Rapid onset of action of calcipotriol/betamethasone dipropionate cutaneous foam in psoriasis, even in patients with more severe disease.

BACKGROUND: The effectiveness of topical therapies in psoriasis is dependent on, amongst other factors, patient adherence. Together with treatment effectiveness and reduction of symptoms, speed of onset and health-related quality of life (HRQoL) are important influencers of adherence. METHODS: This pooled analysis of three Phase II/III trials evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) vs. foam vehicle at early timepoints in mild-to-severe psoriasis using clinically meaningful modified Psoriasis Area and Severity Index (mPASI) and Dermatology Life Quality Index (DLQI) targets. RESULTS: A greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved absolute mPASI targets 0 (15.1% vs. 1.0%), ≤1 (41.4% vs. 5.2%), ≤3 (78.5% vs. 29.2%) and ≤5 (90.2% vs. 62.5%) at week 4 (P < 0.001; all targets). Significant differences between Cal/BD-foam- vs. foam-vehicle-treated patients were observed as early as week 1 in those achieving mPASI ≤1 (6.8% vs. 1.5%; P < 0.01), ≤3 (40.4% vs. 22.8%; P < 0.001) and ≤5 (69.7% vs. 50.8%; P < 0.001). In patients with more severe psoriasis (baseline mPASI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved mPASI ≤1 (20.2% vs. 5.9%; P < 0.05), ≤3 (49.2% vs. 8.8%; P < 0.001) and ≤5 (63.7% vs. 26.5%; P < 0.001) at week 4. In patients with severely impaired HRQoL (baseline DLQI >10), a greater proportion of Cal/BD-foam- vs. foam-vehicle-treated patients achieved target DLQI ≤1 or 0 (week 4: DLQI ≤1, 25.0% vs. 4%; P = 0.001; DLQI 0, 17.4% vs. 2.0%; P = 0.006). CONCLUSION: We report rapid onset of action and greater efficacy with Cal/BD foam vs. foam vehicle, even in patients with more severe psoriasis, manageable with topical treatments. This may support physician management of patient expectations and improve patient adherence, translating into overall topical treatment effectiveness.

Itch relief in patients with psoriasis: effectiveness of calcipotriol plus betamethasone dipropionate foam.

BACKGROUND: Itch is common in psoriasis, adversely affecting health-related quality of life (HRQoL) and sleep. OBJECTIVE: We evaluated the efficacy of topical fixed-dose combination calcipotriol 50 µg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) on itch, itch-related sleep loss and HRQoL vs. foam vehicle. METHODS: We pooled data from three Phase II/III trials (NCT01536886/NCT01866163/NCT02132936) of Cal/BD foam vs. foam vehicle in adults with mild-severe psoriasis. For itch-related analyses, patients with baseline itch visual analogue scale (VAS) >40 (range 0-100) were analysed. Outcomes included the following: itch VAS reduction >40, ≥70% improvement in itch (Itch70) or itch-related sleep loss, 75% improvement in modified Psoriasis Area and Severity Index (excluding head; mPASI75) and Dermatology Life Quality Index (DLQI) scores 0/1 through 4 weeks. RESULTS: Of 837 patients, 800 had baseline itch VAS >0 (Cal/BD foam, n = 610; foam vehicle, n = 190); 484 had baseline itch VAS >40. There was no correlation between itch VAS score and mPASI at baseline (R2  = 0.021). In patients with baseline itch VAS >40, more patients achieved itch VAS reduction >40 in the active vs. vehicle group from Day 5 onwards (Day 5: 57.5% vs. 40.2% [P < 0.05]; Week 4: 83.0% vs. 45.8% [P < 0.001]). More Cal/BD-foam-treated patients achieved Itch70 at Day 3 (34.2% vs. 22.5%; P < 0.05) through to Week 4 (79.3% vs. 38.1%; P < 0.001). In patients with baseline itch VAS >40 and sleep loss >20, improvements in itch-related sleep loss occurred at Week 1 and continued through 4 weeks. Itch-related improvements occurred before improvements in mPASI75. There were significant differences in the proportion of Cal/BD-foam- vs. foam-vehicle-treated patients with baseline DLQI >10 (n = 172 vs. n = 50) achieving DLQI ≤1 (25.0% vs. 4.0%; P = 0.001) and DLQI 0 (17.4% vs. 2.0%; P = 0.006) at Week 4. CONCLUSION: Compared with foam vehicle, Cal/BD foam offers more rapid and effective itch relief, with associated significant improvements in sleep and DLQI.

