Pruritus and quality of life in moderate-to-severe plaque psoriasis: post hoc explorative analysis from the PRISTINE study.

BACKGROUND: Pruritus is a clinically important symptom of psoriasis that has a major impact on quality of life (QoL). OBJECTIVE: The objective of this study was to examine pruritus and QoL in patients with moderate-to-severe psoriasis treated with etanercept (ETN) in the PRISTINE clinical trial. METHODS: Patients were randomized (1 : 1, double-blind) to ETN 50 mg QW or 50 mg BIW for 12 weeks, followed by 50 mg QW for 12 weeks. Pruritus was reported as 0 (no itching) to 5 (severe itching). Associations were examined between pruritus and Psoriasis Area and Severity Index, Dermatology Life Quality Index (DLQI), Hospital Anxiety and Depression Screening (HADS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Euro-Qol 5D (EQ-5D) and Medical Outcomes Study (MOS) Sleep Index II. RESULTS: At baseline, patients (n = 270) had a mean pruritus level of 3.6. Itching (level ≥1) was reported by 96% of patients, 62% of whom had severe itching (level ≥4) and 26% had the highest level of itching. DLQI, HADS-Anxiety, HADS-Depression, FACIT-Fatigue, EQ-5D visual analog scale, and MOS Sleep Index II were significantly associated with itch. At week 12, mean pruritus improvement in the ETN BIW/QW group was greater than in the QW/QW group (2.4 vs. 1.6, P < 0.001), but not at week 24 (2.2 vs. 2.0, P = 0.180). Patients with the most severe itching at baseline (score of 5) had a mean score of 1.7 at week 24. Overall, patients with clinically meaningful pruritus improvement at week 24 reported greater improvement in QoL measures than other patients. CONCLUSION: Most patients with moderate-to-severe psoriasis in this study (96%) reported pruritus. Pruritus improved significantly with ETN therapy and was strongly associated with improvements in QoL. These data support the clinical relevance of pruritus as an important symptom of patients with moderate/severe psoriasis.

Improvement in aspects of sleep with etanercept and optional adjunctive topical therapy in patients with moderate-to-severe psoriasis: results from the PRISTINE trial.

BACKGROUND: Impaired sleep in patients with moderate-to-severe psoriasis and improvement on therapy has not been widely studied. OBJECTIVE: Quantify baseline aspects of sleep and improvement in patients with psoriasis receiving etanercept (ETN) when allowed concomitant topical medications (PRISTINE study). METHODS: Patients with moderate-to-severe psoriasis were randomized to 50 mg ETN once weekly (QW/QW) or 50 mg ETN twice weekly (BIW/QW) for weeks 1-12, followed by 50 mg QW for weeks 13-24; a broad range of topical therapies were permitted during weeks 13-24. Sleep impairment was measured by the Medical Outcomes Study (MOS) sleep questionnaire Index II (population norm = 25.8; minimum clinically important difference = 5.1); quality of life (QoL) measures included Dermatology Life Quality Index (DLQI), EuroQoL 5 Dimension (EQ-5D) Utility Index and Visual Analogue Scale (VAS) and Functional Activity in Chronic Therapy-Fatigue (FACIT-Fatigue). ancova and Fisher's exact test or chi-squared tests were used for between-group testing. RESULTS: Mean baseline MOS-Sleep scores were 34.0 for both groups indicating impairment (N = 270; QW/QW n = 137; BIW/QW n = 133, approximately 64% had impaired sleep). At week 12 of treatment, MOS-Sleep scores improved to 30.8 and 30.1, and at week 24, to 28.4 and 28.2 respectively. Poor sleep was significantly associated with clinically important problems in EQ-5D utility, VAS and FACIT-Fatigue; sleep improvement was associated with improved EQ-5D utility and FACIT-Fatigue (P < 0.001). CONCLUSION: This study confirms that most patients with moderate-to-severe psoriasis have impaired sleep which is associated with impaired QoL. Treatment with etanercept significantly improved sleep, with most improvement occurring before a broad range of topicals were allowed. Sleep improvement was associated with improved QoL.

