Treatment of Periorbital Vascularity, Erythema, and Hyperpigmentation.

Periorbital hyperpigmentation (POH) is a common aesthetic concern that impacts patients' emotional well-being and quality of life. POH can be difficult to manage as the etiology is often multifactorial or difficult to elucidate. An understanding of different contributing factors and ability to classify hyperpigmentation can aid in the management of POH. Classification of POH is divided into pigmented, vascular, structural, and mixed subtypes. A wide array of treatment options has been proposed belying the challenges inherent to improving POH. Modalities vary from topical therapies, chemical peels, dermal fillers, and lasers, to surgical intervention. Because POH can be multifactorial, successful management of POH will depend on elucidating the etiology and often requires a combination of therapies.

Treatment of Periorbital Vascularity, Erythema, and Hyperpigmentation.

Periorbital hyperpigmentation (POH) is a common aesthetic concern that impacts patients' emotional well-being and quality of life. POH can be difficult to manage as the etiology is often multifactorial or difficult to elucidate. An understanding of different contributing factors and ability to classify hyperpigmentation can aid in the management of POH. Classification of POH is divided into pigmented, vascular, structural, and mixed subtypes. A wide array of treatment options has been proposed belying the challenges inherent to improving POH. Modalities vary from topical therapies, chemical peels, dermal fillers, and lasers, to surgical intervention. Because POH can be multifactorial, successful management of POH will depend on elucidating the etiology and often requires a combination of therapies.

Erythema ab igne in patients with sickle cell disease.

Erythema ab igne (EAI) is an asymptomatic dermatosis caused by prolonged exposure to localized heat. Affected areas have net-like hyperpigmentation that may resemble more serious conditions such as livedo racemosa or vasculitis. We report three cases of EAI in pediatric sickle cell disease (SCD) patients who were initially suspected of having a more severe, life-threatening disorder before Dermatology was consulted. Clinicians caring for pediatric SCD patients who regularly use heating pads/devices for pain relief should consider EAI in the differential diagnosis of large areas of net-like hyperpigmentation. This paper aims to increase recognition of EAI and patient education on safe practices while using heating pads.

Superior long-term survival for fixed bearing compared with mobile bearing in ligament-balanced total knee arthroplasty.

PURPOSE: Only few long-term data on ligament-balanced cruciate-retaining total knee arthroplasty (CR TKA) are currently available. Either a mobile- or fixed-bearing insert can be chosen, which showed good mid-term outcome and few complications and revisions. This multi-centre retrospective cross-sectional cohort study investigated the 12-year results of primary TKA using a balancing gap technique and compared survival and clinical outcome between fixed and mobile inserts. METHODS: In this retrospective cross-sectional cohort study, 557 cases of three clinics (2 Swiss, 1 Dutch) operated between 1998 and 2003 with the first series of a TKA implanted with a balanced gap technique (433 (77.7%) fixed, 124 (22.3%) mobile (anterior-posterior gliding (7-9 mm) and rotational (15°) degrees of freedom) inserts) were included for survival analysis (Kaplan-Meier, by insert type). At the 12-year follow-up (FU) examination of 189 cases, range of motion, knee society score (KSS), numeric rating scale (NRS) for pain and satisfaction were determined and radiographs were evaluated by median tests, by insert type. RESULTS: Of 521 cases available for analysis, 28 (5.4%; 11 fixed, 17 mobile bearing) were revised. Mean cumulative survival after 12.4 years was 97.0% (95% CI 94.7-98.4) for fixed bearings and 85.4% (95% CI 77.5-90.7) after 12.2 years for mobile bearings, p < 0.0001. Patients' mean age at 11.0 years FU (n = 189) was 78.0 (range 54.5-97.3) years. Mean total KSS was 157.8 (24-200) points, and mean passive flexion was 114° (45-150); no clinical score differed significantly between fixed and mobile bearings. CONCLUSION: This study showed a superior survival for fixed bearing compared with mobile bearing in a CR TKA using a ligament-balanced technique after more than 12 years. Clinical outcomes are excellent to good after long-term follow-up, and similar for fixed and mobile bearing. LEVEL OF EVIDENCE: Therapeutic studies-retrospective cohort study, Level III.

