Determining neuropsychological impairment using estimates of premorbid intelligence: comparing methods based on level of education versus reading scores.

When inferring brain dysfunction, test scores are typically compared to normative data based on estimates of premorbid intelligence (e.g., by educational level or reading scores). However, these methods are likely to lead to differing results, with important diagnostic and forensic implications. The current study compared estimates of impairment (reported in z-scores) based on educational level versus reading scores in a population with traumatic brain injury. The study included 174 patients (M age = 27.3; M education = 12.3) evaluated as outpatients at a university hospital rehabilitation department. Wilcoxen ranked sign tests indicated that the two methods yielded estimates that were statistically different (p <.0001) for all variables. The education based method yielded greater estimates of impairment than the reading score method for WAIS-R FIQ. Grip Strength, and Finger Tapping, with a pattern of generally consistent impairment across cognitive/motor areas (z-score range = -0.59 to -.97). In contrast, the reading score based method yielded greater estimates of impairment in processing speed (Trails A) and flexibility (Trails B), with a wider range of impairment noted between cognitive and motor domains (z-score range = +0.21 to -2.95). Clinical implications are discussed.     

A COMPARISON OF NSP-RETICULONS WITH CONVENTIONAL NEUROENDOCRINE MARKERS IN IMMUNOPHENOTYPING OF LUNG CANCERS

Neuroendocrine-specific protein (NSP)-reticulons are endoplasmic reticulum-associated protein complexes, which have been identified as markers for neuroendocrine differentiation. In this study, the expression of two members of the family of NSP-reticulons, NSP-A and NSP-C, have been investigated in different types of lung cancer and compared with the expression patterns of five conventional neuroendocrine markers, the neural cell adhesion molecule (NCAM), synaptophysin, chromogranin A, Leu-7, and neurofilament proteins. NSP-A and NSP-C antibodies were reactive with most carcinoid tumour and small cell lung carcinoma (SCLC) cases, while atypical carcinoid tumours showed a variable expression. In the total group of neuroendocrine tumours, a high concordance of expression was found between NSP-A and NSP-C, while their expression correlated well with NCAM and synaptophysin positivity. Chromogranin A, Leu-7, and neurofilament proteins were shown to be expressed to a limited extent in these neuroendocrine tumours. In a selected group of non-SCLCs known to exhibit neuroendocrine features, NSP-A expression was detected at much higher frequency than NSP-C. In virtually all NSP-A positive cases, this expression was associated with one or more of the other neuroendocine markers. NSP-A expression showed a stronger correlation with conventional neuroendocrine markers than NCAM. In detecting neuroendocrine differentiation in non-SCLC, NSP-A is more sensitive than synaptophysin, chromogranin A, Leu-7, and neurofilament proteins. It is concluded that NSP-reticulons are valuable markers in the diagnosis of neuroendocrine differentiation in non-SCLC and should be used in conjunction with NCAM. © 1997 John Wiley & Sons, Ltd.     

Bullet and blast ENT injuries in counter-insurgency area

Background: Many ENT injuries are not recognized easily, but they have the potential of increasing the morbidity.     

Effects of naloxone upon the behavioural organisation of specific defeat activities in intruder mice: assessment by cluster analysis

The present experiment examined the effects of naloxone (0.5, 2.5 and 12.5 mg/kg) upon the responses of male Swiss mice to attack by aggressive male conspecifics in the resident-intruder paradigm by measuring the time spent in broad behavioural categories, frequency of individual acts or postures, and performing a cluster analysis of activities according to their frequency and position within the behavioural sequence. The former two measures detected little naloxone-induced change in behaviour. Cluster analysis revealed changes in behavioural organisation which suggested modification in the motivation and/or function underlying specific defeat behaviour.     

Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients

Introduction

Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing.

Methods

A total of 100 patients with early-onset breast cancer (?? 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues.

Results

We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.

Conclusions

Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.     

Comparison of pneumatic retinopexy with alternative surgical techniques

To determine the efficacy of pneumatic retinopexy, the authors conducted a retrospective study of 56 cases of uncomplicated retinal detachments (RDs) treated with this technique (follow-up, 6-18 months). These were compared with 28 similar cases treated with a Lincoff balloon and 78 similar cases treated with a scleral buckle. The long-term success rates for these three groups were 71, 64, and 96%, with the incidence of new breaks being 20, 18, and 1.3% respectively. In aphakic or pseudophakic patients with an absent or ruptured posterior capsule, the success rate for pneumatic retinopexy was only 43%. In phakic and aphakic patients with an intact posterior capsule, the success rate for pneumatic retinopexy improved to 81%. These data suggest that this technique is less effective in aphakic or pseudophakic patients with an absent or ruptured posterior capsule and that careful follow-up to detect new breaks is necessary in all cases. A prospective randomized study is needed to verify these data.     