The effect of increased classroom ventilation rate indicated by reduced CO2 concentration on the performance of schoolwork by children.

The article reports on an experiment which investigated the effect of increased classroom ventilation rate on the performance of children aged 10-12 years. The experiment was executed at two different schools (two classrooms at each school) as a double-blind 2 × 2 crossover intervention where four different performance tests were used as surrogates for short-term concentration and logical thinking. Only complete pairs of test responses were included in the within-subject comparisons of performance, and data were not corrected for learning and fatigue effects. Analysis of the total sample suggested the number of correct answers was improved significantly in four of four performance test, addition (6.3%), number comparison (4.8%), grammatical reasoning (3.2%), and reading and comprehension (7.4%), when the outdoor air supply rate was increased from an average of 1.7 (1.4-2.0) to 6.6 l/s per person. The increased outdoor air supply rate did not have any significant effect on the number of errors in any of the performance tests. Results from questionnaires regarding pupil perception of the indoor environment, reported Sick Building Syndrome symptoms, and motivation suggested that the study classroom air was perceived more still and pupil were experiencing less pain in the eyes in the recirculation condition compared to the fresh air condition.

Malignant Sertoli cell tumour in a young Simmenthal bull--clinical and pathological observations.

Tumours are rare in the bovine testicle. A case of malignant Sertoli cell tumour in a 29-month-old Simmenthal bull that was hospitalized with a history of severe unilateral scrotal swelling is reported. On inspection and palpation, the scrotal sac was found enlarged with fluctuant content in the right side. The right testicle was enlarged, hard and indolent. Also the right plexus pampiniformis and funiculus spermaticus were enlarged. Sonograms revealed severe changes in the right testicle with a loss of homogeneity and multiple hyperechogenic areas. After slaughter, the scrotum with testicles were removed and evaluated pathologically. On section, the right testicle contained areas of necrosis, haemorrhage, and mineralization. Histology showed Sertoli cells in tubular structures surrounded by dense fibrous stroma replacing normal testicular tissue. Both lymphatic and blood vessels were infiltrated by neoplastic cells. Immunohistochemically, the neoplastic cells stained positive for vimentin and negative for cytokeratin and S-100. Based on the pathological observations a diagnosis of right-sided malignant Sertoli cell tumour with vascular invasion and hydrocele was established.

Enhanced antiviral effect in cell culture of type 1 interferon and ribozymes targeting HCV RNA.

We have recently shown that the replication of an HCV-poliovirus (PV) chimera that is dependent upon the hepatitis C virus (HCV) 5' untranslated region (UTR) can be inhibited by treatment with ribozymes targeting HCV RNA. To determine the antiviral effects of anti-HCV ribozyme treatment in combination with type 1 interferon (IFN), we analysed the replication of this HCV-PV chimera in HeLa cells treated with anti-HCV ribozyme and/or IFN-alpha2a, IFN-alpha2b, or consensus IFN. The anti-HCV ribozyme, or any of the IFNs alone have significant inhibitory effects on HCV-PV replication compared to control treatment (> or = 85%, P < 0.01). The maximal inhibition due to IFN treatment (94%, P < 0.01) was achieved with > or = 50 U/ml for either IFN-alpha2a or IFN-alpha2b compared to control treatment. A similar level of inhibition in viral replication could be achieved with a 5-fold lower dose of IFN if ribozyme targeting the HCV 5' UTR was given in combination. For consensus IFN, the dose could be reduced by > 12.5-fold if ribozyme targeting the HCV 5' UTR was given in combination. Conversely, the dose of ribozyme could be reduced 3-fold if given in combination with any of the IFN preparations. Moreover, treatment with low doses (1-25 U/mL) of IFN-alpha2a, IFN-alpha2b, or consensus IFN in combination with anti-HCV ribozyme resulted in > 98% inhibition of HCV-PV replication compared to control treatment (P < 0.01). These results demonstrate that IFN and ribozyme each have a beneficial antiviral effect that is augmented when given in combination.