GPR91 deficiency exacerbates allergic contact dermatitis while reducing arthritic disease in mice.

BACKGROUND: Succinate, in addition to its role as an intermediary of the citric acid cycle, acts as an alarmin, initiating and propagating danger signals resulting from tissue injury or inflammatory stimuli. The contribution of this immune sensing pathway to the development of allergic and inflammatory responses is unknown. METHODS: Ear thickness of wild-type (wt) and Sucnr1-deficient (Sucnr1-/- ) mice, sensitized and challenged with oxazolone, was used as a criterion to assess the relevance of SUCNR1/GPR91 expression mediating allergic contact dermatitis (ACD). Results obtained in this system were contrasted with data generated using passive cutaneous anaphylaxis, ovalbumin-induced asthma and arthritis models. RESULTS: We found augmented ACD reactions in Sucnr1-/- mice. This observation correlated with increased mast cell activation in vitro and in vivo. However, exacerbated mast cell activation in Sucnr1-/- mice did not contribute to the enhancement of asthma or arthritis and seemed to be due to alterations during mast cell development as augmented mast cell responses could be recapitulated in wt mast cells differentiated in the absence of succinate. CONCLUSIONS: A deficiency in succinate sensing during mast cell development confers these cells with a hyperactive phenotype. Such a phenomenon does not translate into exacerbation of asthma or mast cell-dependent arthritis. On the contrary, the fact that Sucnr1-/- mice developed reduced arthritic disease, using two different in vivo models, indicates that GPR91 antagonists may have therapeutic potential for the treatment of allergic and autoimmune diseases.

Dissociable roles for histone acetyltransferases p300 and PCAF in hippocampus and perirhinal cortex-mediated object memory.

The importance of histone acetylation for certain types of memory is now well established. However, the specific contributions of the various histone acetyltransferases to distinct memory functions remain to be determined; therefore, we employed selective histone acetyltransferase protein inhibitors and short-interference RNAs to evaluate the roles of CREB-binding protein (CBP), E1A-binding protein (p300) and p300/CBP-associated factor (PCAF) in hippocampus and perirhinal cortex (PRh)-mediated object memory. Rats were tested for short- (STM) and long-term memory (LTM) in the object-in-place task, which relies on the hippocampus and PRh for spatial memory and object identity processing, respectively. Selective inhibition of these histone acetyltransferases by small-interfering RNA and pharmacological inhibitors targeting the HAT domain produced dissociable effects. In the hippocampus, CBP or p300 inhibition impaired long-term but not short-term object memory, while inhibition of PCAF impaired memory at both delays. In PRh, HAT inhibition did not impair STM, and only CBP and PCAF inhibition disrupted LTM; p300 inhibition had no effects. Messenger RNA analyses revealed findings consistent with the pattern of behavioral effects, as all three enzymes were upregulated in the hippocampus (dentate gyrus) following learning, whereas only CBP and PCAF were upregulated in PRh. These results demonstrate, for the first time, the necessity of histone acetyltransferase activity for PRh-mediated object memory and indicate that the specific mnemonic roles of distinctive histone acetyltransferases can be dissociated according to specific brain regions and memory timeframe.

Gender, age and ethnic aspects of analgesia in acute abdominal pain: is analgesia even across the groups?

