Effective reduction of post-inflammatory hyperpigmentation with the tyrosinase inhibitor isobutylamido-thiazolyl-resorcinol (Thiamidol).

OBJECTIVE: Post-inflammatory hyperpigmentation (PIH) is a major cosmetic concern especially in individuals with darker skin complexion. Unfortunately, treatment with anti-inflammatory ingredients alone does not prevent the development of hyperpigmented spots. Recently, isobutylamido-thiazolyl-resorcinol (Thiamidol) was described as a very potent inhibitor of human tyrosinase. The objective of this research was to investigate the potential of this compound to prevent PIH induced by epidermal wounding (suction blister) and related to acne. METHODS: Suction blister-induced PIH was treated with a formulation containing Thiamidol or a vehicle for 3 months, and the changes in hyperpigmentation were monitored by spectroscopic measurements. The effect of skin care formulations containing Thiamidol on acne-related PIH was investigated in two studies, a vehicle-controlled, double-blinded, randomized clinical study and a clinical observational study. Both studies had a duration of 3 months and included assessments such as clinical photography, clinical grading and melanin index measurements. RESULTS: Already after 2 weeks of treatment, suction blister sites treated with Thiamidol were significantly lighter than control sites and improved throughout the treatment period. Subjects´ self-grading demonstrated that Thiamidol significantly improved the visibility of acne-induced hyperpigmentation compared to the vehicle treatment. A skin care regimen with Thiamidol significantly improved acne-related PIH over 12 weeks shown by Mexameter measurements, expert grading, self-grading and clinical photography. CONCLUSION: Thiamidol represents a safe and effective ingredient for cosmetic products against post-inflammatory hyperpigmentation.

OBJECTIF: L'hyperpigmentation post-inflammatoire (Post-Inflammatory Hyperpigmentation, PIH) est une préoccupation d'ordre esthétique majeure, en particulier chez les personnes dont le teint est plus foncé. Malheureusement, un traitement par des ingrédients anti-inflammatoires seuls n'empêche pas le développement de taches hyperpigmentées. Récemment, l'isobutylamido-thiazolyl-résorcinol (Thiamidol) a été décrit comme un inhibiteur très puissant de la tyrosinase humaine. L'objectif de cette investigation était d'étudier le potentiel de ce composé pour prévenir la PIH induite par une plaie épidermique (bulle de succion) et liée à l'acné. MÉTHODES: La PIH induite par la bulle de succion a été traitée avec une formulation contenant du Thiamidol ou un véhicule pendant 3 mois et les changements dans l'hyperpigmentation ont été surveillés par le biais de mesures spectroscopiques. L'effet des formulations pour soins de la peau contenant du Thiamidol visant à traiter la PIH liée à l'acné a été étudié au cours de deux études : une étude clinique randomisée, en double aveugle, contrôlée par véhicule et une étude clinique observationnelle. Les deux études avaient une durée de 3 mois et comportaient des évaluations telles que la photographie médicale, l'évaluation par les médecins et les mesures de l'indice de mélanine. RÉSULTATS: Après 2 semaines de traitement seulement, les sites de bulles de succion traités par du Thiamidol étaient significativement plus clairs que les sites-témoins et avaient montré une amélioration tout au long de la période de traitement. L'auto-évaluation des sujets a démontré que le Thiamidol améliorait significativement la visibilité de l'hyperpigmentation induite par l'acné par rapport au traitement par véhicule. Un programme de soins de la peau contenant du Thiamidol a significativement amélioré la PIH liée à l'acné sur 12 semaines, comme l'ont démontré les mesures de Mexameter, l'évaluation par des experts, l'auto-évaluation des sujets et la photographie médicale. CONCLUSION: Le Thiamidol représente un ingrédient sûr et efficace pour les produits cosmétiques contre l'hyperpigmentation post-inflammatoire.

Analytical evaluation of the clonoSEQ Assay for establishing measurable (minimal) residual disease in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma.

