High expression of nitric oxide synthases is a favorable prognostic sign in non-small cell lung carcinoma

Immunohistochemical expression of neuronal (n), endothelial (e), and inducible (i) NOS and their association with the type, grade, apoptotic index, proliferation of tumors and the survival of patients were investigated in 89 biopsies of non-small cell lung carcinoma (NSCLC). In tumor cells, expression of iNOS was detected in 35/89 (40%) cases, while 79/89 (89%) and 72/89 (81%) cases showed weak to intense positivity for eNOS and nNOS, respectively. Strong eNOS staining was seen significantly more often in adenocarcinomas than in squamous cells carcinomas (p=0.016), and iNOS immunoreactivity was seen more often in grade I-II tumors than in grade III tumors (p=0.024). There was no significant difference between the low and high apoptotic indexes or between the low and high proliferation rates of tumors in any instance of NOS staining. The patients with tumors showing high nNOS expression tended to have better survival than the others (p=0.06, log-rank; p=0.04, Bresow; p=0.048, Tarone-Ware). Similarly, the patients with tumors showing high expression of iNOS, eNOS and nNOS, as determined by a combined sum index, had a better survival than those with a low sum index for these enzymes (p<0.05). The results show intense expression of eNOS and nNOS, and moderate expression of iNOS in tumor cells of non-small cell carcinoma. Intense NOSs expression seems to be a favorable prognostic sign in non-small cell lung carcinoma.     

The effects of 28-day early-life exposure to triphenyl phosphate (TPhP) on odor preference and sexual behavior in female rats

Many chemical substances are detectable in house dust, and they are consequently taken into our bodies via the mouth and nose. Triphenyl phosphate (TPhP), a flame retardant that has an estrogen-like effect in vitro, is present in house dust at high concentrations. Estrogen exposure during development has significant influences on reproductive behavior in rodents, and its effects persist until maturity. In the present study, we investigated the effect of early life exposure to TPhP on the reproductive behavior of female rats. Oral treatment with TPhP (25 or 250 mg/kg), ethinyl estradiol (EE; 15 μg/kg) as a positive control, or sesame oil as a negative control, were given to female rats (from birth to 28 days of age). The 8-week-old rats were bilaterally ovariectomized. At 12–15 weeks of age, the rats were subjected to odor preference and sexual behavior tests. In the odor preference test, the oil group showed significantly higher preference for male odor than female odor, but the low-dose TPhP treatment group lost the preference for male odor, indicating a possible outcome of early life TPhP exposure on sexual recognition. In the sexual behavior test, both the EE and TPhP treatment groups displayed significantly less proceptive behavior. These results suggest that early life exposure to TPhP disturbs the normal sexual behavior of female rats.     

Derivation of in vivo source tracking error thresholds for TRUS-based HDR prostate brachytherapy through simulation of source positioning errors

PurposeThe purpose of this study was to simulate treatment planning source positioning errors in transrectal ultrasound–based real-time high-dose-rate prostate brachytherapy treatments and determine appropriate in vivo source tracking error thresholds.Methods and MaterialsTreatment planning source positioning errors were simulated for 20 patient plans in the brachytherapy treatment planning system by manually adjusting the dwell position coordinates within selected catheters without plan reoptimization. The change in dose-volume histogram (DVH) indices was calculated as a function of the source positioning error. The magnitude of the change in the DVH indices was then used to derive appropriate in vivo source tracking error thresholds.ResultsSource positioning error thresholds to prevent potentially significant changes in prostate (target) DVH metrics ranged from 2 to 5 mm, dependent on the direction of the source positioning error, as well as the relative weight of the dwell position within the plan, and its position relative to the patient anatomy. Source positioning error thresholds to prevent potentially clinically significant changes in organ at risk DVH metrics were found to be complex and patient-dependent.ConclusionsIn vivo source tracking error thresholds for transrectal ultrasound–based real-time high-dose-rate prostate brachytherapy were investigated via the simulation of treatment planning source positioning errors. These error thresholds were found to be dependent not only on the direction of the error, but also on the endpoint. There is still the potential for larger changes in DVH indices to occur for catheter shifts smaller than the proposed threshold levels in this study.     

Activated microglia in a rat stroke model express NG2 proteoglycan in peri‐infarct tissue through the involvement of TGF‐β1