Self-reported health outcomes in patients with psoriasis and psoriatic arthritis randomized to two etanercept regimens.

BACKGROUND: Moderate/severe psoriasis combined with psoriatic arthritis (PsA) impairs health-related quality of life (QoL). Etanercept, a fully human tumour necrosis factor-α receptor fusion protein, is approved for treatment of both diseases. OBJECTIVE: To compare patient-reported health outcomes (PROs) of two etanercept regimens in patients with moderate/severe psoriasis and PsA. METHODS: In this randomized, double-blind, multicenter study, participants received etanercept 50 mg twice weekly (BIW; n = 379) or 50 mg weekly (QW; n = 373) for 12 weeks and open-label etanercept 50 mg QW for 12 additional weeks. PROs included: the EuroQOL-5D (EQ-5D), which measures general health status and consists of the utility index measuring five dimensions of health, and a visual analogue scale (VAS) allowing patients to assess health status; the Dermatology Life Quality Index (DLQI), which measures the impact of skin disease on QoL; the Health Assessment Questionnaire-Disability Index (HAQ-DI), an assessment of physical function; the Hospital Anxiety and Depression Scale (HADS), which screens for anxiety and depression symptoms; and individual questions on general health, disease activity, fatigue, itching, joint pain and morning stiffness. RESULTS: At baseline, patients reported QoL worse than that seen in many chronic medical conditions. Significant within-group improvements in each PRO occurred from baseline to Week 12 (P < 0.001) in both groups and were maintained at Week 24; DLQI, EQ-5D, HAQ-DI and self assessments improved significantly (P < 0.001) from baseline as early as Week 3. At Week 12, but not Week 24, improvement in DLQI, itching and psoriasis activity was greater in the BIW arm (P ≤ 0.004). Improvements in other PROs were always similar between groups. CONCLUSIONS: Greater improvements in PROs specific to skin disorders were seen with etanercept BIW than QW at Week 12, but not at Week 24. Both etanercept regimens led to sustained PRO improvements, starting as early as Week 3.

Combination of skin, joint and quality of life outcomes with etanercept in psoriasis and psoriatic arthritis in the PRESTA trial.

BACKGROUND: Psoriasis and psoriatic arthritis (PsA) affect skin, and/or joints and quality of life (QoL). OBJECTIVE: To better assess the success in multiple attributes in subjects with both active psoriasis and PsA, the objective was to quantify the proportion of those who achieved substantial improvement in a composite measure of skin symptoms, joint manifestations, and QoL, on one of two treatment regimens. METHODS: Subjects (n=752) with psoriasis and PsA (mean age: 46.5 years, 62.9% male) received etanercept (ETN) 50mg twice weekly (BIW; n = 379) or 50 mg weekly (QW; n=373) for 12 weeks, followed by open-label ETN 50mg QW for 12 weeks. Skin and joint symptoms and QoL were assessed using psoriasis area and severity index (PASI), American College of Rheumatology criteria (ACR) and Euro-QoL (EQ-5D), respectively. RESULTS: By week 24, 30.6% and 25.8% of subjects receiving ETN 50 mg BIW/QW and ETN 50 mg QW/QW, respectively (P = 0.198) achieved the composite measure of efficacy for skin plus joints plus QoL (PASI 75 + ACR 50 + EQ-5D VAS >82). CONCLUSION: At 24 weeks, 25.8-30.6% met the triad of rigorous efficacy outcomes. Evaluation of treatment efficacy should address the multiple components of this disease complex; therefore it may be important to consider this composite measure in future trials.

The risk of psoriatic arthritis remains constant following initial diagnosis of psoriasis among patients seen in European dermatology clinics.

