Clinimetric properties of relevant criteria for assessing writing and drawing orientation after right hemisphere stroke.

BACKGROUND: Writing and drawing orientation is rarely assessed in clinical routine, although it might have a potential value in detecting impaired verticality perception after right hemispheric stroke (RHS). Assessment tools and criteria must be conceived and validated. We therefore explored the clinimetric properties of a set of quantitative writing and drawing orientation criteria, their ranges of normality, and their tilt prevalence in RHS individuals. NEW METHODS: We asked 69 individuals with subacute RHS and 64 matched healthy controls to write three lines and to copy the Gainotti Figure (house and trees). We determined six criteria referring to the orientation of writing and drawing main axes: for writing, the line and margin orientations, and for drawing, the tree, groundline, wall, and roofline orientations. Orientations were measured by using an electronic protractor from specific landmarks positioned by independent evaluators. RESULTS: The set of criteria fulfilling all clinimetric properties (feasibility, measurability, reliability) comprised the line orientation of the writing and the wall and roofline orientations of the drawing. Writing and drawing tilts were frequent after RHS (about 30% by criterion). COMPARISON WITH EXISTING METHODS: So far, graphomotor orientation was mostly tested qualitatively and could not be objectively appreciated in absence of validated tools and criteria, and without ranges of normality. Writing and drawing tilts may now be assessed both in routine clinical practice and research. CONCLUSIONS: Our study paves the way for investigating the clinical determinants of graphomotor tilts, including impaired verticality perception, to better understand their underlying mechanisms.

Gelatin implant in the treatment of open-angle glaucoma: Safety and efficacy in real-life conditions.

OBJECTIVE: To evaluate the safety and efficacy of the Xen® implant for the treatment of open-angle glaucoma. MATERIAL AND METHOD: Retrospective study including patients who received the Xen® implant between January 2019 and December 2020 in a university hospital. Demographic and medical data were collected using DxCare® software. The primary endpoint was a 20% reduction in intraocular pressure (IOP) at 12 months according to Société Française du Glaucome (SFG) recommendations. The secondary endpoints were decrease in glaucoma medications and incidence of adverse events. RESULTS: Fifty-three patients (65 eyes) were included (sex ratio 0.65, age 75.38±7.31 years). IOP decreased by 18.51% from 17.86±4.22mmHg to 14.55±2.66mmHg (P<0.05). The number of glaucoma medications was 2.16±1.01 preoperatively vs 0.49±0.94 postoperatively (P<0.05). Adverse events included 8 malpositionings, 3 of which required reoperation, 1 case of increased IOP resolved by trabeculectomy, 1 case of venous ischemia treated by photocoagulation, 3 choroidal detachments and 3 corneal ulcers. Needling was required for 18 eyes. CONCLUSION: At 12 months, the IOP was lower than previously reported in the literature (14.55 vs 15.90mmHg, P<0.05), probably due to a lower preoperative IOP. The number of postoperative medications was similar to the literature (0.49 vs 0.40, P=0.51), as was the frequency of needling (27.69% vs 32.00%, P=0.36). The frequency of malpositioning was higher (12.31% vs 7.70%, P<0.05), probably due to the management of complicated patients. The efficacy of Xen® was in line with recommendations. It would be interesting to compare the efficacy of Xen® with trabeculectomy.

Identification of neutralising pembrolizumab anti-drug antibodies in patients with melanoma.

