binding of NU2058 and NU6027 has direct consequences for enzyme and cell growth inhibition.

Monomer, dimer, tetramer, polymer: structural diversity in zinc and cadmium complexes of chelate-tethered nucleobases.

A series of ZnII and CdII complexes of adenine and guanine derivatives containing a diamine tether have been isolated from aqueous solutions and characterised by single crystal X-ray analysis. These studies reveal a wide range of structural types including monomeric, dimeric, tetrameric and polymeric architectures. The extended structures arise from the ability of the ligands to bridge metal ions using the chelating tether in conjunction with N7 of the nucleobase. Additional metal-nucleobase co-ordination is generally observed at the N3-site of the adenine derivatives. With CdII, ethylenediamine-N9-ethylguanine forms an inverted G-tetrad type structure.

The natural history of X-linked retinoschisis.

OBJECTIVE: To evaluate long-term changes in visual acuity, clinical features and complications in X-linked retinoschisis, and to analyse recombinant chromosomes in affected males, carrier females and unaffected males to further refine the retinoschisis gene locus. DESIGN: Longitudinal study. SETTING: Ophthalmology department at a university-affiliated hospital in Saskatoon. PATIENTS: A total of 92 male patients from 6 pedigrees affected with X-linked retinoschisis examined between 1962 and 1994. Of the 92, 73 were followed for a mean of 19.78 (standard deviation 8.74) years (range 1.5 to 31 years). Blood samples were taken from 91 affected males, 100 unaffected males and 86 carrier females for DNA analysis. OUTCOME MEASURES: Significant visual loss was defined as a doubling or more in the visual angle. Clinical comparisons of fundus features were aided by stereoscopic fundus photographs. RESULTS: The mean geometric visual acuity was 20/67 on initial examination and 20/78 on last assessment. Significant loss in visual acuity occurred in 18 (21.2%) of 85 eyes of 43 patients during childhood or adolescence and in 20 (17.1%) of 117 eyes of 59 patients in the postadolescent period. All 183 eyes had changes at the macula. Peripheral schisis was detected in 106 eyes (57.9%), with a mean of 1.48 (standard deviation 1.03) involved quadrants. Asymmetric disease was detected in 19 patients (20.6%). Vitreal hemorrhages occurred in 24 eyes (13.1%), retinal detachments in 10 (5.5%). Thirteen eyes (7.1%) of eight patients had a very poor visual outcome (light perception or no light perception). A new gene, XLRSI, was identified by means of positional cloning. XLRSI is mutated in affected people. CONCLUSIONS: In uncomplicated cases of X-linked retinoschisis the visual prognosis is good. There is wide variation in clinical features among those affected and in the disease over time.

A comparison of tricompartmental and unicompartmental arthroplasty for the treatment of gonarthrosis.

An historical prospective study was performed to compare two surgical management alternatives in the treatment of patients with knee arthritis. There were 120 unicompartmental and 81 tricompartmental knee arthroplasties in 98 and 66 patients, respectively. All living patients were available for follow-up observation, and survivorship data on all arthroplasties were obtained. The average follow-up interval was 78 months (range, eight-162 months) in the unicompartmental series and 68 months (range, two- 186 months) in the tricompartmental group. Patients receiving the unicompartmental arthroplasty were treated with nonmetal-backed polyethylene tibial components. Prosthetic survivorship was 92% at ten years in the unicompartmental patient group. There were no statistically significant differences in aseptic loosening between these two patient groups. In appropriately selected patients unicompartmental arthroplasty was associated with better range of motion and ambulatory function than patients being treated with tricompartmental knee replacement.

Phenylarsine oxide inhibition of endocytosis: effects on asialofetuin internalization.

The aim of this work was to establish to what extent the concentrations over which phenylarsine oxide (PAO) inhibits oxygen consumption and decreases cellular ATP content overlap with those used to inhibit protein internalization. The effects of PAO (1-100 microM) on 125I-labeled asialofetuin internalization, oxygen consumption, ATP content, and lactate dehydrogenase (LDH) latency of isolated rat hepatocytes were determined. Ten micromoles/liter PAO blocked 125I-asialofetuin internalization but had no effect on ATP content up to 20 min, only a slight inhibition (18%) on oxygen consumption, and no effect on LDH latency. Higher concentrations of PAO had increasingly deleterious effects on the parameters. These results show that higher concentrations of PAO severely affect the energy stores as well as integrity of the hepatocyte. We concluded that 1) use of PAO requires careful evaluation of its effects in each experimental preparation and 2) it should be possible to establish time and concentration parameters for use of PAO as an inhibitor of endocytosis while minimizing the influence of its other cellular actions.