BACKGROUND: The clonoSEQ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) identifies and tracks unique disease-associated immunoglobulin (Ig) sequences by next-generation sequencing of IgH, IgK, and IgL rearrangements and IgH-BCL1/2 translocations in malignant B cells. Here, we describe studies to validate the analytical performance of the assay using patient samples and cell lines. METHODS: Sensitivity and specificity were established by defining the limit of detection (LoD), limit of quantitation (LoQ) and limit of blank (LoB) in genomic DNA (gDNA) from 66 patients with multiple myeloma (MM), acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia (CLL), and three cell lines. Healthy donor gDNA was used as a diluent to contrive samples with specific DNA masses and malignant-cell frequencies. Precision was validated using a range of samples contrived from patient gDNA, healthy donor gDNA, and 9 cell lines to generate measurable residual disease (MRD) frequencies spanning clinically relevant thresholds. Linearity was determined using samples contrived from cell line gDNA spiked into healthy gDNA to generate 11 MRD frequencies for each DNA input, then confirmed using clinical samples. Quantitation accuracy was assessed by (1) comparing clonoSEQ and multiparametric flow cytometry (mpFC) measurements of ALL and MM cell lines diluted in healthy mononuclear cells, and (2) analyzing precision study data for bias between clonoSEQ MRD results in diluted gDNA and those expected from mpFC based on original, undiluted samples. Repeatability of nucleotide base calls was assessed via the assay's ability to recover malignant clonotype sequences across several replicates, process features, and MRD levels. RESULTS: LoD and LoQ were estimated at 1.903 cells and 2.390 malignant cells, respectively. LoB was zero in healthy donor gDNA. Precision ranged from 18% CV (coefficient of variation) at higher DNA inputs to 68% CV near the LoD. Variance component analysis showed MRD results were robust, with expected laboratory process variations contributing ≤3% CV. Linearity and accuracy were demonstrated for each disease across orders of magnitude of clonal frequencies. Nucleotide sequence error rates were extremely low. CONCLUSIONS: These studies validate the analytical performance of the clonoSEQ Assay and demonstrate its potential as a highly sensitive diagnostic tool for selected lymphoid malignancies.

High-energy visible light at ambient doses and intensities induces oxidative stress of skin-Protective effects of the antioxidant and Nrf2 inducer Licochalcone A in vitro and in vivo.

BACKGROUND: Solar radiation causes skin damage through the generation of reactive oxygen species (ROS). While UV filters effectively reduce UV-induced ROS, they cannot prevent VIS-induced (400-760 nm) oxidative stress. Therefore, potent antioxidants are needed as additives to sunscreen products. METHODS: We investigated VIS-induced ROS formation and the photoprotective effects of the Nrf2 inducer Licochalcone A (LicA). RESULTS: Visible spectrum of 400-500 nm dose-dependently induced ROS in cultured human fibroblasts at doses equivalent to 1 hour of sunshine on a sunny summer day (150 J/cm2 ). A pretreatment for 24 hours with 1 µmol/L LicA reduced ROS formation to the level of unirradiated cells while UV filters alone were ineffective, even at SPF50+. In vivo, topical treatment with a LicA-containing SPF50 + formulation significantly prevented the depletion of intradermal carotenoids by VIS irradiation while SPF50 + control did not protect. CONCLUSION: LicA may be a useful additive antioxidant for sunscreens.

Early Practice Patterns of Hand Surgeons: An American Board of Orthopaedic Surgery Database Study.

PURPOSE: To investigate the variety of cases that are performed by newly graduated fellowship-trained orthopedic hand surgeons. METHODS: All cases submitted by board-eligible orthopedic surgeons taking part II of their board examination between 2004 and 2013 were obtained from the database of the American Board of Orthopaedic Surgery (ABOS). Each case was then categorized based on the fellowship training of the treating surgeon and whether it was a hand surgery case. Each hand surgery case was then further categorized into 1 of the 8 surgical categories used by the ABOS to determine eligibility for the Subspecialty Certificate in Orthopaedic Surgery of the Hand (SCOSH). RESULTS: During our study period, 6,854 orthopedic surgeons submitted 858,146 cases to the ABOS. Fellowship-trained hand surgeons made up 13% of all surgeons, and 24% of all submitted cases were hand surgery cases. Based on the cases submitted, 44% of hand surgeons were not on track to become eligible for the SCOSH. The most common reason for not reaching eligibility was failure to meet the minimum requirements in 1 of either the congenital, the skin and wound problems, the contracture and joint stiffness, the microvascular, or the tumor categories. CONCLUSIONS: A large proportion of fellowship-trained orthopedic hand surgeons are not on track to meet the minimum eligibility requirements for the ABOS SCOSH during their part II case collections. Their case profile is not sufficiently diverse to be considered an active hand surgery practice for the purpose of SCOSH eligibility. CLINICAL RELEVANCE: This study highlights 1 possible reason why over one-third of young hand surgeons do not obtain their subspecialty certification.

