Systemic CXCL10 is a predictive biomarker of vitiligo lesional skin infiltration, PUVA, NB-UVB and corticosteroid treatment response and outcome.

Vitiligo is an acquired pigmentary skin disorder that currently lacks standardized treatment and validated biomarkers to objectively evaluate disease state or therapeutic response. Although prior studies have linked vitiligo autoimmunity with CXCL10/CXCL9-mediated recruitment of leukocytes to the skin, only limited clinical data are available regarding CXCL10 as vitiligo biomarker. To evaluate the utility of systemic CXCL10 as a predictor of disease progression and treatment response on a large cohort of vitiligo patients. CXCL10 levels in lesional, perilesional, and unaffected skin of vitiligo patient (n = 30) and in the serum (n = 51) were measured by quantitative ELISA. CXCL10 expression, recruitment of leukocytes, and inflammatory infiltrates were evaluated by histochemical (n = 32) and immunofluorescence (n = 10) staining. Rigorous cross-sectional and longitudinal biostatistical analysis were employed to correlate CXCL10 levels with disease variables, treatment response, and outcome. We demonstrated that elevated CXCL10 level (2 pg/mm2 and higher) in lesional skin correlates with increased leukocytic infiltrate, disease duration (< 2 year), and its higher level in the serum (50 pg/ml and higher). Changes in CXCL10 serum levels in patients treated with psoralen plus UVA (PUVA) phototherapy, narrowband UVB (NB-UVB) phototherapy, and systemic steroids (SS) correlated with changes in the intralesional CXCL10 levels in repigmented skin. NB-UVB and SS regimens provided most consistent CXCL10 mean change, suggesting that these regimens are most effective in harnessing CXCR3-mediated inflammatory response. Serum CXCL10 is a useful vitiligo biomarker, which predicts lesional skin leukocytic infiltration, and vitiligo treatment response and outcome.

Development of an abbreviated symptom score for the neonatal abstinence syndrome.

OBJECTIVE: We sought a shortened MOTHER neonatal abstinence syndrome (NAS) and Finnegan score that would retain comparable performance characteristics of the full instrument. STUDY DESIGN: Retrospective cohort. RESULTS: In total, 124,170 MOTHER NAS scores between August 2007 and May 2016 from 775 infants (≥36 weeks) were examined. Classification and regression tree model identified the most important subsets of the scored variables. A 9-element shortened scale yielded >90% sensitivity and specificity to predict clinical endpoints based on the full 19-element MOTHER NAS score. Conversion of the data sets to the Finnegan score, and applying the same procedure resulted in a nine-element score with similar performance characteristics. CONCLUSION: Shortened scoring instruments were identified with the high-predictive power for clinical endpoints based on the 19-element full MOTHER NAS score. There was no substantial variation in performance for age, supporting the current practice of utilizing a single scoring tool regardless of postnatal age.

Reversibility of Apixaban Anticoagulation with a Four-Factor Prothrombin Complex Concentrate in Healthy Volunteers.

It was hypothesized that the four-factor prothrombin complex concentrate (4F-PCC) Kcentra 25 unit/kg would reverse impairment of thrombin generation in healthy volunteers dosed with apixaban to steady state. In this randomized, two-period crossover, assessor-blinded trial, 12 healthy subjects received 5 mg apixaban every 12 h. Three h after the fifth dose, four-factor prothrombin complex concentrate (4F-PCC) 25 unit/kg or saline were infused. Serial blood samples were assessed for thrombin generation using PPP-reagent and PPP-reagent low, anti-Xa, PT, and PTT assays. Geometric mean ratio was calculated at 30 min postinfusion, and at 24, 48, and 72 h. Peak thrombin generation was 76% higher at 30 min postinfusion with 4F-PCC (p = 0.025). The difference declined to 24% at 24 h and resolved by 48 h. Other thrombin generation parameters were also partially normalized. There was no difference between 4F-PCC and saline in anti-Xa assessment at 30 min or later time points.

Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression.

Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.

Predictors of short-term outcome in brain-injured patients with disorders of consciousness.

