Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy.

Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt-1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy.

Activity-Dependent Dysfunction in Visual and Olfactory Sensory Systems in Mouse Models of Down Syndrome.

Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivoSIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients.

Phenotypic characteristics in metabolically healthy but obese patients with schizophrenia.

The purpose of this study was to characterize phenotypic characteristics of metabolically healthy but obese individuals with schizophrenia. Participants were non-diabetic outpatients 19 to 75 years old diagnosed with schizophrenia or schizoaffective disorder. Obese patients (body mass index (BMI)>30 kg/m(2)) were included in the present analysis. Patients were further defined as metabolically healthy but obese or obese individuals with metabolic abnormalities based on a cut-off value of 2.5 using the homeostasis model assessment of insulin resistance (HOMA-IR). Fasting blood samples were collected to determine levels of various metabolic parameters. Lipoprotein subclass concentrations and sizes were analyzed using nuclear magnetic resonance (NMR) spectroscopy. Fourteen metabolically healthy but obese patients and 62 obese patients with metabolic abnormalities were identified from 206 patients with schizophrenia. After controlling for age, there were no significant differences between the two groups on anthropometric measures. However, the metabolically healthy but obese group had significantly lower levels of large VLDL particle, significantly higher levels of intermediate VLDL particle, and significantly smaller mean particle size in VLDL compared with the obese group with metabolic abnormalities (metabolically obese). A metabolically healthy but obese phenotype characterized by high levels of intermediate VLDL particle and low levels of large VLDL particle exists in obese, non-diabetic patients with schizophrenia.

Topical steroid risk analysis: differentiating between physiologic and pathologic adrenal suppression.

BACKGROUND: Topical corticosteroids are a mainstay of therapy for inflammatory skin disorders. Hypothalamic-pituitary-adrenal (HPA) axis suppression is a potential systemic risk of topical steroid use. Our aim was to review available data on the risk of HPA axis suppression associated with long-term topical steroid use and to distinguish between pathologic and physiologic adrenal suppression. METHODS: We performed a PubMed search for literature that evaluated the risk of HPA axis suppression associated with topical steroid use. RESULTS: Fifteen of sixteen clinical trials reviewed did not report any pathologic adrenal suppression. In the single clinical trial that reported pathologic adrenal suppression, the patients used twice the maximum recommended amount of clobetasol propionate continuously for as long as 18 months. Physiologic adrenal suppression was seen as early as 1-2 weeks after treatment with class I-IV topical corticosteroids. In about half of these patients, cortisol levels spontaneously returned to normal within a few weeks, despite continuous therapy. CONCLUSION: Even when adrenal suppression occurs, topical corticosteroids are unlikely to be associated with clinical signs or symptoms of HPA axis suppression and are extremely safe as long as they are used within the current safety guidelines.

Mucinous carcinoma: a translucent blue papule on an 89-year-old man.

An 89-year-old man with no significant medical history presented with a slow-growing, asymptomatic translucent blue mass noticed 1 year prior to evaluation. Review of symptoms was negative for constitutional symptoms, gastrointestinal (GI) disturbance, and visual complaints. Physical evaluation revealed a 4-mm firm light blue translucent papule on the left medial canthus (Figure 1). No cervical or axillary adenopathy was present. No further lesions were identified during full body skin examination, including chest wall masses. A diagnostic study was performed and stained with hematoxylin-eosin (Figure 2) and periodic acid-Schiff (Figure 3).

Intralesional injections of alefacept may predict systemic response to intramuscular alefacept: results from a pilot study.

BACKGROUND: Alefacept (Amevive®) was the first biologic agent to be approved by the FDA for use in moderate to severe chronic plaque psoriasis and remains one of the safest systemic agents. However, alefacept is the least utilized of all the biologic agents due to the finding that it is only effective in a small proportion of patients and its maximal efficacy is not seen until approximately 6 weeks after treatment completion. OBJECTIVE: To determine whether intralesional injections with a biologic agent can predict who will be a responder or a non-responder to the medication. METHODS: This was a single-center 22-week study consisting of three phases: i) intralesional injection to a target plaque, ii) intramuscular alefacept injections for 12 weeks (standard dose) and iii) post-treatment follow-up. RESULTS: There appears to be a perfect correlation between patients who show a response to an intralesional injection of alefacept to a small, target plaque and those who eventually respond to a full 12-week systemic course of the medication (achieve at least 70% improvement in their PASI scores from baseline) (p = 0.0003). LIMITATIONS: This study had a small sample size and was limited by the fact that it was open-label without a control arm. CONCLUSION: The results from this pilot study demonstrated that alefacept appears to work intralesionally and this may be usable to predict systemic response. More importantly, these results strongly suggest that a biologic agent can work locally - a novel concept that contradicts the common notion that biologic agents must work "systemically".