BACKGROUND: Numerous studies have shown differences in pain perception between men and women, which may affect pain management strategies. AIM: Our primary aim was to investigate whether there are gender-based differences in pain management in patients admitted to our emergency department with acute, non-specific abdominal pain (NSAP). Our secondary aim was to evaluate if other factors influence administration of analgesia for patients admitted with NSAP. METHODS: From June 2007 to June 2008, we carried out a retrospective, gender-based, frequency-matched control study with 150 patients (75 consecutive men and 75 women) who presented with NSAP at our emergency department. Pain was documented using a numerical rating scale ('0' no pain, '10' most severe pain). A multinomial regression model was used to assess factors that might influence pain management. RESULTS: No statistically significant difference was seen between men and women with respect to pain management (P= 0.085). Younger patients were, however, more likely to receive weaker (P= 0.011) and fewer analgesics (P < 0.001). Patients with previous abdominal surgery (P= 0.012), known chronic pain conditions (P= 0.029) or relevant comorbidities (P= 0.048) received stronger analgesia. Nationality (P= 0.244), employment status (P= 0.988), time of admission (P= 0.487) and known psychiatric illness (P= 0.579) did not influence pain management. CONCLUSIONS: No statistically significant gender-dependent differences in pain management were observed. However, younger patients received less potent analgesic treatment. There is no reason for certain groups to receive suboptimal treatment, and greater efforts should be made to offer consistent treatment to all patients.

Functional performance of mobile versus fixed bearing total knee prostheses: a randomised controlled trial.

PURPOSE: The primary goal of this study was to assess the difference in active flexion between patients with a mobile versus a fixed bearing, cruciate retaining, and total knee arthroplasty. The study was designed as a randomised controlled multi-centre trial. METHODS: Participants were assigned to interventions by using block-stratified, random allocation. Outcome parameters were active flexion, passive flexion, and Knee Society Score (KSS). Outcome parameters were assessed preoperatively and at 3, 6, and 12 months postoperatively by an independent nurse. RESULTS: Ninety-two patients from one centre were included, 46 in each group. Active flexion was comparable for the two groups, 99.9° for the mobile bearing group and 101° for the fixed bearing group with a baseline controlled difference of 1.0 (95% CI -3.9 to 5.8, n.s.). The Clinical KSS was comparable between the two bearing groups (Mobile 90.0 vs. fixed 92.4, n.s.). The functional KSS showed a difference that was attributable to the stair climbing subscore, which showed a difference in favour of the fixed bearing design between preoperative and 3 months (7.3 point difference; 95% CI 2.3-12.5; P = 0.005) as well as 12 months (4.8 point difference; 95% CI 0.1-9.6; P = 0.045). CONCLUSIONS: There were no short-term differences in active flexion between fixed bearing and mobile bearing total knee arthroplasty. LEVEL OF EVIDENCE: I.

Application of magnetic-resonance-spectroscopy- based metabolomics to the fine-needle aspiration diagnosis of papillary thyroid carcinoma.

OBJECTIVE: This study explores the potential use of high-resolution magic angle spinning proton magnetic resonance spectroscopy as an ancillary diagnostic technique for papillary thyroid carcinoma in thyroid fine-needle aspiration biopsies. The method has already been shown to be effective in the classification of various other nonthyroid cancers. STUDY DESIGN: Twenty-six samples (13 paired cytologic and histologic samples) from patients being evaluated for thyroid abnormalities at the Massachusetts General Hospital were spectroscopically analyzed, and included: papillary thyroid carcinomas (n = 4), follicular adenomas (n = 4), and normal thyroid samples (n = 5). Metabolic profiles were statistically generated based on the spectroscopy results, which were then correlated with the final cytologic and histologic diagnoses from the same samples to determine the diagnostic capacity of the profiles. RESULTS: Principal component analysis of the tissue samples revealed statistically significant correlations among principal components and various cytologic and histologic features. Canonical score 1, calculated with principal components in correlation with analyzed pathologies, revealed the ability of the metabolic profile to differentiate all three examined histologic tissue groups (ANOVA, p < 0.0001). Applying coefficients of principal components and canonical scores obtained with tissue samples directly onto spectral results of cytology samples, the calculated canonical score 1 also revealed similar trends among the three fine-needle aspiration biopsy groups. In particular, the papillary thyroid carcinoma group exhibited significant differences from both the adenomatous and normal cytology groups (p < 0.0170). CONCLUSIONS: The results indicate the potential of high-resolution magic angle spinning proton magnetic resonance spectroscopy as an ancillary marker for papillary thyroid carcinoma in fine-needle aspiration biopsy specimens.