We investigated activated microglia in ischemic brain lesions from rats that had been subjected to transient middle cerebral artery occlusion. Activated microglia expressing NG2 chondroitin sulfate proteoglycan (NG2) were found only in the narrow zone (demarcation zone) that demarcated the peri‐infarct tissue and ischemic core. NG2^? activated microglia were abundantly distributed in the peri‐infarct tissue outside the demarcation zone. NG2⁺ microglia but not NG2^? microglia expressed both CD68 and a triggering receptor expressed on myeloid cells 2 (TREM‐2), suggesting that NG2⁺ microglia eliminated apoptotic neurons. In fact, NG2⁺ microglia often attached to degenerating neurons and sometimes internalized NeuN⁺ or neurofilament protein⁺ material. Kinetic studies using quantitative real‐time RT‐PCR revealed that expression of transforming growth factor‐β1 (TGF‐β1) was most evident in the ischemic core; with this marker produced mainly by macrophages located in this region. TGF‐β receptor mRNA expression peaked at 3 days post reperfusion (dpr) in the peri‐infarct tissue, including the demarcation zone. Primary cultured rat microglia also expressed the receptor mRNA. In response to TGF‐β1, primary microglia enhanced the expression of NG2 protein and TREM‐2 mRNA as well as migratory activity. A TGF‐β1 inhibitor, SB525334, abolished these effects. The present results suggest that TGF‐β1 produced in the ischemic core diffused toward the peri‐infarct tissue, driving activated microglial cells to eliminate degenerating neurons. Appropriate control of NG2⁺ microglia in the demarcation zone might be a novel target for the suppression of secondary neurodegeneration in the peri‐infarct tissue. GLIA 2014;62:185–198     

Delayed maturation of interstitial cells of Cajal in meconium obstruction

Background/Purpose: The etiology of meconium obstruction without cystic fibrosis is unclear. Interstitial cells of Cajal (ICC) function as pacemakers in gut motility and may play a role in the pathophysiology of the disease. Methods: The ICC were examined by immunohistochemical staining with anti-c-kit antibody in the bowel walls of 6 neonates who had meconium obstruction without cystic fibrosis, and the results were compared with specimens from normal neonates (n = 2). Results: Six patients underwent ileostomy between 2 and 15 days after birth, and 5 of them presented with microcolon. Ganglion cells were present in the ileum and colon. Whereas ICC were evenly distributed in the control specimens, they were not seen at the time of ileostomy in the colons of 2 patients, and the other 4 showed scanty distribution in muscle layers. However, ileum showed normal distribution of ICC in all patients. The ileostomies were closed between 39 and 104 days of age, and the ICC distribution was changed to a normal pattern in the colons of all 6 patients. Their bowel movements were restored to normal after closure. Conclusion: The findings of this study suggest that delayed maturity of ICC may be a cause of meconium obstruction without cystic fibrosis.     

Electrostimulation at sensory level improves function of the upper extremities in children with cerebral palsy: a pilot study

The aim of this study was to evaluate the effect of electrical stimulation (ES) on the function of the upper extremities in children with cerebral palsy (CP). The participants were 12 children (seven females and five males) with spastic hemiplegia (mean age 5 years 7 months, SD 3 years 9 months). Indications were weak wrist dorsiflexion and elbow extension. The ES was given at sensory level (20–40 minutes) on the infraspinatus muscle and on the wrist dorsiflexors during 12 regularly scheduled physical and occupational therapy sessions (during 4–5 weeks). The Goal Attainment Scale, the Zancolli classification of hand function, muscle testing according to Daniels and Worthington, and King hypertonicity scale were used for evaluation. Assessments were made twice before (between 4 weeks) and twice after (between 12 weeks) the stimulation period except the King hypertonicity scale, which was used once before and 3 months after the stimulation period. Active elbow extension, wrist dorsiflexion, and forearm supination with the elbow flexed and extended improved when the results of assessments before ES were compared with those made immediately before (p < 0.001) and three months after (p < 0.01) this treatment. Results of this pilot uncontrolled study suggest that ES at sensory level can be used as an adjunct to physiotherapy and/or occupational therapy in children with spastic hemiplegia. These results will be used as basis for further research.     

Immunization of Early Adolescent Females with Human Papillomavirus Type 16 and 18 L1 Virus-Like Particle Vaccine Containing AS04 Adjuvant

PurposeIn female individuals 15–25-years of age, the AS04-containing human papillomavirus (HPV)–16/18 vaccine is highly immunogenic and provides up to 100% protection against HPV-16/18 persistent infection and associated cervical lesions up to 4.5 years. Optimal cervical cancer prevention will require prophylactic vaccination against oncogenic HPV 16 and 18 before the onset of sexual activity in early adolescent girls. To establish the feasibility of vaccination in girls 10–14 years of age, we compared the immunogenicity and safety in early adolescent female individuals to those 15–25 years in whom vaccine efficacy has been demonstrated.MethodsWe enrolled 773 female participants aged 10–14 years and 15–25 years to receive the HPV-16/18 L1 VLP AS04 vaccine, which was administered at months 0, 1, and 6. Serum samples were collected at months 0 and 7; antibodies to HPV 16 and 18 VLPs were measured by enzyme-linked immunosorbent assay. Vaccine safety was assessed at 7 or 30 days after each dose; serious adverse events were recorded during the entire study period.ResultsBoth age groups achieved 100% seroconversion for HPV 16 and 18. Participants in the group aged 10–14 years were not only noninferior to those 15–25 years in terms of HPV 16 and 18 seroconversion rates but also had approximately twice as high geometric mean titers. The vaccine was generally safe and well tolerated.ConclusionsThese findings suggest that HPV vaccination during early adolescence is generally safe, well tolerated, and highly immunogenic. The observed higher antibody titers in the group 10–14 years of age are likely to result in longer antibody persistence. Overall, these data support the implementation of prophylactic HPV vaccination in this age group.