Multiples in dermatology: markers for special considerations in diagnosis, therapy, and prognosis.

Multiples of certain cutaneous lesions should alert the clinician to a wider differential diagnosis and possible systemic associations although the individual skin lesion is often benign in nature and banal in appearance. This article focuses on such findings in selected multiple cutaneous lesions that may be classified according to the primary cutaneous feature as vascular, pigmentary, nevoid hamartomas, and tumors/neoplastic conditions. The clinical presentation of each entity and its significance, appropriate diagnostic evaluation, therapeutic and prognostic considerations and pertinent differential diagnoses will be reviewed.

Psoriasis responds to intralesional injections of alefacept and may predict systemic response to intramuscular alefacept: interim results of a single-arm, open-label study.

BACKGROUND: Alefacept is a remittive treatment for generalized psoriasis but is rarely used due to its erratic efficacy. OBJECTIVE: To determine if psoriasis plaques will respond to intralesional alefacept and if this predicts a systemic response to intramuscular (IM) alefacept. METHODS: We describe a 25-week, single-center, open-label study. Patients received weekly intralesional alefacept of increasing concentrations into target plaques for 3 weeks followed by IM injections for 12 weeks and concluded with an observation period of 9 weeks. The psoriasis area and severity index (PASI) was used to assess the efficacy of IM alefacept. RESULTS: Interim results are reported for the first seven patients enrolled. Two patients responded intralesionally to the most dilute 1:100 concentration of alefacept to sterile water and achieved a 59% and 100% improvement in PASI. Five patients did not respond intralesionally to the most dilute form of alefacept and none achieved PASI 75. Two of these five patients did not respond to any concentration and achieved a 26% and 38% improvement in PASI. Limitations to this study include a small sample size and being non-placebo-controlled. CONCLUSION: Alefacept is effective intralesionally and may predict a systemic response - challenging the concept that biologics must work systemically.

Hydroxychloroquine and lichen planopilaris: efficacy and introduction of Lichen Planopilaris Activity Index scoring system.

BACKGROUND: Lichen planopilaris (LPP) and its variant frontal fibrosing alopecia (FFA) are primary lymphocytic cicatricial alopecias for which there is no evidence-based therapy. OBJECTIVE: We assessed the efficacy of hydroxychloroquine in active LPP and FFA using the LPP Activity Index (LPPAI), a numeric score that allows quantification of the symptoms and signs of the condition for statistical comparison. In addition, we determined with the LPPAI if any improvement (reduction) in the numeric score pretreatment and posttreatment reached statistical significance. METHODS: This was a retrospective, single-center chart review of 40 adult patients with LPP, FFA, or both who were treated with hydroxychloroquine for up to 12 months from 2004 to 2007 at the University of California, San Francisco Hair Center. Symptoms, signs, activity, and spreading were scored at each visit in the standardized cicatricial alopecia flow chart. A numeric score was assigned to these markers of disease activity and a numeric score was calculated at each visit. RESULTS: There was significant reduction (P < .001) in the LPPAI at both 6 and 12 months. After 6 months, 69% had improved (reduced) symptoms and signs. At 12 months, 83% had improvement (reduction) in symptoms and signs. LIMITATIONS: Retrospective analysis and uncontrolled study are limitations. CONCLUSIONS: Hydroxychloroquine is effective in decreasing symptoms and signs in LPP and FFA as shown by significant reduction in the LPPAI in 69% and 83% of patients after 6 and 12 months of treatment, respectively.

Efficacy and safety of mycophenolate mofetil for lichen planopilaris.