The cyclin-dependent kinase inhibitor p21 protects the lung from oxidative stress.

The lung is a major target tissue for oxidative stress, including hyperoxia used to relieve tissue hypoxia. Unfortunately, severe hyperoxia damages DNA, inhibits proliferation, and kills cells, resulting in morbidity and mortality. Although hyperoxia induces the tumor suppressor p53 and its downstream target, the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1) (p21), their role in pulmonary injury remains unknown. Using p53- and p21-deficient mice we demonstrate that hyperoxia induces p21 in the absence of p53, suggesting that previous conclusions that p53 does not modify hyperoxic lung injury cannot be extrapolated to p21. In fact, mean survival of p21-deficient mice decreased by 40% and was associated with terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling staining of alveolar debris, indicative of DNA fragmentation and cell death. Ultrastructural analyses revealed that alveolar endothelial and type I epithelial cells died rapidly by necrosis. Although hyperoxia decreased DNA replication in p21-wild-type lungs, it had no effect on replication in p21-deficient lungs. Our findings suggest that p21 protects the lung from oxidative stress, in part, by inhibiting DNA replication and thereby allowing additional time to repair damaged DNA. Our findings have implications for patients suffering from the toxic effects of supplemental oxygen therapies.

New results in the theory of Fowler-Nordheim plots and the modelling of hemi-ellipsoidal emitters.

This paper reports further progress in understanding the theory of emission-area extraction from Fowler-Nordheim plots, and reports some useful interim results derived by modelling field electron emission from hemi-ellipsoidal emitters. The mathematical nature of the relationship between a new approach to emission-area extraction, recently proposed, and older approaches is demonstrated. The new approach is extended to cover field dependence in emission area. Preliminary results are reported from an investigation into the effects of making erroneous assumptions about the tunnelling barrier seen by the electron and the absence of field dependence in emission area. If wrong theoretical assumptions are made, then emission area can be overpredicted by a factor of as much as 10 or 20. On the other hand, if correct theoretical assumptions are made, then the extracted emission area is close to an emission area derived directly from the model calculations. The problematical nature of the concept of emission area, when emission area is a function of field, is pointed out.

Randomised clinical trials in the Scandinavian Journal of Rheumatology.

OBJECTIVE: To identify all reports of randomised clinical trials in the Journal and compare our findings with reports available in Medline. METHODS: We handsearched the Scandinavian Journal of Rheumatology with supplements for the years 1955-1997 to identify reports of randomised clinical trials and controlled clinical trials. RESULTS: We identified 445 trial reports. In Medline, 134 of these trials (30%) were indexed as randomised or controlled trials; an additional 50 trials (11%) were available in Medline but were indexed differently. Thus, 261 of the trials (59%) we identified were not indexed in Medline; most of these trials were published in supplements to the Journal. CONCLUSION: Handsearching of medical journals for randomised trials can be a worthwhile effort. Clinicians and patients will become better informed about the value of different treatment options and researchers will reduce their risk of performing trials that are unnecessary.

Antitumor and antimetastatic activity of ribozymes targeting the messenger RNA of vascular endothelial growth factor receptors.

