Photorefractive keratectomy for myopia and myopic astigmatism correction using the WaveLight Allegretto Wave Eye-Q excimer laser system

To analyze photorefractive keratectomy (PRK) outcomes in myopia and myopic astigmatism correction using the WaveLight Allegretto Wave Eye-Q^® excimer laser system (WaveLight Laser Technologie AG, Erlangen, Germany). 222 eyes of 151 patients underwent PRK (mean age 33.5 ± 6.8 years). Pre-operative best spectacle-corrected visual acuity (BSCVA) ranged from 0.4 to ?0.1 logMAR (mean ?0.03 ± 0.06). Mean spherical equivalent (SE) was ?3.29 ± 1.20 D. Efficacy, predictability and safety were evaluated. Minimum follow-up was 3 months. Accountability at 3 and 6 months was 100 and 54 %, respectively (median follow-up 5 months, mean 5.2 ± 2.6 months). At 3 months, mean uncorrected visual acuity (UCVA) was ?0.02 ± 0.07 logMAR, BSCVA ?0.03 ± 0.05 logMAR, efficacy index 0.98 and safety index 1.02. UCVA was ≥20/16 in 40.1 %, ≥20/20 in 86.5 % and ≥20/25 in 98.2 %. Mean SE was ?0.02 ± 0.20 D. Residual refractive error was ± 0.13 D in 81.5 %, ± 0.25 D in 88.7 % and ± 0.50 D in 97.7 %. At 6 months, outcomes were similar: mean UCVA was ?0.02 ± 0.07 logMAR, BSCVA ?0.03 ± 0.06 logMAR, efficacy index 1.00 and safety index 1.03. UCVA was ≥20/16 in 43.7 %, ≥20/20 in 86.6 % and ≥20/25 in 96.6 %. Mean SE was ?0.02 ± 0.17 D. Residual refractive error was ± 0.13 D in 86.6 %, ± 0.25 D in 93.3 % and ± 0.50 D in 98.3 %. Refractive stability was achieved at 3 months. No patient lost more than one line of BSCVA. There were no retreatments. The WaveLight Allegretto Wave Eye-Q is effective, predictable and safe in low-to-moderate myopia and myopic astigmatism PRK correction.     

Evolution of TRIM5α B30.2 (SPRY) domain in New World primates

The tripartite motif 5 protein (TRIM5) has been extensively studied in view of its ability to restrict retroviruses in mammalian hosts. The B30.2 domain, encoded by exon 8 of TRIM5, contains the major restriction determinants. We have analyzed the genetic diversity of the TRIM5 B30.2 domain in a wide range of New World primates (NWP). The TRIM5 region encoding the B30.2 domain of 35 animals, representing all NWP families and 10 genera, was PCR-amplified, sequenced and analyzed at the amino acid level. Comparisons were carried out with available GenBank data; analyses were carried out with a dataset of 44 representative sequences of 32 NWP species and 15 genera, with a human B30.2 sequence as outgroup. A high genetic diversity was observed, both with respect to length and amino acid substitutions, mainly at the three variable regions of this domain associated with the restriction phenotype. Phylogenetic reconstructions based on B30.2 DNA differed from the consensus NWP topology due to positive selection along different lineages and definite codon positions, with robust evidence either with a complete or a pruned dataset. This was especially evident in codons 406 and 496, consistently demonstrated with all methods. Positive selection was virtually absent in all NWP species when analyzing intra-specific polymorphisms except for Saguinus labiatus. Our findings indicated that NWP TRIM5 proteins have been subjected to selection, probably by retroviruses and/or retroelements. We anticipate that the diversity of NWP TRIM5 is indicative of disparate retroviral restriction phenotypes representing a plentiful source of factors countering HIV infection.     

Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity

Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer’s disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-β (oAβ) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAβ challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aβ precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aβ toxicity.

Alzheimer’s disease (AD) is the most prevalent of all the neurodegenerative disorders. Distinct protein inclusions, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) characterize the AD brain (1). The exact causes of neuronal cell death in AD are still debated but several neuropathological studies have linked neuronal death to unexpected reappearance of cell cycle events (2–4). Accordingly, cell cycle activation, aberrant DNA replication, as well as aneuploidy have been found in neurons of AD brains (5–11). Furthermore, numbers of aneuploid neurons that are rare in control brains were increased in AD brains (5, 12, 13). However, mitosis itself has not been reported, and it appears that postmitotic neurons in AD patients cannot complete the cell cycle (14). In dividing cells, the coordination of the cell cycle requires interplay between cyclins and cyclin-dependent kinases (CDKs) at different checkpoints and the transitions between different phases are tightly regulated (15, 16). Therefore, it has been suggested that cell cycle reentry of differentiated mature neurons would have detrimental consequences, rendering them vulnerable and contribute to neurodegeneration (4, 8, 17). However, it remains unclear whether cell cycle events are a prerequisite for neuronal death, and why aneuploid neurons accumulate in AD brains.The introduction of the fluorescent ubiquitination-based cell cycle indicator (FUCCI) system enabled live tracking of cell cycle progress in dividing cells (18) and has been valuable in understanding the implications of the cell cycle in disease pathogenesis, e.g., in cancer (19–21).Briefly, the FUCCI system allows live monitoring of the cell cycle in cells, visualized by the ectopic expression of red and green fluorescent-tagged truncated proteins, mKO2-hCdt1 (30-120) and mAG-hGem (1-110), respectively, distinguishing the G1 from S, G2, and M phases (22). While frequently used in cancer and developmental biology research (23–25) to our knowledge, the FUCCI system has not been used to study mature neurons, including in the context of neurodegenerative diseases.Here, we applied FUCCI to primary hippocampal neuronal cultures challenged with oligomeric Aβ (oAβ) and transgenic mice with expression of mutant human amyloid precursor protein (APP), which are both established models of AD (26–29). By obtaining quantitative and qualitative information about cell cycle events (CCEs) in response to Aβ, we show that increased FUCCI reporter activity was associated with resistance to Aβ-induced cell death, which is contrary to the current opinion of CCEs contributing to neurodegeneration in AD.     