Fate of prions in soil: a review.

Prions are the etiological agents of transmissible spongiform encephalopathies (TSSEs), a class of fatal neurodegenerative diseases affecting humans and other mammals. The pathogenic prion protein is a misfolded form of the host-encoded prion protein and represents the predominant, if not sole, component of the infectious agent. Environmental routes of TSE transmission areimplicated in epizootics of sheep scrapie and chronic wasting disease (CWD) of deer, elk, and moose. Soil represents a plausible environmental reservoir of scrapie and CWD agents, which can persist in the environment for years. Attachment to soil particles likely influences the persistence and infectivity of prions in the environment. Effective methods to inactivate TSE agents in soil are currently lacking, and the effects of natural degradation mechanisms on TSE infectivity are largely unknown. An improved understanding of the processes affecting the mobility, persistence, and bioaviailability of prions in soil is needed for the management of TSE-contaminated environments.

Metabolomic imaging for human prostate cancer detection.

As current radiological approaches cannot accurately localize prostate cancer in vivo, biopsies are conducted at random within prostates for patients at risk for prostate cancer, leading to high false-negative rates. Metabolomic imaging can map cancer-specific biomolecular profile values onto anatomical structures to direct biopsy. In this preliminary study, we evaluated five whole prostates removed during prostatectomy from biopsy-proven cancer patients on a 7-tesla human whole-body magnetic resonance scanner. Localized, multi-cross-sectional, multivoxel magnetic resonance spectra were used to construct a malignancy index based on prostate cancer metabolomic profiles obtained from previous intact tissue analyses with a 14-tesla spectrometer. This calculated malignancy index is linearly correlated with lesion size and demonstrates a 93 to 97% overall accuracy for detecting the presence of prostate cancer lesions, suggesting the potential clinical utility of this approach.

Assessing prostate cancer growth with mRNA of spermine metabolic enzymes.

Statistical data from prostate cancer (PCa) clinics indicates that a large patient population discovered by annual prostate specific antigen (PSA) screening may have a latent form of the disease. However, current medical tests cannot differentiate slow from fast growing PCa, resulting in many unnecessary radical treatments and morbidities. It is thus necessary to find new screening tests that enable us to differentiate between fast- and slow-growing tumors. Inspired by the reported functions of spermine in carcinogenesis, we analyzed spermine and mRNA expression levels of rate-limiting enzymes in the spermine metabolic pathway for nine cases of PCa with accurately defined PSA velocity (Vpsa). Using MR spectroscopy, histopathology, laser-capture microdissection and real-time PCR techniques, we analyzed relationships between changes in spermine levels, mRNA expression levels of spermine anabolic and catabolic enzymes and human prostate cancer growth rates represented by serum Vpsa. The expression levels of spermine anabolic enzymes: ornithine decarboxylase (ODC1) and S-adenosylmethionine decarboxylase (AMD1) in benign epithelia surrounding cancer glands was logarithmically reduced with the increase of Vpsa (ODC1, p < 0.016; AMD1, p < 0.048), and antizyme (OAZ1) expression in cancer cells was increased with the increase of Vpsa (p < 0.001). Finally, we observed an inverse correlation between ODC1 and OAZ1 (p < 0.019) measured in cancer cells. These correlations may function to evaluate the aggressiveness of human prostate cancer, and assist patients and clinicians to select appropriate treatment strategies based on biological activities of individual tumors.

Retrospective analysis of prostate cancer recurrence potential with tissue metabolomic profiles.