BACKGROUND: Estimates of psoriatic arthritis (PsA) prevalence among psoriasis patients vary widely (5-40%). The time to development of PsA in patients with plaque psoriasis also remains unclear. OBJECTIVES: To examine whether length of time since diagnosis of psoriasis affects risk of developing PsA, and to assess differences in quality of life (QoL), work-related issues, comorbidities and healthcare resource utilization (HCRU) for patients with PsA vs. psoriasis. METHODS: This large cross-sectional observational study was conducted in the UK, Italy, France, Spain and Germany in 2006. Dermatologists who actively treated patients with psoriasis recruited 10 consecutive patients with psoriasis. Presence of PsA, body surface area (BSA) affected with psoriasis and HCRU were recorded; patients completed EUROQoL (EQ5D) and employment disadvantages questionnaires. RESULTS: Patients with psoriasis (n = 1560) included 126 with PsA. Ninety per cent of these patients with PsA were seen by dermatologists who involved a rheumatologist in the care of their patients with PsA. Survival analysis indicated that the incidence of PsA among psoriasis patients remained constant (74 per 1000 person-years), while the prevalence increased with time since diagnosis of psoriasis, reaching 20.5% after 30 years. In addition, those with high BSA currently affected by psoriasis were more likely to have developed PsA (P < 0.028). PsA patients reported reduced QoL compared with psoriasis patients (EQ5D score: 0.56 vs. 0.82: P < 0.0005), as well as more work problems. PsA patients were more likely to be hospitalized (0.27 +/- 0.84 vs. 0.14 +/- 0.71 per year; P < 0.0005) and have additional comorbidities than those without PsA. CONCLUSIONS: The incidence of PsA was constant after initial diagnosis of psoriasis, leading to a higher prevalence of concomitant PsA over time. PsA is associated with decreased QoL and increased work-related problems, HCRU and comorbidities. Dermatologists should screen for PsA in their patients, especially long-standing patients who did not initially present with PsA.

Sustained improvement in joint pain and nail symptoms with etanercept therapy in patients with moderate-to-severe psoriasis.

BACKGROUND: To determine the prevalence of joint and nail symptoms, impact of these symptoms on health-related quality of life (HR-QoL), and the effects of etanercept on them in patients with moderate-to-severe plaque psoriasis. METHODS: In CRYSTEL, patients with psoriasis received etanercept continuously (n = 357) or as paused therapy (n = 363) for 54 weeks. In post hoc analyses, baseline characteristics and after-treatment changes were evaluated in patients with baseline joint pain or nail psoriasis, pooling across treatment groups. Assessments of symptom severity and HR-QoL included the Subject Global Assessment question on joint pain, NAPSI, DLQI and EQ-5D. RESULTS: Of 711 patients, 64% reported joint pain and 79% nail psoriasis at baseline. Patients with baseline joint pain or nail psoriasis had significantly worse HR-QoL than unaffected patients. Mean baseline differences between patients with and without joint pain in DLQI (3.3), EQ-5D utility (0.2), and EQ-5D VAS (7.3) were clinically meaningful. In patients with nail psoriasis, a clinically meaningful difference in EQ-5D VAS (5.0) was seen. Etanercept significantly improved symptom severity and HR-QoL. Patients with joint pain had improvements of 47%, 61%, 29%, and 23% in mean joint pain score, DLQI, EQ-5D utility, and EQ-5D VAS, respectively, at Week 54. Patients with nail psoriasis had improvements of 51%, 63%, and 24% in NAPSI, DLQI, and EQ-5D VAS. CONCLUSION: In this study of moderate-to-severe plaque psoriasis, joint and nail symptoms were prevalent and patients with these symptoms had significantly greater HR-QoL impairment at baseline than unaffected patients. Etanercept provided significant improvement in symptom severity and HR-QoL.

Improvements in patient-reported outcomes in moderate-to-severe psoriasis patients receiving continuous or paused etanercept treatment over 54 weeks: the CRYSTEL study.

