Genetic diversity among clinical isolates of Acremonium strictum determined during an investigation of a fatal mycosis

Primarily saprophytic in nature, fungi of the genus Acremonium are a well-documented cause of mycetoma and other focal diseases. More recently, a number of Acremonium spp. have been implicated in invasive infections in the setting of severe immunosuppression. During the course of routine microbiological studies involving a case of fatal mycosis in a nonmyeloablative hematopoietic stem cell transplant patient, we identified a greater-than-expected variation among strains previously identified as Acremonium strictum by clinical microbiologists. Using DNA sequence analysis of the ribosomal DNA intergenic transcribed spacer (ITS) regions and the D1-D2 variable domain of the 28S ribosomal DNA gene (28S), the case isolate and four other clinical isolates phenotypically identified as A. strictum were found to have <99% homology to the A. strictum type strain, CBS 346.70, at the ITS and 28S loci, while a sixth isolate phenotypically identified only as Acremonium sp. had >99% homology to the type strain at both loci. These results suggest that five out of the six clinical isolates belong to species other than A. strictum or that the A. strictum taxon is genetically diverse. Based upon these sequence data, the clinical isolates were placed into three genogroups.     

Posttraumatic stress symptoms in parents of children with acute burns

OBJECTIVE: To develop a model of risk factors for posttraumatic stress disorder (PTSD) symptoms in parents of children with burns. METHODS: Immediately following the burn and 3 months later, parents reported on their children's and their own psychological functioning and traumatic stress responses. RESULTS: Approximately 47% of the parents reported experiencing significant posttraumatic stress symptoms 3 months after the burn. Our model indicates three independent pathways to PTSD symptoms (i.e., parent-child conflict, parents' dissociation, and children's PTSD symptoms). Additionally, parents' anxiety predicted increased parent-child conflict, conflict with extended family and size of the burn predicted parents' dissociation, and size of the burn and children's dissociation predicted children's PTSD symptoms. CONCLUSIONS: This study suggests that many parents of children with burns suffer from posttraumatic stress symptoms. Interventions that target factors such as family conflict, children's symptoms, and parents' acute anxiety and dissociation may diminish the risk for PTSD.     

Massively parallel signature sequencing profiling of fetal human neural precursor cells

We have examined gene expression in multipotent neural precursor cells (NPCs) derived from human fetal (f) brain tissue and compared its expression profiles with embryonic stem (ESC) cells, embryoid body cell (EBC), and astrocyte precursors using the technique of massively parallel signature sequencing (MPSS). Gene expression profiles show that fNPCs express core neural stem cells markers and share expression profiles with astrocyte precursor cells (APCs) rather than ESC or EBC. Gene expression analysis shows that fNPCs differ from other adult stem and progenitor cells in their marker expression and activation of specific functional networks such as the transforming growth factorbeta (TGFbeta) and Notch signaling pathways. In addition, our results allow us to identify novel genes expressed in fNPCs and provide a detailed profile of fNPCs.     

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

Objective

Recent studies have demonstrated that lymphovascular space invasion (LVSI) is associated with increased risk of hematogenous and lymphatic metastasis and poor clinical outcome of women with epithelial ovarian cancer. Given the suspected role of estrogen in promoting ovarian cancer metastasis, we examined potential links between estrogen receptor and LVSI in high-grade serous ovarian carcinoma.

Methods

Tumoral expression of ER, PR, p53, MDR1, EGFR, HER2, DNA ploidy, and S-phase fraction was examined for 121 cases of stage I–IV high-grade serous ovarian carcinoma samples obtained at primary cytoreductive surgery. Biomarker expression was correlated to LVSI and survival outcomes.

Results

LVSI was observed in 101 (83.5%) of all cases. Immunohistochemistry of tested biomarkers showed ER (86.7%) to be the most commonly expressed followed by p53 (71.4%), HER2 (68.3%), EGFR (52.1%), MDR-1 (14.3%), and PR (8.9%). ER expression was positively correlated to PR expression (r = 0.31, p = 0.001). LVSI was only correlated with ER (odds ratio 6.27, 95%CI 1.93–20.4, p = 0.002) but not with other biomarkers. In multivariate analysis, ER remained significantly associated with LVSI (p = 0.039). LVSI remained a significant prognostic factor for decreased progression-free survival (HR 3.01, 95%CI 1.54–5.88, p = 0.001) and overall survival (HR 2.69, 95%CI 1.18–6.23, p = 0.021) while ER-expression did not remain as a significant variable in multivariate analysis.

Conclusion

Our data demonstrated that estrogen receptor was positively correlated with LVSI that was an independent prognostic indicator of poor survival outcomes of high-grade serous ovarian carcinoma. This study emphasizes the importance of estrogen pathway in promoting lymphatic or vascular spread of high-grade serous ovarian carcinoma.     