Development of anti-drug antibodies (ADAs) can interfere with therapeutic monoclonal antibodies and may lead to drug neutralisation and clinical disease progression. Measurement of circulating drug levels and development of ADAs in the setting of anti-programmed cell death-1 agent pembrolizumab has not been well-studied. Enzyme-linked immunosorbent assays were used to measure pembrolizumab drug level and ADAs in 41 patients with melanoma at baseline, Time-point 1 (3 weeks) and Time-point 2 (21 weeks). Assay results were related to patient demographics and clinical outcome data at 6 months. The median pembrolizumab drug level at 3 weeks was 237 ng/µL and did not correlate with age, sex or body surface area.17/41 patients had an ADA detected at any timepoint, with the highest prevalence at Timepoint 1 (median concentration = 17 ng/µL). The presence of an ADA did not correlate with clinical progression at 6 months. 3/41 (7%) of patients displayed a falling pembrolizumab drug level and rising ADA titre between Timepoint 1 and 2 suggestive of a neutralising ADA. Pembrolizumab drug levels and ADAs can be readily measured. The rates of total and treatment-emergent ADAs may be higher in "real-word" settings than those previously reported. Larger studies are needed to determine effect of neutralising ADAs on long-term clinical outcome.

Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis.

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg ). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not IN-COL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg , reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis.

Effects of Obesity on the Regulation of Macrophage Population in the Prostate Tumor Microenvironment.

Obesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions. Matrigel invasion chambers were used to assess macrophage recruitment in vitro, and immunohistochemical analysis evaluated recruitment in a PTEN knockout mouse model. qPCR was used to measure mRNA levels of CCL2, COX-2, IL-10, TGF-beta, VEGF-A, arginase-1, and MMP-9. PGE2 production was measured by ELISA. Obesity increased macrophage and TAM recruitment, and increased mRNA levels of TAM markers in macrophages. Similarly, obese conditions increased CCL2 and COX-2 expression, as well as PGE2 levels in prostate cancer cells. COX-2 inhibition resulted in lower expression of obesity-induced TAM markers. Our data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway.

Functional Characterisation of Eel Dopamine D2 Receptors and Involvement in the Direct Inhibition of Pituitary Gonadotrophins.

In various vertebrate species, dopamine (DA) exerts an inhibitory action on reproduction. In the European eel, DA plays a pivotal role in the inhibitory control of gonadotroph function and the blockade of puberty. In vivo studies have suggested that this effect is mediated by receptors pharmacologically related to the D2 family. In the European eel, two distinct D2 receptor (D2-R) paralogous genes have been identified (D2A-R and D2B-R) and both were shown to be expressed in the pituitary. We investigated the potential role of each paralogue in the control of gonadotroph function in this species. Eel recombinant D2A-R or D2B-R were expressed in HEK 293 cells, with a universal Gα subunit, and receptor activation was followed by inositol phosphate production. Recombinant D2-Rs exhibited a comparable affinity for DA, although they had differential affinities for mammalian D2-R agonists and antagonists, supporting subtle structure/activity differences. Furthermore, using eel pituitary cell primary cultures, the expression by gonadotroph cells of both native eel D2-R paralogues was examined by in situ hybridisation of D2A-R or D2B-R transcripts, coupled with immunofluorescence of luteinising hormone (LH)ß or follicle-stimulating (FSH)ß. LH and to a lesser extent, FSH cells expressed both D2-R transcripts but with a clear predominance of D2B-R. Notably, D2B-R transcripts were detected for the majority of LH cells. Accordingly, using these cultures, we showed that DA potently inhibited basal and testosterone-stimulated LHß expression and less potently basal and activin-stimulated FSHß expression. We also tested some D2-R antagonists, aiming to select the most adequate one to be used in innovative protocols for induction of eel sexual maturation. We identified eticlopride as the most potent inhibitor of DA action on basal and stimulated LH expression in vitro. Our data suggest a differential functionalisation of the duplicated receptor genes and demonstrate that mainly D2B-R is involved in the dopaminergic inhibitory control of eel gonadotroph function.

Optimal electrode length to match patient specific cochlear anatomy.