OBJECTIVE: To assess patient-reported outcomes (PRO) in patients with moderate-to-severe plaque psoriasis receiving continuous or paused etanercept treatment. METHODS: In a multicentre European open-label study, one group (n = 352) received continuous therapy: 25 mg subcutaneously (SC) twice weekly (BIW) throughout 54-weeks. The other group (n = 359) received paused therapy: 50 mg SC BIW (

Bioavailability of acetylated derivatives of methionine, threonine, and lysine.

Supplementation of vegetable proteins with various essential amino acids is an effective means of improving proteins quality. Unfortunately, simple amino acid additions to foods which must be heat processed and cooked is not without consequences. Under these conditions, methionine interacts with reducing sugars yielding methional through the Strecker degradation reaction. This generation of methional during heat treatment imparts undesirable sulfur odors and flavors to the food rendering it organoleptically unacceptable. Similarly, threonine and lysine are also susceptible to interaction with reducing sugars rendering them nutritionally unavailable. Acetylated derivatives of methionine, threonine and lysine have been studied to determine their utility in overcoming the inherent problems associated with each amino acid. To this end, N-acetyl-L-methionine and N-acetyl-L-threonine were found to be fully available to promote growth of rats. To the contrary, neither the alpha nor the epsilon, monoacetylated derivative of L-Lysine nor the alpha, epsilon diacetyl derivative of L-Lysine were effective in significantly promoting the growth of rats. Utilization of N-acetyl-L-methionine by humans has also been studied and shown to be as effective as methionine in improving the quality of vegetable proteins deficient in sulfur amino acids.

MicroRNA expression in canine mammary cancer.

MicroRNAs (miRNAs) are 18-22-nt noncoding RNAs that are involved in post-transcriptional regulation of genes. Oncomirs, a subclass of miRNAs, include genes whose expression, or lack thereof, are associated with cancers. Until the last decade, the domestic dog was an underused model for the study of various human diseases that have genetic components. The dog exhibits marked genetic and physiologic similarity to the human, thereby making it an excellent model for study and treatment of various hereditary diseases. Furthermore, because the dog presents with distinct, spontaneously occurring mammary tumors, it may serve as a model for genetic analysis and treatments of humans with malignant breast tumors. Because miRNAs have been found to act as both tumor suppressors and oncogenes in several different cancers, expression patterns of ten miRNAs (miR-15a, miR-16, miR-17-5p, miR-21, miR-29b, miR-125b, miR-145, miR-155, miR-181b, let-7f) known to be associated with human breast cancers were compared to malignant canine mammary tumors (n = 6) and normal canine mammary tissue (n = 10). Resulting data revealed miR-29b and miR-21 to have a statistically significant (p < 0.05 by MANOVA analysis) upregulation in cancerous samples. The ten canine miRNAs follow the same pattern of expression as in the human, except for miR-145 which does not show a difference in expression between the normal and cancerous canine samples. In addition, when analyzed according to specific cancer phenotypes, miR-15a and miR-16 show a significant downregulation in canine ductal carcinomas while miRsR-181b, -21, -29b, and let-7f show a significant upregulation in canine tubular papillary carcinomas.

Effects of excess dietary l-methionine and N-acetyl-l-methionine on growing rats.

We have determined the effects of excessive dietary intakes of L-methionine and N-acetyl-L-methionine by measuring parameters which are known to be affected by excess methionine. Male Sprague-Dawley weanling rats were fed complete diets containing 10% protein supplied as isolated soybean protein and graded levels of supplemental L-methionine (from 0.30% to 5.0%) or equimolar levels of N-acetyl-L-methionine. The basal diet without supplemental methionine contained 0.15% methionine. Rats fed diets containing 0.3% supplemental L-methionine or the equivalent levels of supplemental N-acetyl-L-methionine grew best. Higher dietary levels of either L-methionine or N-acetyl-L-methionine caused progressive decreases in weight gain. However, L-methionine at 1.8% and above tended to more severely depress growth than did equivalent amounts of N-acetyl-L-methionine. L-Methionine at levels of 1.2% and above, or equivalent levels of N-acetyl-L-methionine caused comparable hypertrophy of the spleen and comparable increases in spleen iron levels. Hematocrits were not affected by either L-methionine or N-acetyl-L-methionine at the levels used in this experiment. We have concluded that N-acetyl-L-methionine is no more detrimental than L-methionine and is less detrimental at very high levels as evidenced by weight gain.