BACKGROUND: In clinical care of prostate cancer patients, an improved method to assess the risk of recurrence after surgical treatment is urgently needed. We aim to retrospectively evaluate the ability of ex vivo tissue magnetic-resonance-spectroscopy-based metabolomic profiles to estimate the risk of recurrence. METHODS: PCa recurrence is defined biochemically as the detection of serum PSA after radical prostatectomy. Sixteen consecutive PCa-recurrent cases, those with an initial PSA increase of 0.69 +/- 0.26 ng/ml monitored 47.7 +/- 2.6 months after prostatectomy were paired by age and Gleason score with cases without recurrence of the same pathological and clinical stages (n = 16/each). We analyzed ex vivo intact-tissue spectroscopy results from these 48 individuals at the time of prostatectomy at 14T. From these spectra, we identified the 27 most common and intense spectral metabolic regions for statistical analyses. RESULTS: Principal component analysis (PCA) on these spectral regions from cases of clinical-stage-matched groups with and without recurrence identified four pathology-related principal components. Canonical analysis of these four and the first nine principal components for cases in the two groups defined metabolomic profiles as the canonical score that can differentiate the two groups with statistical significance. By applying the coefficients from PCA and canonical analysis to the pathological-stage-matched groups, recurrence was predicted with an accuracy of 78%. CONCLUSIONS: Results indicate the potential of tissue metabolomic profiles measured with ex vivo spectroscopy to identify PCa aggressiveness in terms of cancer recurrence. With further study, this may greatly contribute to the future design of clinical strategy for personalized treatment of PCa patients.

Posterior cruciate ligament balancing in total knee replacement: the quantitative relationship between tightness of the flexion gap and tibial translation.

We have examined the relationship between the size of the flexion gap and the anterior translation of the tibia in flexion during implantation of a posterior cruciate ligament (PCL)-retaining BalanSys total knee replacement (TKR). In 91 knees, the flexion gap and anterior tibial translation were measured intra-operatively using a custom-made, flexible tensor-spacer device. The results showed that for each increase of 1 mm in the flexion gap in the tensed knee a mean anterior tibial translation of 1.25 mm (SD 0.79, 95% confidence interval 1.13 to 1.37) was produced. When implanting a PCL-retaining TKR the surgeon should be aware that the tibiofemoral contact point is related to the choice of thickness of the polyethylene insert. An additional thickness of polyethylene insert of 2 mm results in an approximate increase in tibial anterior translation of 2.5 mm while the flexed knee is distracted with a force of between 100 N and 200 N.

Cellular and molecular mechanisms of regeneration in Xenopus.

We have employed transgenic methods combined with embryonic grafting to analyse the mechanisms of regeneration in Xenopus tadpoles. The Xenopus tadpole tail contains a spinal cord, notochord and segmented muscles, and all tissues are replaced when the tail regenerates after amputation. We show that there is a refractory period of very low regenerative ability in the early tadpole stage. Tracing of cell lineage with the use of single tissue transgenic grafts labelled with green fluorescent protein (GFP) shows that there is no de-differentiation and no metaplasia during regeneration. The spinal cord, notochord and muscle all regenerate from the corresponding tissue in the stump; in the case of the muscle the satellite cells provide the material for regeneration. By using constitutive or dominant negative gene products, induced under the control of a heat shock promoter, we show that the bone morphogenetic protein (BMP) and Notch signalling pathways are both essential for regeneration. BMP is upstream of Notch and has an independent effect on regeneration of muscle. The Xenopus limb bud will regenerate completely at the early stages but regenerative ability falls during digit differentiation. We have developed a procedure for making tadpoles in which one hindlimb is transgenic and the remainder wild-type. This has been used to introduce various gene products expected to prolong the period of regenerative capacity, but none has so far been successful.

Nerve-independence of limb regeneration in larval Xenopus laevis is correlated to the level of fgf-2 mRNA expression in limb tissues.