Cochlear implantation (CI) has reached over years of practicing high standards of surgical outcomes. Even patients with significant residual hearing are nowadays benefiting from a cochlear implant. However, the speech perception still depends to great extent on the adequate pitch match between the frequency components delivered by an electrode array and individual cochlear tonotopic map. Compression, deletion or shift of frequency components can be tolerated by patients only to some extent. Furthermore, low frequency information delivered to the cochlear apex is particularly important for spatial hearing. It is therefore important to use the electrode array of an appropriate length for each individual cochlea. The large variability in the anatomy makes this task difficult as a single design does not fit all cochlear shapes. Fortunately, preoperative CT imaging, routinely taken in most of ENT clinics, can be exploited also for the prediction of the cochlear duct length (CDL). It turns out that a single radiological measurement, the diameter of the basal turn, is highly correlated with CDL and its measurement can be used for the informed selection of the most suitable electrode array length from the available array portfolio for each CI patient.

Anti-androgens act jointly in suppressing spiggin concentrations in androgen-primed female three-spined sticklebacks - prediction of combined effects by concentration addition.

Increasing attention is being directed at the role played by anti-androgenic chemicals in endocrine disruption of wildlife within the aquatic environment. The co-occurrence of multiple contaminants with anti-androgenic activity highlights a need for the predictive assessment of combined effects, but information about anti-androgen mixture effects on wildlife is lacking. This study evaluated the suitability of the androgenised female stickleback screen (AFSS), in which inhibition of androgen-induced spiggin production provides a quantitative assessment of anti-androgenic activity, for predicting the effect of a four component mixture of anti-androgens. The anti-androgenic activity of four known anti-androgens (vinclozolin, fenitrothion, flutamide, linuron) was evaluated from individual concentration-response data and used to design a mixture containing each chemical at equipotent concentrations. Across a 100-fold concentration range, a concentration addition approach was used to predict the response of fish to the mixture. Two studies were conducted independently at each of two laboratories. By using a novel method to adjust for differences between nominal and measured concentrations, good agreement was obtained between the actual outcome of the mixture exposure and the predicted outcome. This demonstrated for the first time that androgen receptor antagonists act in concert in an additive fashion in fish and that existing mixture methodology is effective in predicting the outcome, based on concentration-response data for individual chemicals. The sensitivity range of the AFSS assay lies within the range of anti-androgenicity reported in rivers across many locations internationally. The approach taken in our study lays the foundations for understanding how androgen receptor antagonists work together in fish and is essential in informing risk assessment methods for complex anti-androgenic mixtures in the aquatic environment.

Kinda baboons (Papio kindae) and grayfoot chacma baboons (P. ursinus griseipes) hybridize in the Kafue river valley, Zambia.

The ranges of small kinda (Papio kindae) and much larger grayfooted chacma (P. ursinus griseipes) baboons adjoin in the Kafue National Park, Zambia. In a visual survey of baboons at 48 sites in the Kafue River drainage we found that, contrary to previous reports, groups at the species interface near the town of Ngoma are phenotypically diverse and presumably formed by multigenerational hybridization. Mitochondrial and/or Y-chromosome genetic markers from fecal samples (N=164) collected at 29 sites support this conclusion. Groups with phenotypic signs of a history of hybridization also had taxon-specific mitochondria and Y-haplotypes from both parental species. Although the distribution of mitochondrial haplotypes largely mirrored that of external phenotypes, a significant proportion of male specimens from grayfoot as well as hybrid groups carried kinda Y-chromosomes, and kinda Y-chromosomes were involved in all observed cases of mitochondrial/Y-chromosome discordance. These observations are consistent with, though they do not prove, a population history in which the range of chacmas and the hybrid zone have advanced at the expense of the kinda range. They also suggest that, unexpectedly, kinda male×chacma female matings are much more common than the reciprocal cross in the ancestry of hybrids. We suggest that distinctive male kinda behavior and the "juvenile" appearance of kinda baboons of both sexes, perhaps combined with obstetric difficulties of a small kinda female carrying the large offspring of a chacma male, may account for this bias.

Role of Mangifera indica bark polyphenols on rat gastric mucosa against ethanol and cold-restraint stress.