Effective Tyrosinase Inhibition by Thiamidol Results in Significant Improvement of Mild to Moderate Melasma.

Melasma is a pigmentary disorder characterized by hyperpigmented patchy skin in sun-exposed areas, especially the face. Treatment of melasma can be challenging because long-term therapy is required, reoccurrence is common, and existing therapies are insufficient and unsatisfactory. To investigate new treatment options, we performed an exploratory double-blinded, randomized split-face study to assess the efficacy of the tyrosinase inhibitor Thiamidol compared to hydroquinone in women with mild to moderate melasma. After 12 weeks, modified Melasma Area and Severity Index scores significantly improved on both the Thiamidol-treated and the hydroquinone-treated sides of the face. Additionally, Thiamidol treatment improved modified Melasma Area and Severity Index scores significantly better than hydroquinone, and more subjects improved following treatment with Thiamidol (79%) compared with hydroquinone (61%). During treatment, no subjects displayed worsening of modified Melasma Area and Severity Index scores on the Thiamidol-treated side, while approximately 10% of the subjects showed a worsening of modified Melasma Area and Severity Index scores on the hydroquinone-treated side. All subjects routinely used sunscreens and consistent results were obtained in low and in high UV ambient conditions. Subjects rated the efficacy of the Thiamidol formulation significantly better with regard to overall decreased intensity of dark spots and their overall appearance throughout the study. Thiamidol was well-tolerated and well-perceived and represents an effective agent to reduce hyperpigmentation.

FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is caused by an expansion of cytosine-guanine-guanine (CGG) repeats in the FMR1 gene. Female premutation allele carriers (55-200 CGG repeats) are at risk to have an affected child. Currently, specific population-based carrier screening for FXS is not recommended. Previous studies exploring female premutation carrier frequency have been limited by size or ethnicity. This retrospective study provides a pan-ethnic estimate of the Fragile X premutation carrier frequency in a large, ethnically diverse population of women referred for routine carrier screening during a specified time period at Progenity, Inc. Patient ethnicity was self-reported and categorized as: African American, Ashkenazi Jewish, Asian, Caucasian, Hispanic, Native American, Other/Mixed/Unknown, or Sephardic Jewish. FXS test results were stratified by ethnicity and repeat allele category. Total premutation carrier frequency was calculated and compared against each ethnic group. A total of 134,933 samples were included. The pan-ethnic premutation carrier frequency was 1 in 201. Only the Asian group differed significantly from this frequency. Using the carrier frequency of 1 in 201, a conservative pan-ethnic risk estimate for a male fetus to have FXS can be calculated as 1 in 2,412. This risk is similar to the highest ethnic-based fetal risks for cystic fibrosis and spinal muscular atrophy, for which population-wide screening is currently recommended. This study adds to the literature and supports further evaluation into specific population-wide screening recommendations for FXS.

Structure-Activity Relationships of Thiazolyl Resorcinols, Potent and Selective Inhibitors of Human Tyrosinase.

Tyrosinase inhibitors are of great clinical interest as agents for the treatment of hyperpigmentary disorders; however, most compounds described in the literature lack clinical efficiency due to insufficient inhibitory activity against human tyrosinase (hTyr). Recently, we reported that thiazolyl resorcinols (4-resorcinylthiazol-2-amines and -amides) are both selective and efficacious inhibitors of hTyr in vitro and in vivo. Here, we measured dose-activity profiles of a large number of thiazolyl resorcinols and analogous compounds to better understand the molecular basis of their interaction with hTyr. We show that both the resorcinyl moiety and the thiazole ring must be intact to allow efficient inhibition of hTyr, while the substituents at the thiazole 2-amino group confer additional inhibitory activity, depending on their size and polarity. The results of molecular docking simulations were in excellent agreement with the experimental data, affording a rationale for the structural importance of either ring. We further propose that a special type of interaction between the thiazole sulfur and a conserved asparagine residue is partially responsible for the superior inhibitory activity of thiazolyl resorcinols against hTyr.

Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase.

Tyrosinase is the rate-limiting enzyme of melanin production and, accordingly, is the most prominent target for inhibiting hyperpigmentation. Numerous tyrosinase inhibitors have been identified, but most of those lack clinical efficacy because they were identified using mushroom tyrosinase as the target. Therefore, we used recombinant human tyrosinase to screen a library of 50,000 compounds and compared the active screening hits with well-known whitening ingredients. Hydroquinone and its derivative arbutin only weakly inhibited human tyrosinase with a half-maximal inhibitory concentration (IC50) in the millimolar range, and kojic acid showed a weak efficacy (IC50 > 500 µmol/L). The most potent inhibitors of human tyrosinase identified in this screen were resorcinyl-thiazole derivatives, especially the newly identified Thiamidol (Beiersdorf AG, Hamburg, Germany) (isobutylamido thiazolyl resorcinol), which had an IC50 of 1.1 µmol/L. In contrast, Thiamidol only weakly inhibited mushroom tyrosinase (IC50 = 108 µmol/L). In melanocyte cultures, Thiamidol strongly but reversibly inhibited melanin production (IC50 = 0.9 µmol/L), whereas hydroquinone irreversibly inhibited melanogenesis (IC50 = 16.3 µmol/L). Clinically, Thiamidol visibly reduced the appearance of age spots within 4 weeks, and after 12 weeks some age spots were indistinguishable from the normal adjacent skin. The full potential of Thiamidol to reduce hyperpigmentation of human skin needs to be explored in future studies.

Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II.

The most polymorphic part of the human genome, the MHC, encodes over 160 proteins of diverse function. Half of them, including the HLA class I and II genes, are directly involved in immune responses. Consequently, the MHC region strongly associates with numerous diseases and clinical therapies. Notoriously, the MHC region has been intractable to high-throughput analysis at complete sequence resolution, and current reference haplotypes are inadequate for large-scale studies. To address these challenges, we developed a method that specifically captures and sequences the 4.8-Mbp MHC region from genomic DNA. For 95 MHC homozygous cell lines we assembled, de novo, a set of high-fidelity contigs and a sequence scaffold, representing a mean 98% of the target region. Included are six alternative MHC reference sequences of the human genome that we completed and refined. Characterization of the sequence and structural diversity of the MHC region shows the approach accurately determines the sequences of the highly polymorphic HLA class I and HLA class II genes and the complex structural diversity of complement factor C4A/C4B It has also uncovered extensive and unexpected diversity in other MHC genes; an example is MUC22, which encodes a lung mucin and exhibits more coding sequence alleles than any HLA class I or II gene studied here. More than 60% of the coding sequence alleles analyzed were previously uncharacterized. We have created a substantial database of robust reference MHC haplotype sequences that will enable future population scale studies of this complicated and clinically important region of the human genome.

Differences in the Treatment of Distal Radius Fractures by Hand Fellowship Trained Surgeons: A Study of ABOS Candidate Data.

PURPOSE: The management of distal radius fractures differs based on the nature of the fracture and the experience of the surgeon. We hypothesized that patients requiring surgical intervention would undergo different procedures when in the care of a surgeon with subspecialty training in hand surgery as compared with surgeons with no subspecialty training in hand surgery. METHODS: We queried the ABOS database for case log information submitted for part II of the ABOS examination. Queries for all codes involved with distal radius fracture management were combined with associated codes for the management of median nerve neuropathy, triangular fibrocartilage complex tears, ulnar shaft, and styloid fractures. Hand fellowship trained orthopedic surgeons were compared with those completing other fellowships and non-fellowship trained orthopedic surgeons during their board collection period. RESULTS: During the study period, 2,317 orthopedic surgeons reported treatment of 15,433 distal radius fractures. Of these surgeons, 411 had hand fellowship training. On a per surgeon basis, fellowship trained hand surgeons operatively treated more multifragment intra-articular distal radius fractures than their non-hand fellowship trained counterparts (5.3 vs 1.2). Additional procedures associated with the management of distal radius fractures were also associated with the fellowship training of the treating surgeon. CONCLUSIONS: Among orthopedic surgeons taking part II of the ABOS certifying examination, differences exist in the type, management, and reporting of distal radius fractures among surgeons with different areas of fellowship training. CLINICAL RELEVANCE: This study describes the association of hand surgery fellowship training on the choice of intervention for distal radius fractures and associated conditions.