OBJECTIVES: To investigate predictors of recovery from the vegetative state (VS) and minimally conscious state (MCS) after brain injury as measured by the widely used Disability Rating Scale (DRS) and to explore differences in rate of recovery and predictors of recovery during inpatient rehabilitation in patients with non-traumatic (NTBI) and traumatic brain injury (TBI). DESIGN: Longitudinal observational cohort design and retrospective comparison study, in which an initial DRS score was collected at the time of study enrollment. Weekly DRS scores were recorded until discharge from the rehabilitation center for both NTBI and TBI patients. SETTING: Seven acute inpatient rehabilitation facilities in the United States and Europe with specialized programs for VS and MCS patients (the Consciousness Consortium). PARTICIPANTS: One hundred sixty-nine patients with a non-traumatic (N=50) and a traumatic (N=119) brain injury who were in the VS or MCS states. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: DRS score at 13 weeks after injury; change in DRS score over 6 weeks post-admission; and time until commands were first followed (for patients who did not show command-following at or within 2 weeks of admission). RESULTS: Both time between injury and enrollment and DRS score at enrollment were significant predictors of DRS score at week 13 post-injury but the main effect of etiology only approached significance. Etiology was however a significant predictor of the amount of recovery observed over the 6 weeks following enrollment. Time between injury and enrollment was also a good predictor of this outcome, but not DRS score at enrollment. For the time until commands were first followed, patients with better DRS scores at enrollment, and those with faster early rates of change recovered command following sooner than those with worse DRS scores or slower initial rates of change. The etiology was not a significant predictor for this last outcome. None of these predictive models explained sufficient variance to allow their use in individual clinical decision making. CONCLUSIONS: Time post-injury and DRS score at enrollment are predictors of early recovery among patients with disorders of consciousness, depending on the outcome measure chosen. Etiology was also a significant predictor in some analyses, with traumatically injured patients recovering more than those with non-traumatic injuries. However, the hypothesized interaction between etiology and time post-injury did not reach significance in any of the analyses suggesting that, within the time frame studied, the decline in prognosis with the passage of time was similar in the two groups.

A comparison of glycaemic variability in CSII vs. MDI treated type 1 diabetic patients using CGMS.

OBJECTIVE: To evaluate and compare glucose variability, hypoglycaemic events and daily glycaemic control in well-controlled (HbA1c or= 180 mg/dl] and hypoglycaemic (BG

Proteomic analysis of nipple aspirate fluid to detect biologic markers of breast cancer.

The early detection of breast cancer is the best means to minimise disease-related mortality. Current screening techniques have limited sensitivity and specificity. Breast nipple aspirate fluid can be obtained noninvasively and contains proteins secreted from ductal and lobular epithelia. Nipple aspirate fluid proteins are breast specific and generally more concentrated than corresponding blood levels. Proteomic analysis of 1 microl of diluted nipple aspirate fluid over a 5-40 kDa range from 20 subjects with breast cancer and 13 with nondiseased breasts identified five differentially expressed proteins. The most sensitive and specific proteins were 6500 and 15 940 Da, found in 75-84% of samples from women with cancer but in only 0-9% of samples from normal women. These findings suggest that (1) differential expression of nipple aspirate fluid proteins exists between women with normal and diseased breasts, and (2) analysis of these proteins may predict the presence of breast cancer.

Differential expression of lumican and fibromodulin regulate collagen fibrillogenesis in developing mouse tendons.

Collagen fibrillogenesis is finely regulated during development of tissue-specific extracellular matrices. The role(s) of a leucine-rich repeat protein subfamily in the regulation of fibrillogenesis during tendon development were defined. Lumican-, fibromodulin-, and double-deficient mice demonstrated disruptions in fibrillogenesis. With development, the amount of lumican decreases to barely detectable levels while fibromodulin increases significantly, and these changing patterns may regulate this process. Electron microscopic analysis demonstrated structural abnormalities in the fibrils and alterations in the progression through different assembly steps. In lumican-deficient tendons, alterations were observed early and the mature tendon was nearly normal. Fibromodulin-deficient tendons were comparable with the lumican-null in early developmental periods and acquired a severe phenotype by maturation. The double-deficient mice had a phenotype that was additive early and comparable with the fibromodulin-deficient mice at maturation. Therefore, lumican and fibromodulin both influence initial assembly of intermediates and the entry into fibril growth, while fibromodulin facilitates the progression through growth steps leading to mature fibrils. The observed increased ratio of fibromodulin to lumican and a competition for the same binding site could mediate these transitions. These studies indicate that lumican and fibromodulin have different developmental stage and leucine-rich repeat protein specific functions in the regulation of fibrillogenesis.