Bromodomain inhibition overcomes treatment resistance in distinct molecular subtypes of melanoma

Therapy of BRAF-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF-mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS- and NF1-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.

Melanoma is the fifth most common malignancy in the Unites States, with an estimated 106,110 new cases in 2021 (1). The death toll attributed to melanoma has decreased sharply, owing in part to the revolution that has taken place in the therapy of advanced disease, with significant advances both in immunotherapeutic and targeted interventions. In the realm of targeted therapy, the efficacy of small molecule inhibitors targeting mutant BRAF in metastatic melanoma (2, 3) represented a landmark in the targeted therapy of cancer. Subsequently, the combination of BRAF and MEK inhibition resulted in increased response rates and prolonged survival (4–6). More recently, durable responses have been reported with BRAF/MEK-targeted therapy (7). However, despite these clear improvements in patient outcome, many patients eventually progress. As a result, the development of acquired resistance to targeted agents constitutes a significant clinical obstacle. While numerous mechanisms of resistance to targeted therapy have been described (8), many of these mechanisms result in reactivation of the mitogen activated protein kinase (MAPK) pathway in which BRAF operates (9, 10). Therefore, new therapeutic approaches will be required to increase the proportion of responding patients, the durability of the responses observed, and to resensitize melanoma cells to BRAF inhibitors upon the development of acquired resistance. To date, few effective targets for combinatorial therapy with BRAF inhibitors (beyond MEK) have been identified, and none that have proved superior to the BRAFi/MEKi combination.Previously, we identified an important role for the BPTF gene in melanoma progression, and as a potential therapeutic target (11). BPTF promotes melanoma progression by activating a cascade of gene expression including ERK, BCL2, and BCL-XL, resulting in promotion of cell-cycle progression and suppression of apoptosis. BPTF gene silencing resulted in abrogation of the proliferative and metastatic potential of melanoma cells and in sensitization to BRAF inhibition (11).Recently, bromodomain inhibition has emerged as a novel approach to cancer therapy. Bromodomains are protein motifs that bind to acetylated lysine residues on histones, with a critical role in chromatin remodeling (12, 13). The development of ligands targeting the BET (bromodomain and extracellular-terminal) family member BRD4 (14) demonstrated the potential of small molecule inhibition of the bromodomain-acetyl-lysine interaction and is being pursued actively in the clinical arena. However, BET family bromodomains do not share significant sequence homology with that of BPTF (15), indicating that distinct inhibitors will be required to effectively target BPTF. Collectively, these observations suggest the potential utility of a bromodomain inhibitor, alone or in combination with MAPK pathway inhibition, as a rational therapeutic strategy for melanoma, which represents the focus of the current analysis.     

Changes in 12-month outcomes over time for age-related macular degeneration,diabetic macular oedema and retinal vein occlusion

ObjectivesTo identify whether the outcomes of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in routine clinical practice have changed over time.MethodsWe analysed 12-month outcomes in treatment-naïve eyes that started aflibercept or ranibizumab for nAMD (3802 eyes), DMO (975 eyes), Branch RVO (BRVO, 357 eyes), Central RVO (CRVO, 371 eyes) and Hemi-RVO (HRVO, 54 eyes) from 2015 and 2019 tracked in the prospectively designed observational Fight Retinal Blindness! Registry.ResultsThe mean VA change at 12-month for each year between 2015 and 2019 remained stable or otherwise showed no discernible trends over time in eyes with nAMD (+3.3 to +6 letters), DMO (+3.6 to +6.7 letters) and RVO (+10.3 to +11.7 letters for BRVO, +5.9 to +17.7 letters for CRVO and 10.2 to 20.7 letters for HRVO). The median number of VEGF-inhibitor injections in eyes that completed 12-month follow-up also remained stable at 8–9 for nAMD, 6–7 for DMO, 7–9 for RVO. Fewer eyes (<one-fourth) that started treatment between 2015 and 2018 and more eyes starting in 2019 did not complete 12-month’s follow-up visit. The mean VA in non-completers at their last visit was higher than that of their baseline visit.ConclusionsTreatment patterns and outcomes for nAMD, DMO and RVO in routine clinical practice have stabilised over the past 5 years at levels inferior to those reported by the pivotal phase 3 studies. A conscious effort to treat these conditions more intensively, or with longer lasting agents, would likely improve outcomes further in our patients.Subject terms: Outcomes research, Education