This study was carried out in order to investigate the potential and antioxidant effects of polyphenols from Mangifera indica stem bark against gastric damage induced by ethanol and cold-restraint stress. The polyphenols possess good capacity for scavenging nitric oxide (NO) radical and ferric-reducing antioxidant power (FRAP) assay in vitro. Rats were sacrificed after the experiment, and their stomachs were removed for biochemical and histopathological analysis. The severity of lesions was found to markedly decrease by the administration of polyphenols in both models. The increased gastric nitrite level of ethanol administered rats were significantly (p < 0.001) reduced by polyphenol treatment. Administration of polyphenols reduced thiobarbituric acid reactive substance (TBARS) level and increased the GSH level significantly in a dose-dependent manner in both models. Our study revealed the ulcer-protective effects of the polyphenols and could possibly reside for the most part on its anti-radical effects.

Use of cutaneous flap for continent cystostomy (daoud technique).

PURPOSE: We present the results of a new technique using a pedicled cutaneous flap for continent cystostomy. MATERIALS AND METHODS: A total of 15 boys and 8 girls (mean +/- SD age 13.4 +/- 6.4 years) underwent continent cystostomy for neurogenic bladder (20), bladder exstrophy (2) and sequelae of hypospadias (1) between 1999 and 2008. In this procedure a rectangular pedicled flap is surgically elevated from a hairless area on the abdomen. The flap is tubularized and passed through the anterior abdominal wall directly into the bladder. A submucosal detrusor incision is made to expose the bladder mucosa, and the distal part of the flap is anastomosed to the bladder mucosa in a circular manner. The tube is positioned along the incised detrusor, which is closed over. Viability of the flap, self-catheterization management and continence status are then evaluated. RESULTS: Mean +/- SD followup was 4.5 +/- 3.1 years. There was 1 case of distal necrosis of the flap, which required a secondary surgery using the Mitrofanoff technique. The 22 remaining flaps were initially viable, although 2 patients were eventually lost to followup and 3 subsequently presented with false-passage incidents requiring a few days of calibration using a balloon catheter. Dryness was achieved immediately in 73% of the cases. After adding a complementary bulking agent the dryness rate reached 77%. CONCLUSIONS: We present a novel approach to continent cystostomy that is safe and easy to perform. This technique is a less invasive and more efficient alternative to other commonly used approaches.

Electrode features for hearing preservation and drug delivery strategies.

BACKGROUND/AIMS: Reducing the risk of hearing loss after cochlear implantation requires optimization of the electrode array to minimize the physical trauma caused by insertion and placement. Furthermore, the electrode design must be optimized for atraumatic surgical approaches. Even greater levels of protection may be achieved by the use of a drug during and after implantation. The electrode array offers a potential vehicle for drug delivery. METHODS: This article reviews the laboratory and clinical data available thus far relating to the importance of electrode design parameters for trauma minimization, and the possibility of further reduction through pharmaceutical intervention. Candidate drugs were identified through literature review and laboratory evaluation. The most promising have been investigated in vitro and in animal models of implantation trauma. Three delivery devices are currently under development to satisfy the specific demands of different therapy regimes. The delivery profiles of each were evaluated through both modelling and bench testing and the concepts investigated in vitro and in vivo. RESULTS: Current evidence favours a thin, flexible electrode array with wires in a zigzag shape. Steroids and an apoptosis inhibitor (AM111) performed well in animal models of electrode trauma and are both good drug candidates for reduction of the risk of hearing loss after implantation. Semi-chronic dexamethasone elution, acute drug delivery by intracochlear catheter, and longer-term delivery through diffusion from a reservoir were all shown to be feasible. CONCLUSION: An extensive programme focussed on minimizing hearing loss through device optimization and the development of new technologies has yielded positive results and new concepts for further development and clinical application.