Comparative metabolism of L-methionine and N-acetylated derivatives of methionine.

These experiments compared the metabolism of the N-acetylated derivatives of D- or L-methionine to that of L-methionine. Spargue-Dawley rats were orally or intraperitoneally dosed with N-[1-14C]acetyl-L-methionine, N-[1-14C]acetyl-D-methionine, or sodium [1-14C]acetate. 14CO2 was collected at intervals over 24 hours. In addition, groups of rats were orally dosed with either 35S-labeled N-acetyl-L-methionine or L-methionine. The animals were killed 3, 24, and 168 hours after dosing. Urine and feces were collected, and tissues were excised for 35S determinations. With either route of dosing, N-[1-14C]acetyl-L-methionine yielded the same amount of 14CO2 as sodium [1-14C]acetate over a 24-hour period. The acetate moiety of N-[1-14C]acetyl-D-methionine is not readily metabolized to 14CO2. Within each time period after dosing, the tissue distribution of 35S from 35S-labeled N-acetyl-L-methionine and L-methionine was similar. Protein specific activities for the two isotopes were also the same. After 168 hours, 30% of both isotopes of 35S appeared in the urine and feces, and the two isotopes were similarly distributed in the organic -S and inorganic -S fractions of urine. The studies show that L-methionine from N-acetyl-L-methionine is metabolically equivalent to free L-methionine. This conclusion is consistent with rat feeding studies showing that N-acetyl-L-methionine is nutritionally equivalent to L-methionine.

Glucogenic and ketogenic capacities of lard, safflower oil, and triumdecanoin in fasting rats.

The glucogenic and ketogenic capicities of lard, safflower oil, and triundecanoin were compared. Rats were fed diets containing 30 percent of either lard (a ketogenic fat), triundercanoin (a glucogenic fat), or safflower oil (a fat high in linoleic acid). After 61 days, the rats were fasted for 72 hours. Plasma glucose and ketone body concentrations and carcass fatty acid loss were measured during fasting. The lard-fed animals, which lost mostly saturated even-chain length fatty acids during fasting, did not maintain their prefasting plasma glucose levels and became ketotic. The animals that had been fed triundecanoin (which mobilized considerable odd-chain fatty acid) maintained their prefasting plasma glucose levels and did not become ketotic. The animals fed safflower oil (which mobilized massive amounts of linoleic acid) showed even lower levels of plasma glucose and higher levels of ketone bodies than did the animals fed lard. This failure of safflower oil to avert fasting hypoglycemia suggests that linoleic acid is oxidized in a manner more like the saturated fatty acid of lard than like the glucogenic odd-chain fatty acid (undecanoic).

Intraoperative ultrasound of hepatic tumors.

Intraoperative ultrasound (IOUS) scanning of liver masses was compared with those of preoperative computed tomography (CT) and intraoperative palpation. Between March 1989 and May 1991, 24 patients underwent 25 IOUS procedures during laparotomy. Intraoperative ultrasound provided more information than the other modalities in 10 patients (40%) and affected operative management in eight patients (32%). It was concluded that IOUS, when used in conjunction with CT and palpation, is an important technique in the surgical management of patients with hepatic neoplasms.

Ectopic expression of the female transformer gene product leads to female differentiation of chromosomally male Drosophila.