In both larval and adult urodele amphibians, limb blastema formation requires the presence of an adequate nerve supply. In previous research, we demonstrated that the hindlimb of early Xenopus laevis larvae formed a regeneration blastema even when denervated, while the denervated limb of late larvae did not. We hypothesized that the nerve-independence was due to the autonomous synthesis of a mitogenic neurotrophic-like factor by undifferentiated limb bud cells. In this paper, we demonstrate that fgf-2 mRNA is present in larval limb tissues and that its level is correlated to the extent of mesenchymal cells populating the limb: in early limbs, fgf-2 mRNA is present at high levels all over the limb, while, in late limbs, the fgf-2 expression is low and detectable only in the distal autopodium. After denervation, fgf-2 mRNA synthesis increases in amputated early limbs but not in amputated late limbs. The implantation of anti-FGF-2 beads into amputated early limbs hardly lowers the mitotic activity of blastema cells. However, FGF-2 beads implanted into the blastema of late limbs prevent the denervation-induced inhibition of mitosis and oppose blastema regression. Our data indicate that FGF-2 is a good candidate for the endogenous mitogenic factor responsible for blastema formation and growth in amputated and denervated early limbs. However, in amputated late limbs, the very limited fgf-2 expression is not sufficient to promote blastema formation in the absence of nerves.

Spatial response to fibroblast growth factor signalling in Xenopus embryos.

We have examined the spatial pattern of activation of the extracellular signal-regulated protein kinase (ERK) during Xenopus development, and show that it closely resembles the expression of various fibroblast growth factors (FGFs). Until the tailbud stage of development, all ERK activation domains are sensitive to the dominant negative FGF receptor, showing that activation is generated by endogenous FGF signalling. ERK is not activated by application of other growth factors like BMP4 or activin, nor is endogenous activation blocked by the respective dominant negative receptors. This shows that various domains of FGF expression, including the periblastoporal region and the midbrain-hindbrain boundary, are also sites of FGF signalling in vivo. Wounding induces a transient (<60 minutes) activation of ERK which is not significantly reduced by the dominant negative FGF receptor. An artificial FGF source, created by injection of eFGF mRNA into cleavage stage embryos, provokes ERK activation outside of its injection site over a range of several cell diameters. The range and extent of ERK activation outside the source region is unchanged by co-injection of a dominant negative form of Ras, which blocks ERK-activation within the source. This suggests that FGF protein can diffuse over several cell diameters.

dMi-2, a hunchback-interacting protein that functions in polycomb repression.

Early in Drosophila embryogenesis, gap gene products directly repress transcription of homeotic (HOX) genes and thereby delimit HOX expression domains. Subsequently, Polycomb-group proteins maintain this repression. Currently, there is no known molecular link between gap and Polycomb-group proteins. Here, dMi-2 is identified as a protein that binds to a domain in the gap protein Hunchback that is specifically required for the repression of HOX genes. Genetic analyses show that dMi-2 participates in both Hunchback and Polycomb repression in vivo. Hence, recruitment of dMi-2 may serve as a link between repression of HOX genes by Hunchback and Polycomb proteins.

A descriptive analysis of "not aeronautically adaptable" dispositions in the U.S. Navy.

BACKGROUND: All aviation personnel in the U.S. Navy are evaluated for aeronautical adaptability (AA) in both initial and periodic examinations and for daily aeromedical disposition. By definition, all aviation personnel with a diagnosed personality disorder or those with maladaptive personality traits that have had a documented effect on safety of flight, crew coordination, or mission completion, are determined to be Not Aeronautically Adapted (NAA). METHODS: NAA dispositions were examined for demographic data, basis for disposition, and frequency of personality features. RESULTS: NAA dispositions were made on the basis of personality disorders and maladaptive personality traits in 29% and 35% of the cases, respectively. The officer and enlisted NAA dispositions were distinctly different in terms of frequency of personality features. Obsessive-compulsive features were present in 58% of officer and 10% of enlisted NAA dispositions. Dependent and avoidant features were present in excess in comparison to psychologically healthy aviators, suggesting the incompatibility of these features with aviation.