Can Radiocarpal-Spanning Fixation Be Made More Functional by Placing the Wrist in Extension? A Biomechanical Study Under Physiologic Loads.

We investigate whether applying an internal radiocarpal-spanning plate with the wrist in slight extension affects the biomechanical stability of the construct. An unstable distal radius fracture was simulated in 10 cadaveric specimens and immobilized with a radiocarpal-spanning plate holding the wrist in a neutral position. This construct was then physiologically loaded through the wrist flexor and extensor tendons. The resulting motion at the fracture was captured with a displacement sensor. The plate was then extended using an in situ bending technique, placing the wrist in extension, and the experiment was repeated. No statistically significant difference in the biomechanical stability afforded by the radiocarpal-spanning plate was detected with the wrist in extension compared to that in the traditional neutral position. The radiocarpal-spanning plate fixation was more stable when loaded through the extensor tendons. We conclude that immobilizing a distal radius fracture with an internal radiocarpal-spanning plate that holds the wrist in extension does not compromise biomechanical stability.

Larger femoral periprosthetic bone mineral density decrease following total hip arthroplasty for femoral neck fracture than for osteoarthritis: a prospective, observational cohort study.

Studies on patients with degenerative joint disease of the hip show that femoral periprosthetic bone mineral decreases following total hip arthroplasty. Scarcely any osteodensitometric data exist on femoral neck fracture (FNF) patients and periprosthetic bone remodelling. In two parallel cohorts we enrolled 87 patients (mean age, 72 ± 12 years; male:female ratio, 30:57) undergoing total hip arthroplasty for either primary osteoarthritis (OA) of the hip (n = 37) or for an acute FNF (n = 50) and followed them for a mean of 5.4 years. Outcomes were bone mineral density (BMD) changes in the periprosthetic Gruen zones 1-7, the incidence of periprosthetic fractures and clinical outcome. The bone mineral loss in the fracture group was more than twice that of the osteoarthritis group, -16.9% versus -6.8% (p = 0.004). The incidence of periprosthetic fractures was 12% (6/50) in the fracture cohort compared with none (0%) in the OA cohort (p = 0.03). Periprosthetic bone mineral loss following total hip arthroplasty is significantly greater in patients who are treated for acute FNF than in OA patients. This decrease of BMD follows a different pattern with the FNF patients losing larger proportions of bone in Gruen zones 1, 2, 6, and 7 while the OA patients tend to have larger losses only in zones 1 and 7.

High incidence of hemiarthroplasty for shoulder osteoarthritis among recently graduated orthopaedic surgeons.