The transformer (tra) gene of Drosophila is necessary for all aspects of female somatic sexual differentiation. tra uses a single set of precursor RNAs to produce female- and non-sex-specific RNAs by alternative splicing. Ectopic expression of the female-specific RNA causes chromosomal males to develop as females, indicative of a linear pathway of regulated genes controlling sex. Genetic and molecular tests with this ectopically expressed gene are consistent with the following order of gene action: X chromosome to autosome ratio----Sex lethal----transformer----transformer-2----doublesex----intersex--- - terminal differentiation. Expression of the female-specific tra RNA in tra mutants is sufficient to lead to female differentiation. Expression of the non-sex-specific tra RNA in tra mutants is not sufficient to lead to female differentiation. The tra female-specific activity is not required for female-specific splicing of the tra precursor RNAs.

Higher plant chloroplasts: Evidence that all the chlorophyll exists as chlorophyll-protein complexes.

By using the polyacrylamide gel electrophoresis system described in this report, it was possible to fractionate all the photosynthetic pigments of maize (Zea mays L.) thylakoids into chlorophyll-protein complexes with negligible formation of free or detergent-complexed chlorophyll. Identical sodium dodecyl sulfate extracts of thylakoids have previously resulted in up to 50% of the chlorophyll migrating as free chlorophyll after electrophoresis. The major difference from previous gel electrophoresis systems is the replacement of sodium dodecyl sulfate in the electrophoresis buffer by Deriphat 160 (disodium N-lauryl-beta-iminodipropionate), a zwitterionic detergent. The results suggest that: (i) no significant amount of free chlorophyll exists in the chloroplast thylakoid membranes in vivo, and (ii) most of the free pigment seen previously on gels was generated during the electrophoresis and was not a result of the solubilization technique. Additionally, the new chlorophyll-protein complexes resolved appear to have different characteristics (pigment content and size) that those observed in former systems.

Acetylmethionine as a source of methionine for the rat.

A-Acetyl-L-methionine and N-acetyl-D-methionine were compared with L-methionine and D-methionine as sources of methionine. These derivatives were added to a sulfer amino acid-limited diet containing 10% soybean protein isolate. Weight gains, food intake, and protein efficiency ratios (PER) were determined in growing rats. N-Acetyl-L-methionine, L-methionine, and D-methionine produced an equivalent growth response and increase in PER above that of the basal diet. There was no response to supplementation with N-acetyl-D-methionine. An equivalent maximum growth response of rats fed-L-methionine or N-acetyl-D-methionine. An equivalent maximum growth response of rats fed L-methionine or N-acetyl-L-methionine was obtained when the total dietary sulfur amino acids compromised 0.36-0.41% of the diet. The nutritional similarities of methionine and N-acetyl-L-methionine suggest that the latter may be useful as a supplement to diets containing vegetable proteins that are deficient in sulfur amino acids.

Molecular genetics of transformer, a genetic switch controlling sexual differentiation in Drosophila.

The transformer gene is one of a set of regulatory genes that form the hierarchy controlling all aspects of somatic sexual differentiation in Drosophila melanogaster. The gene transformer occupies an intermediate position in this hierarchy. Analysis of this gene has allowed us to determine the mechanism by which it is regulated in a sex-specific manner and to examine the way in which the regulatory hierarchy is organized. The female-specific expression of the tra gene, previously inferred from genetic observations, is based on sex-specific alternative splicing of tra pre-mRNA and is not the result of sex-specific transcriptional activation. The female-specific RNA produced by this alternative splicing is the functional mediator of tra activity. Multiple genetic, molecular, and transformation experiments show that female-specific activation of genes or gene products occurs in the order Sex lethal greater than transformer greater than transformer-2 greater than doublesex greater than or equal to intersex greater than female differentiation. The results do not distinguish the level at which transformer might regulate the downstream gene transformer-2. Neither transformer nor any of the down-stream genes feedback on, or participate in, alternative splicing of transformer RNA. The mechanism by which Sex lethal regulates transformer splicing appears to be a repression of the use of one of a pair of splice acceptor sites.