Risks of ingestion of aflatoxin-contaminated groundnuts in Benin: scale measurements, beliefs, and socioeconomic factors.

This study evaluates farmers' beliefs and perceived risks of aflatoxin (AF) on the consumption, production, and marketing of groundnuts. A survey was conducted with 181 farmers in Benin to assess their beliefs of AF effects on the marketing of groundnuts, and finally human and animal health. Awareness and action factors were also evaluated. Relationships of the belief and action factors with socioeconomic variables were evaluated using multiple indicators and multiple causes (MIMIC) models within a socioeconomic framework using a health belief model (HBM). The results indicate that the scale of the various constructs is reliable and the validity conforms to expectations. The unifactorial models developed in this study provide a satisfactory fit with NFl, CFI, and GFI exceeding 0.90. The results reveal that gender, age, and years of experience in farming significantly impact farmers' action regarding the reduction of AF in groundnut production and marketing. Male farmers are more likely to be aware of AF problems in groundnuts and feel more susceptible to the problems than their female counterparts. Gender and education seem to be dominating factors in the perception of barriers to mitigating the effects of AF, and male and older farmers are more likely to perceive the benefits of producing and marketing good quality groundnuts.

Free radical scavenging and anti-inflammatory properties of Lagerstroemia speciosa (L).

The in vitro antioxidant activity of the successive extracts (ethyl acetate, ethanol, methanol and water) of the leaves of Lagerstroemia speciosa L. (Lythraceae) were studied by examining their superoxide, hydroxyl ion scavenging and by measuring lipid peroxidation. The ethyl acetate and ethanol extracts were found to possess greater antioxidant property than the methanol and water extracts. Anti-inflammatory activity of the ethyl acetate and ethanol extracts were examined using the carrageenan-induced acute inflammation and formalin-induced (chronic) paw edema models. In acute and chronic inflammation models, the ethyl acetate extract reduced the paw edema significantly in a dose-dependent manner. Whereas, ethanol extract did not show dose-dependent activity. This results suggests that the anti-inflammatory activity is possibly attributed to its free radical scavenging activity. It was found that ethyl acetate extract reduced the inflammation more significantly than the ethanol extract.

Measuring bidirectional mutation.

The estimation of mutation rates is usually based on a model in which mutations are rare independent Poisson events. Back-mutation of mutants, an even rarer event, is ignored. In the hypermutating B cells of the immune system, mutation between phenotypes exhibiting, vs. not exhibiting, surface immunoglobulin is common in both directions. We develop three strategies for the estimation of mutation rates under circumstances such as these, where mutation rates in both directions are estimated simultaneously. Our model for the growth of a cell culture departs from the classical assumption of cell division as a memoryless (Poisson) event; we model cell division as giving rise to sequential generations of cells. On this basis, a Monte-Carlo simulation is developed. We develop also a numerical approach to calculating the probability distribution for the proportion of mutants in each culture as a function of forward- and backward-mutation rates. Although both approaches are too computationally intensive for routine laboratory use, they provide the insight necessary to develop and evaluate a third, 'hand-calculator' approach to extracting mutation rate estimators from experiments of this type.

Amelioration of cisplatin induced nephrotoxicity in mice by an ethyl acetate extract of Lagerstroemia speciosa (L).

We studied an ethyl acetate (EtoAC) extract of leaves obtained from the medicinal and ornamental tree, Lagerstroemia speciosa L, for nephroprotective activity in cisplatin-induced acute renal injury in Balb/C mice. The EtoAC extract at dose levels of 50 and 250 mg/kg showed a dose-dependent reduction in cisplatin-induced elevations in urea and creatinine concentrations. Additionally, treatment with the EtoAC extract prevented the cisplatin-induced decline of the renal antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and reduced glutathione. The findings suggest that the EtoAC extract from L. speciosa possesses marked nephroprotective activity and could offer a promising role in the treatment of acute renal injury caused by a nephrotoxin like cisplatin.