BACKGROUND: Primary glenohumeral osteoarthritis is a common indication for shoulder arthroplasty. Historically, both total shoulder arthroplasty (TSA) and hemi-shoulder arthroplasty (HSA) have been used to treat primary glenohumeral osteoarthritis. The choice between procedures is a topic of debate, with HSA proponents arguing that it is less invasive, faster, less expensive, and technically less demanding, with quality of life outcomes equivalent to those of TSA. More recent evidence suggests TSA is superior in terms of pain relief, function, ROM, strength, and patient satisfaction. We therefore investigated the practice of recently graduated orthopaedic surgeons pertaining to the surgical treatment of this disease. QUESTIONS/PURPOSES: We hypothesized that (1) recently graduated, board eligible, orthopaedic surgeons with fellowship training in shoulder surgery are more likely to perform TSA than surgeons without this training; (2) younger patients are more likely to receive HSA than TSA; (3) patient sex affects the choice of surgery; (4) US geographic region affects practice patterns; and (5) complication rates for HSA and TSA are not different. METHODS: We queried the American Board of Orthopaedic Surgery's database to identify practice patterns of orthopaedic surgeons taking their board examination. We identified 771 patients with primary glenohumeral osteoarthritis treated with TSA or HSA from 2006 to 2011. The rates of TSA and HSA were compared based on the treating surgeon's fellowship training, patient age and sex, US geographic region, and reported surgical complications. RESULTS: Surgeons with fellowship training in shoulder surgery were more likely (86% versus 72%; OR 2.32; 95% CI, 1.56-3.45, p<0.001) than surgeons without this training to perform TSA rather than HSA. The mean age for patients receiving HSA was not different from that for patients receiving TSA (66 versus 68, years, p=0.057). Men were more likely to receive HSA than TSA when compared to women (RR 1.54; 95% CI, 1.19-2.00, p=0.0012). The proportions of TSA and HSA were similar regardless of US geographic region (Midwest HSA 21%, TSA 79%; Northeast HSA 25%, TSA 75%; Northwest HSA 16%, TSA 84%; South HSA 27%, TSA 73%; Southeast HSA 24%, TSA 76%; Southwest HSA 23%, TSA 77%; overall p=0.708). The overall complication rates were not different with the numbers available: 8.4% (15/179) for HSA and 8.1% (48/592) for TSA (p=0.7555). CONCLUSIONS: The findings of this study are at odds with the recommendations in the current clinical practice guidelines for the treatment of glenohumeral osteoarthritis published by the American Academy of Orthopaedic Surgeons. These guidelines favor using TSA over HSA in the treatment of shoulder arthritis. Further investigation is needed to clarify if these practice patterns are isolated to recently graduated board eligible orthopaedic surgeons or if the use of HSA continues with orthopaedic surgeons applying for recertification. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Reverse total shoulder arthroplasty for the treatment of proximal humeral fractures: patterns of use among newly trained orthopedic surgeons.

BACKGROUND: This study compared the use of reverse and hemishoulder arthroplasty for the treatment of proximal humeral fractures among orthopedic surgeons taking part II of the American Board of Orthopaedic Surgery board examination. We hypothesized that the use of reverse shoulder arthroplasty for fractures in the elderly is increasing amongst newly trained orthopedic surgeons. MATERIALS AND METHODS: We queried the American Board of Orthopaedic Surgery database for the cases of proximal humeral fractures treated with arthroplasty submitted between 2005 and 2012. We evaluated the prosthesis used, patient-specific factors, complications, and the difference in use by shoulder fellowship-trained surgeons. RESULTS: From 2005 to 2012, 5395 board-eligible orthopedic surgeons submitted cases to the database. Of these, 435 (mean, 54 per year) were proximal humeral fractures treated with arthroplasty. The overall incidence of reverse shoulder arthroplasty for fracture increased from 2% to 4% during 2005 to 2007 to 38% in 2012. Shoulder surgeons treated 5 times more proximal humeral fractures with shoulder arthroplasty and were also more than 20 times more likely to use a reverse implant (P < .0001). The difference in complication rates between reverse and hemishoulder arthroplasty was not significant (P = .49). Patients who received a hemiarthroplasty tended to be younger (mean age, 70.8 vs 75.7 years; P = .0015). CONCLUSIONS: Overall, the use of a hemiarthroplasty for fracture is still more common (62% in 2012), although the relative proportion of reverse implants is rising. Among shoulder surgeons, more than 50% of the arthroplasties performed for fractures during the past 3 years (2010-2012) have been reverse arthroplasties.

In vitro efficacy and release study with anti-inflammatory drugs incorporated in adhesive transdermal drug delivery systems.