BACKGROUND: Lichen planopilaris (LPP) is a chronic inflammatory disorder that causes permanent scalp hair loss and significant patient discomfort. OBJECTIVES: We sought to determine the efficacy and safety of mycophenolate mofetil (MMF) for treatment of LPP in patients who had failed prior topical, intralesional, or oral anti-inflammatory medications such as hydroxychloroquine or cyclosporine. METHODS: We conducted a retrospective chart review of 16 adult patients with LPP treated with at least 6 months of MMF in an open-label, single-center study from 2003 to 2007. Subjective and objective end points were quantified using the LPP Activity Index (LPPAI) and scores before and after treatment were assessed using a paired t test. Adverse events were monitored. RESULTS: Patients who completed treatment with MMF had significantly decreased signs and symptoms of active LPP despite having failed multiple prior therapies (P < .005). Five of 12 patients were complete responders (LPPAI score decreased>85%), 5 of 12 patients were partial responders (LPPAI score decreased 25%-85%), and two of 12 patients were treatment failures (LPPAI score decreased<25%). Four patients withdrew from the trial because of adverse events. LIMITATIONS: Retrospective analysis and small sample size were limitations. CONCLUSIONS: MMF was effective at reducing the signs and symptoms of active LPP in 83% of patients (10 of 12) who had failed multiple prior treatments after at least 6 months of treatment.

Quantitative assessment of combination bathing and moisturizing regimens on skin hydration in atopic dermatitis.

Standard recommendations for skin care for patients with atopic dermatitis stress the importance of skin hydration and the application of moisturizers. However, objective data to guide recommendations regarding the optimal practice methods of bathing and emollient application are scarce. This study quantified cutaneous hydration status after various combination bathing and moisturizing regimens. Four bathing/moisturizer regimens were evaluated in 10 subjects, five pediatric subjects with atopic dermatitis and five subjects with healthy skin. The regimens consisted of bathing alone without emollient application, bathing and immediate emollient application, bathing and delayed application, and emollient application alone. Each regimen was evaluated in all subjects, utilizing a crossover design. Skin hydration was assessed with standard capacitance measurements. In atopic dermatitis subjects, emollient alone yielded a significantly (p < 0.05) greater mean hydration over 90 minutes (206.2% baseline hydration) than bathing with immediate emollient (141.6%), bathing and delayed emollient (141%), and bathing alone (91.4%). The combination bathing and emollient application regimens demonstrated hydration values at 90 minutes not significantly greater than baseline. Atopic dermatitis subjects had a decreased mean hydration benefit compared with normal skin subjects. Bathing without moisturizer may compromise skin hydration. Bathing followed by moisturizer application provides modest hydration benefits, though less than that of simply applying moisturizer alone.

Central centrifugal cicatricial alopecia: Superimposed tinea capitis as the etiology of chronic scalp pruritus.

We discuss a patient with central centrifugal cicatricial alopecia (CCCA) who developed severe scalp pruritus that was initially attributed to the cicatricial alopecia and ultimately diagnosed as tinea capitis. The rarity of severe pruritus in CCCA should prompt a search for a fungal infection in these patients.

Comparative study of intra-articular lidocaine and intravenous meperidine/diazepam for shoulder dislocations.

The purpose of this study was to compare the analgesic effectiveness of intra-articular lidocaine versus intravenous meperidine and diazepam during the reduction of anterior shoulder dislocations. Patients were randomized to one of the two methods before the reduction of shoulder dislocations. Patients marked a visual analog pain scale at baseline, after anesthesia just before reduction, and at the time of discharge. Interference with the procedure caused by pain or lack of muscle relaxation, perception of adequacy of analgesia by the patient, adverse effects, and time to discharge from the Emergency Department (ED) were measured. Differences of outcomes, relative risks (RR), and 95% confidence intervals (CIs) were derived. Fifty-four patients with anterior shoulder dislocations presenting from May 21, 1998 through January 21, 1999 were included in this study; 29 were randomly assigned to receive intra-articular lidocaine (IAL) and 25 to receive intravenous meperidine/diazepam (IVMD). IAL was less effective than IVMD in relieving pre-reduction pain (p = 0.045) but equally effective in overall pain relief (p = 0.98). IAL was more effective than IVMD in shortening recovery time (p = 0.025). There was an indication favoring IVMD in terms of physician-perceived muscle relaxation and patient's perception of analgesia adequacy. In conclusion, although the IVMD method appears to have some clinically and statistically significant advantages, IAL possesses some favorable features that render it to be an analgesia alternative in shoulder dislocation reduction.