Chemically stabilized hammerhead ribozymes are nuclease-resistant, RNA-based oligonucleotides that selectively bind and cleave specific target RNAs. Due to their potential for specifically inhibiting gene expression, ribozymes are being investigated for therapeutic applications as well as for the elucidation of gene function. In particular, we have investigated ribozymes that target the mRNA of the vascular endothelial growth factor (VEGF) receptors because VEGF signaling is an important mediator of tumor angiogenesis and metastasis. Here we report pharmacodynamic studies testing anti-Flt-1 (VEGFR-1) and anti-KDR (VEGFR-2) ribozymes in animal models of solid tumor growth and metastasis. Ribozymes targeting either Flt-1 or KDR significantly inhibited primary tumor growth in a highly metastatic variant of Lewis lung carcinoma. However, only treatment with the anti-Flt-1 ribozyme resulted in a statistically significant and dose-dependent inhibition of lung metastasis in this model. The anti-Flt-1 ribozyme was then tested in a xenograft model of human metastatic colorectal cancer in which significant inhibition of liver metastasis was observed. Taken together, these data represent the first demonstration that synthetic ribozymes targeting VEGF receptor mRNA reduced the growth and metastasis of solid tumors in vivo.

Inhibition of hepatitis C virus (HCV)-RNA-dependent translation and replication of a chimeric HCV poliovirus using synthetic stabilized ribozymes.

Ribozymes are catalytic RNA molecules that can be designed to cleave specific RNA sequences. To investigate the potential use of synthetic stabilized ribozymes for the treatment of chronic hepatitis C virus (HCV) infection, we designed and synthesized hammerhead ribozymes targeting 15 conserved sites in the 5' untranslated region (UTR) of HCV RNA. This region forms an internal ribosome entry site that allows for efficient translation of the HCV polyprotein. The 15 synthetic ribozymes contained modified nucleotides and linkages that stabilize the molecules against nuclease degradation. All 15 ribozymes were tested for their ability to reduce expression in an HCV 5' UTR/luciferase reporter system and for their ability to inhibit replication of an HCV-poliovirus (HCV-PV) chimera. Treatment with several ribozymes resulted in significant down-regulation of HCV 5' UTR/luciferase reporter expression (range 40% to 80% inhibition, P <.05). Moreover, several ribozymes showed significant inhibition (>90%, P <.001) of chimeric HCV-PV replication. We further show that the inhibitory activity of ribozymes targeting site 195 of HCV RNA exhibits a sequence-specific dose response, requires an active catalytic ribozyme core, and is dependent on the presence of the HCV 5' UTR. Treatment with synthetic stabilized anti-HCV ribozymes has the potential to aid patients who are infected with HCV by reducing the viral burden through specific targeting and cleavage of the viral genome.

Widespread occurrence of a highly conserved RING-H2 zinc finger motif in the model plant Arabidopsis thaliana.

Several novel Arabidopsis thaliana proteins containing a RING-H2 zinc finger motif were predicted after database searches. Alignment of 29 RING-H2 finger sequences shows that the motif is strikingly conserved in otherwise unrelated proteins. Only short, non-conserved polar/charged sequences distinguish these domains. The RING-H2 domain is most often present in multi-domain structures, a number of which are likely to contain a membrane-spanning region or an additional zinc finger. However, there are several small (126-200 residues) proteins consisting of an N-terminal domain, rich in aliphatic residues, and a C-terminal RING-H2 domain. Reverse-transcription PCR suggests that the RING-H2 genes are widely expressed at low levels.

Shoulder arthroplasty in recreational golfers.