The topical application of two different anti-inflammatory extracts incorporated in adhesive transdermal drug delivery systems (TDDSs) was investigated. Therefore, anti-inflammatory properties and percutaneous absorption behavior of adhesive TDDSs were characterized in vitro conducting experiments with a dermatologically relevant human skin model. Anti-inflammatory efficacy against UV irradiation of both TDDSs was determined in vitro with EpiDerm™. The reduction of the release of proinflammatory cytokines by topically applied TDDSs was compared with the reduction during the presence of the specific cyclooxygenase inhibitor diclofenac in the culture medium. A similar anti-inflammatory efficacy of the topically applied TDDSs in comparison with the use of diclofenac in the culture medium should be achieved. Furthermore, percutaneous absorption in efficacy tests was compared with percutaneous absorption in diffusion studies with porcine cadaver skin. Both the topically applied TDDSs showed a significant anti-inflammatory activity. Permeation coefficients through the stratum corneum and the epidermis gained from the release studies on porcine cadaver skin (Magnolia: 2.23·10(-5) cm/h, licorice: 4.68·10(-6) cm/h) were approximately five times lower than the permeation coefficients obtained with the EpiDerm™ skin model (Magnolia: 9.48·10(-5) cm/h, licorice: 24.0·10(-6) cm/h). Therefore, an adjustment of drug doses during experiments with the EpiDerm™ skin model because of weaker skin barrier properties should be considered.

Intra-articular hip injections for lateral hip pain.

Occult intra-articular hip pathology is commonly found in patients with greater trochanteric pain syndrome, and may be a possible pain generator in patients with recalcitrant lateral hip pain. We investigated the effect of intra-articular hip injections in patients with recalcitrant lateral hip pain. Between September 2012 and May 2013, patients over the age of 18 with a history lateral hip pain who had received prior treatment with non-steroidal anti-inflammatory medications, physical therapy and peritrochanteric corticostroid injections were enrolled. Treatment consisted of an ultrasound guided intra-articular corticosteroid injection followed by a course of directed physical therapy and a non-steroidal anti-inflammatory medication. Patients performed GaitRite analysis at baseline and 12 weeks following the injection. In addition, the Modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Scores (HOS), Short Form 36 (SF-36) and a visual analogue pain score (VAS) were collected at baseline, 1, 6 and 12 weeks.A total of 16 patients were studied. Patients experienced significant improvements from their baseline mHHS at 1 and 12 weeks (P = 0.03, P = 0.04). The minimal clinically important difference (MCID) was exceeded at multiple timepoints on various clinical outcome surveys. Velocity and stride length were not significantly improved at 12 weeks. Intra-articular hip injections may decrease pain and improve function in patients with recalcitrant lateral hip pain, and occult intra-articular hip pathology should be considered in the etiology of lateral hip pain. Though low enrollment numbers left this study underpowered, MCID comparisons demonstrated potential benefit from this treatment.

Fracture-dislocations of the proximal interphalangeal joint.

Fracture-dislocations of the proximal interphalangeal joint encompass a spectrum of injury severity, ranging from injuries that require little intervention to those that require advanced reconstructive surgery for optimal outcome. Three fracture-dislocation patterns are recognized: dorsal, volar, and pilon. Acceptable outcome is dependent on achieving and maintaining a well-aligned and well-reduced joint, re-establishing normal joint kinematics, and restoring motion. Anatomic articular surface reduction is desirable but not absolutely necessary for a good outcome. Treatment depends on both the type of injury and patient-dependent factors. Optimal outcome for a specific injury is predicated on expedient diagnosis and recognition of injury severity, which enables initiation of appropriate management.

Maintaining replication origins in the face of genomic change.

Origins of replication present a paradox to evolutionary biologists. As a collection, they are absolutely essential genomic features, but individually are highly redundant and nonessential. It is therefore difficult to predict to what extent and in what regard origins are conserved over evolutionary time. Here, through a comparative genomic analysis of replication origins and chromosomal replication patterns in the budding yeasts Saccharomyces cerevisiae and Lachancea waltii, we assess to what extent replication origins survived genomic change produced from 150 million years of evolution. We find that L. waltii origins exhibit a core consensus sequence and nucleosome occupancy pattern highly similar to those of S. cerevisiae origins. We further observe that the overall progression of chromosomal replication is similar between L. waltii and S. cerevisiae. Nevertheless, few origins show evidence of being conserved in location between the two species. Among the conserved origins are those surrounding centromeres and adjacent to histone genes, suggesting that proximity to an origin may be important for their regulation. We conclude that, over evolutionary time, origins maintain sequence, structure, and regulation, but are continually being created and destroyed, with the result that their locations are generally not conserved.