Community-Partnered Cluster-Randomized Comparative Effectiveness Trial of Community Engagement and Planning or Resources for Services to Address Depression Disparities

BACKGROUND

Depression contributes to disability and there are ethnic/racial disparities in access and outcomes of care. Quality improvement (QI) programs for depression in primary care improve outcomes relative to usual care, but health, social and other community-based service sectors also support clients in under-resourced communities. Little is known about effects on client outcomes of strategies to implement depression QI across diverse sectors.

OBJECTIVE

To compare the effectiveness of Community Engagement and Planning (CEP) and Resources for Services (RS) to implement depression QI on clients’ mental health-related quality of life (HRQL) and services use.

DESIGN

Matched programs from health, social and other service sectors were randomized to community engagement and planning (promoting inter-agency collaboration) or resources for services (individual program technical assistance plus outreach) to implement depression QI toolkits in Hollywood-Metro and South Los Angeles.

PARTICIPANTS

From 93 randomized programs, 4,440 clients were screened and of 1,322 depressed by the 8-item Patient Health Questionnaire (PHQ-8) and providing contact information, 1,246 enrolled and 1,018 in 90 programs completed baseline or 6-month follow-up.

MEASURES

Self-reported mental HRQL and probable depression (primary), physical activity, employment, homelessness risk factors (secondary) and services use.

RESULTS

CEP was more effective than RS at improving mental HRQL, increasing physical activity and reducing homelessness risk factors, rate of behavioral health hospitalization and medication visits among specialty care users (i.e. psychiatrists, mental health providers) while increasing depression visits among users of primary care/public health for depression and users of faith-based and park programs (each p?<?0.05). Employment, use of antidepressants, and total contacts were not significantly affected (each p?>?0.05).

CONCLUSION

Community engagement to build a collaborative approach to implementing depression QI across diverse programs was more effective than resources for services for individual programs in improving mental HRQL, physical activity and homelessness risk factors, and shifted utilization away from hospitalizations and specialty medication visits toward primary care and other sectors, offering an expanded health-home model to address multiple disparities for depressed safety-net clients.     

Prognostic value of RT-PCR tyrosinase detection in peripheral blood of melanoma patients

Malignant melanoma (MM) prognosis has been related to tumour thickness and clinical stage and metastasis risk has been associated with presence of tumour cells in peripheral blood. The aim of this study was to determine the relationship between presence of tyrosinase in peripheral blood of MM patients and their clinical prognosis. Blood samples from 58 MM patients (stage I-IV) were analysed, using RT-PCR assay to detect tyrosinase mRNA. The results showed that positive RT-PCR assay for tyrosinase were significantly associated with clinical status and tumour thickness. After a median follow-up of 24 months, RT-PCR results were found to be significant correlated with recurrence (p<0.05) and clinical stage III (p<0.05). Separate analysis of stage III tumours to determine the prognostic value of tyrosinase presence in peripheral blood showed an overall 24-month survival rate of 70% in the RT-PCR negative group versus 10% in the positive group (p<0.02). These results suggest that detection of circulating melanoma cells may be especially relevant in stage III patients, in whom RT-PCR positivity defines a subpopulation at high risk of recurrence.     

Intrathecal anti-CD20 antibody: an effective and safe treatment for leptomeningeal lymphoma

A patient with relapsed B cell non-Hodgkin lymphoma (NHL) infiltrating the Central nervous system (CNS) and resistant to chemotherapy was treated with intrathecal Rituximab (IT RTX), administered weekly for eight weeks at increasing doses, from 10 to 40 mg. After the second administration the patient showed significant clinical improvement and Cerebro spinal fluid (CSF) clearance of lymphomatous cells. A MRI scan performed after 30 days from the start of therapy showed full regression of lymphomatous infiltration. This report confirms the efficacy and safety of IT RTX in the treatment of CNS B-cell NHL.