A retrospective review of 24 patients who had shoulder arthroplasty revealed that 23 were able to resume playing golf. The 23 patients (mean age 52.4 years, range 26.4 to 71.9 years) underwent 26 shoulder arthroplasties, 20 total shoulder arthroplasties, and 6 hemiarthroplasties. The average follow-up was 53.4 months (range 24.4 to 127.2 months). The average length of time from shoulder arthroplasty to playing an entire round of golf was 4.5 months. Eighteen patients were able to report their preoperative handicap and noted an average improvement after surgery of almost 5 strokes. Playing golf did not result in increased radiographic evidence of component loosening, and no increase occurred in lucent lines when the golfers were compared with a control group of 76 patients with osteoarthritis who had 103 shoulder arthroplasties (P < .05). Fifty members of the American Shoulder and Elbow Society were mailed a standardized questionnaire of 11 questions concerning patients who had shoulder arthroplasty and played golf. Most surgeons (91%) encouraged such patients to resume playing golf. The average length of time members of the Society recommended that patients should wait after shoulder arthroplasty before resuming golf was 4.3 months. Approximately 60% of surgeons believed that no limit should be placed on the number of golf rounds played weekly, and 91% denied an increase in complications among those who returned to playing golf after undergoing shoulder arthroplasty. Fewer than one third of the surgeons (29.5%) believed that component wear would be a problem in patients who undergo shoulder arthroplasty and play golf frequently and would recommend a hemiarthroplasty for an active golfer because of concern about future glenoid problems.

Transvaginal ultrasound, endometrial cytology sampled by Gynoscann and histology obtained by Uterine Explora Curette compared to the histology of the uterine specimen. A prospective study in pre- and postmenopausal women undergoing elective hysterectomy.

BACKGROUND: The purpose of this study was to evaluate the diagnostic value of transvaginal ultrasound measurement of endometrial thickness, cytology obtained by Gynoscann, and histology of the endometrium sampled by Uterine Explora Curette compared with histology of the uterine specimen as the gold standard. METHODS: Consecutive patients admitted for hysterectomy had transvaginal ultrasound, sampling by Gynoscann, and Uterine Explora Curette done just before surgery, after informed consent. RESULTS: A total of 181 women entered the study. Sixteen had endometrial cancer, seven had atypical hyperplasia and nine had complex hyperplasia. A total of 168 patients had a transvaginal ultrasound done. At a cutoff limit of 4mm (endometrial thickness of 4mm or less indicating normal endometrium), the sensitivity was 90.3%, the specificity 24.8%, the positive predictive value 21.4% and the negative predictive value 91.9%. One endometrial cancer, one atypical and one complex hyperplasia were missed. The Gynoscann method showed a sensitivity of 62.5%, a specificity of 94.0%, a positive predictive value of 69.0% and a negative predictive value of 92.1%. Two cancers, three atypical and six complex hyperplasia were missed. The Uterine Explora Curette showed a sensitivity of 90.6%, a specificity of 100.0%, a positive predictive value of 100.0% and a negative predictive value of 98.0%. One endometrial cancer and two complex hyperplasia were missed. CONCLUSION: Transvaginal ultrasound is a reliable method in excluding endometrial pathology. The Uterine Explora Curette was superior to Gynoscann in diagnosing neoplasia of the endometrium. It was found to have the same diagnostic accuracy as conventional dilatation and curettage.

[Randomized clinical trials in the Ugeskrift for Laeger 1948-1995]. / Randomiserede kliniske forsøg i Ugeskrift for Laeger 1948-1995.

The Danish Medical Journal (Ugeskrift for Laeger) was handsearched for randomised and pseudorandomised clinical trials over the years 1948-1995. We found 665 trials of which 539 (81%) were classified as randomised; the randomisation method was not stated for 422 of them (78%) and was insufficiently described in the majority of the rest. This problem became worse with time (p = 0.01). In contrast to the international literature where the increase was more gradual and occurred several years later, the number of randomised trials increased markedly around 1973. This change is associated with the introduction of courses in clinical research methodology during the previous years. Since randomisation is the most important safeguard against bias, the method should be described in detail.

Delayed primary repair of a kyrogenic spinal accessory nerve injury: a case report.