Distinctive anthropometric characteristics of women with mitral valve prolapse

We examined the hypothesis that mitral valve prolapse is often associated with an inherited, anthropometrically distinct habitus. Using standard echo- and phonocardiographic techniques, we identified 60 subjects with mitral valve prolapse, 21 first-degree relatives (12 with mitral valve prolapse and nine normal) and a control group of 57 normal women. Patients with “silent” (echo only) mitral valve prolapse or the Marfan syndrome were excluded. Analysis of measurements taken of the first 39 patients and 46 control subjects revealed that, in relation to their height, patients with mitral valve prolapse had narrower anteroposterior chest diameters and longer arm spans than did the women in the control group. Linear discriminant analysis produced the equation: Z = 17.511 + 98.6 (anteroposterior chest diameter/height) ? 27.3 (arm span/height). Those with mitral valve prolapse tended to score below zero (mean, ?0.62), whereas normal subjects tended to score above zero (mean, 0.39; p < 0.001). The equation was tested prospectively on 53 subjects, including the 21 family members, and correctly classified 75 percent of all unrelated subjects and 86 percent of the family members as normal or having mitral valve prolapse. Both mitral valve prolapse and discriminant classification followed an autosomally dominant pattern of inheritance. We conclude that a significant proportion of patients with mitral valve prolapse have an autosomally dominant, inherited, anthropometrically distinct habitus, suggesting that mitral valve prolapse is only one component of a generalized developmental syndrome.     

Stroke risk in women: the role of menopause and hormone therapy

Although women have a lower risk of stroke during middle age than men, the menopausal transition is a time when many women develop cardiovascular risk factors. Additionally, during the 10 years after menopause, the risk of stroke roughly doubles in women. Endogenous oestrogen concentrations decline by 60% during the menopausal transition, leading to a relative androgen excess, which could contribute to the increased cardiovascular risk factors in women. Earlier onset of menopause might affect the risk of stroke, but the data are not clear. Because of the stroke risk associated with it, hormone therapy is recommended only for treatment of vasomotor symptoms, and some formulations might be safer than others. More research is needed to understand which women are at greatest stroke risk during midlife and to identify the safest formulation, dose, and duration of hormone therapy that can be used to treat vasomotor symptoms without increasing the risk of stroke.     

Phase 1/2 pilot study of methotrexate-laurocapram topical gel for the treatment of patients with early-stage mycosis fungoides

OBJECTIVES: To assess the safety and tolerability of a topical gel formulation combining methotrexate and laurocapram and to obtain preliminary information on the therapeutic potential of methotrexate-laurocapram in patients with early-stage mycosis fungoides (stage IA or IB). DESIGN: An open-label, phase 1/2 pilot study. SETTING: Two academic referral centers. PATIENTS: Ten patients 18 years or older with histologically confirmed stage IA or IB mycosis fungoides.Intervention The gel formulation of methotrexate-laurocapram was applied to the total body surface, excluding genital, perianal areas, nipples, face, and skin under the breasts, on an every-other-day basis for 24 consecutive weeks. MAIN OUTCOME MEASURES: The safety of methotrexate-laurocapram was assessed in this study by reviewing adverse events and laboratory data. Efficacy outcomes included changes in lesion condition and severity assessments, reduction in area of sample lesions, and the investigator's global evaluation. RESULTS: Adverse events consisted of skin reactions of mild severity. No clinically significant laboratory abnormalities were observed. Based on the investigator's global evaluation at the end of the treatment phase (week 24), 7 (78%) of 9 patients demonstrated a slight-to-moderate response to treatment with methotrexate-laurocapram. Statistical significance (P =.049) was reached for induration and pruritus, a trend (P =.10) was observed for erythema, and no change was found for scaling (P =.37). CONCLUSIONS: These findings indicate that the topical administration of methotrexate-laurocapram is safe and in general well tolerated. This treatment may represent a new therapeutic potential for patients with mycosis fungoides.     

Protein Kinase C Translocation and Src Protein Tyrosine Kinase Activation Mediate Isoflurane-induced Preconditioning In Vivo: Potential Downstream Targets of Mitochondrial Adenosine Triphosphate-sensitive Potassium Channels and Reactive Oxygen Species

Background: The authors tested the hypotheses that protein kinase C (PKC)-specific isoform translocation and Src protein tyrosine kinase (PTK) activation play important roles in isoflurane-induced preconditioning in vivo.

Methods: Rats (n = 125) instrumented for measurement of hemodynamics underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion and received 0.9% saline (control); PKC inhibitors chelerythrine (5 mg/kg), rottlerin (0.3 mg/kg), or PKC-[epsilon]V1-2 peptide (1 mg/kg); PTK inhibitors lavendustin A (1 mg/kg) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1; 1 mg/kg); mitochondrial adenosine triphosphate-sensitive potassium channel antagonist 5-hydroxydecanote (10 mg/kg); or reactive oxygen species scavenger N-acetylcysteine (150 mg/kg) in the absence and presence of a 30-min exposure to isoflurane (1.0 minimum alveolar concentration) in separate groups. Isoflurane was discontinued 15 min before coronary occlusion (memory period). Infarct size was determined using triphenyltetrazolium staining. Immunohistochemistry and confocal microscopic imaging were performed to examine PKC translocation in separate groups of rats.

Results: Isoflurane significantly (P < 0.05) reduced infarct size (40 +/- 3% [n = 13]) as compared with control experiments (58 +/- 2% [n = 12]). Chelerythrine, rottlerin, PKC-[epsilon]V1-2 peptide, lavendustin A, PP1, 5-hydroxydecanote, and N-acetylcysteine abolished the anti-ischemic actions of isoflurane (58 +/- 2% [n = 8], 50 +/- 3% [n = 9], 53 +/- 2% [n = 9], 59 +/- 3% [n = 6], 57 +/- 3% [n = 7], 60 +/- 3% [n = 7], and 53 +/- 3% [n = 6], respectively). Isoflurane stimulated translocation of the [delta] and [epsilon] isoforms of PKC to sarcolemmal and mitochondrial membranes, respectively.