The course of the accessory nerve through the posterior cervical triangle is superficial and in close juxtaposition to the posterior cervical lymph node chain. These anatomic features contribute to the common occurrence of kyrogenic injury to the accessory nerve. Unfortunately, the diagnosis of this injury often is delayed because the clinical presentation may mimic shoulder impingement or adhesive capsulitis. The authors present a case with a 15-year followup of a 48-year-old woman who underwent successful delayed primary repair of an accessory nerve injury after a lymph node biopsy. Electromyographic examination is recommended at 3 weeks after a suspected accessory nerve lesion, and if evidence of trapezial denervation is present, early surgical exploration is indicated because spontaneous recovery is rare.

Phosphoinositide 3-kinase activity is necessary for insulin-dependent inhibition of apolipoprotein B secretion by rat hepatocytes and localizes to the endoplasmic reticulum.

Insulin inhibits apolipoprotein B (apoB) secretion by primary rat hepatocytes through activation of phosphoinositide 3-kinase (PI 3-K). Current studies demonstrate that the PI 3-K inhibitor wortmannin inhibits both basal and insulin-stimulated PI 3-K activities. Wortmannin and LY 294002, two structurally distinct PI 3-K inhibitors, prevent insulin-dependent inhibition of apoB secretion in a dose-dependent manner. To link PI 3-K activation to insulin action on apoB, we investigated whether insulin induced localization of activated PI 3-K to the endoplasmic reticulum (ER), where apoB biogenesis is initiated. Insulin action results in a significant redistribution of PI 3-K to a low density microsome (LDM) fraction containing apoB protein and apoB mRNA. Insulin stimulates a significant increase in PI 3-K activity associated with insulin receptor substrate-1 as well as an increase in insulin receptor substrate-1/PI 3-K mass in LDM. Subfractionation of LDM on sucrose density gradients shows that insulin significantly increases the amount of PI 3-K present in an ER fraction containing apoB. Insulin stimulates PI 3-K activity in smooth and rough microsomes isolated from rat hepatocytes, the latter of which contain rough ER as demonstrated by electron microscopy. Studies indicate that 1) PI 3-K activity is necessary for insulin-dependent inhibition of apoB secretion by rat hepatocytes; 2) insulin action leads to the activation and localization of PI 3-K in an ER fraction containing apoB; and 3) insulin stimulates PI 3-K activity in the rough ER.

A comparison of three-dimensional computed tomography scans and stereolithographic models for evaluation of craniofacial anomalies.

PURPOSE: This article describes the use of stereolithographic (SL) models as an adjunct to treatment planning in patients with Apert's syndrome, scaphocephaly, brachycephaly, and turricephaly. PATIENTS AND METHODS: Four syndrome patients had computed tomography (CT) scans done presurgically, and one of these patients was additionally scanned postoperatively. SL models and three-dimensional (3D) CT image reconstructions were produced from the CT data, and linear measurements were compared between the two modalities. RESULTS: All cases showed mean differences between measurements with 3D-CT and SL models of -0.3 to 0.8 mm, except on the CT scans with a gantry tilt (-1.7 mm) and the brachycephalic patient in whom larger deviations were demonstrated (-9.5 mm). CONCLUSION: The results of the study indicate that the accuracy of the SL technique is not always sufficient, necessitating additional validation studies before it can be recommended for routine clinical use.

Proximal humeral reconstruction after excision of a primary sarcoma.

From 1978 to 1991, 19 patients underwent wide resection of the proximal humerus for a primary bone tumor. Reconstructions included intercalary autoclaved autograft and Neer prosthesis composites in 11 patients, intercalary allograft and Neer prosthesis composites in 4 patients, and a Neer prosthesis with methylmethacrylate in 4 patients. All patients were observed for at least 2 years or until death. The functional results and complications of the 19 procedures were evaluated. Function was rated as excellent for 17 patients and good for 2 patients. There were no failures of fixation. Local recurrence occurred in 2 patients. There were 2 cases of recurrent anterior subluxation and 1 of dislocation. Two superficial wound infections were treated successfully with local debridement and antibiotics. The authors conclude that autoclaved autograft or allograft when combined with a long-stem cemented Neer prosthesis offers an excellent composite for proximal humeral reconstruction.