The contribution of rat studies to contemporary knowledge of Major Depressive Disorder: Results from citation analysis

Funding: This study was financed by Animalfree Research—Switzerland, a grant from the Johns Hopkins Center for Alternatives to Animal Testing (CAAT) and by Portuguese National Funds through FCT—Fundação para a Ciência e a Tecnologia, within the CFCUL Unit funding UIDB/00678/2020. TM thanks partial support by CEAUL (funded by FCT—Fundação para a Ciência e a Tecnologia, Portugal, through the project UID/MAT/00006/2019). FP thanks FCT/MCTES for the financial support to CESAM (UIDP/50017/2020 and UIDB/50017/2020), through national funds. Open access publication costs were covered by Animalfree Research-Switzerland and by funding provided by the Ketty and Leif Hjordt Foundation.Major depressive disorder (MDD) is the most severe depression type and one of the leading causes of morbidity worldwide. Animal models are widely used to understand MDD etiology, pathogenesis, and treatment, but the efficacy of this research for patients has barely been systematically evaluated. Such evaluation is important given the resource consumption and ethical concerns incurred by animal use. We used the citation tracking facilities within Web of Science and Scopus to locate citations of original research papers on rats related to MDD published prior to 2013—to allow adequate time for citations—identified in PubMed and Scopus by relevant search terms. Resulting citations were thematically coded in eight categories, and descriptive statistics were calculated. 178 publications describing relevant rat studies were identified. They were cited 8,712 times. More than half (4,633) of their citations were by other animal studies. 794 (less than 10%) were by human medical papers. Citation analysis indicates that rat model research has contributed very little to the contemporary clinical understanding of MDD. This suggests a misuse of limited funding hence supporting a change in allocation of research and development funds targeting this disorder to maximise benefits for patients.Publisher PDFPeer reviewe

Ocular albinism with infertility and late-onset sensorineural hearing loss

Ocular albinism type 1 (OA1) is caused by mutations in the GPR143 gene located at Xp22.2. The manifestations, which are due to hypopigmentation, are confined to the eyes and optic pathway. OA1 associated with late-onset sensorineural hearing loss was previously reported in a single family and hypothesized to be caused by a contiguous gene deletion syndrome involving GPR143 and the adjacent gene, TBL1X. Here, we report on a family with OA1, infertility, late-onset sensorineural hearing loss, and a small interstitial Xp microdeletion including the GPR143, TBL1X, and SHROOM2 genes. In addition, we re-examined a patient previously described with OA1, infertility and a similar Xp deletion with audiologic follow-up showing a late-onset sensorineural hearing loss. Our results raise an intriguing question about the possibility for TBL1X (absence) involvement in this type of hearing loss. However, our study cannot claim a causative relationship and more convincing evidence is needed before the hypothesis can be accepted that TBL1X could be involved in late-onset sensorineural hearing loss and that ocular albinism with late-onset sensorineural hearing loss can present itself as a contiguous gene deletion/microdeletion syndrome. The finding of infertility in all affected male patients demonstrates that this deletion, including the SHROOM2 gene, may be a potentially causative X-linked genetic factor of male infertility

In vivo quantification of rolling and adhered leukocytes in human sepsis

Abstract Background The use of in vivo videomicroscopy at the bedside has demonstrated microcirculatory flow disturbances in sepsis. The ability of in vivo videomicroscopy to detect changes in the prevalence of rolling and adhered leukocytes that occur in sepsis is not well-described in humans. We sought to (1) develop methodology for accessing and quantifying sublingual leukocyte rolling and adherence with sidestream dark field (SDF) imaging; (2) compare the number of rolling and adhered leukocytes between patients with septic shock and non-infected controls; and (3) compare the number of rolling and adhered leukocytes between survivors and non-survivors of septic shock. Methods We included adult (age > 18 years) patients in the emergency department presenting with septic shock prospectively enrolled in the ProCESS trial. We recruited comparison non-infected patients as emergency department controls. Using a SDF videomicroscope, we obtained image sequences from the sublingual mucosa, quantifying rolling and adhered leukocytes per 1 mm × 1 mm visual field in a standardized 3-s clip. We report data as median and interquartile range and depicted as box plots. We compared groups using the Mann-Whitney U test, considering a p value < 0.05 significant. Results We included a total of 64 patients with septic shock and 32 non-infected controls. The median number of adhered leukocytes per field in the sepsis group was 1.0 (IQR 0–3.5) compared to 0 (0–0) in the non-infected group (p < 0.001). The median number of rolling leukocytes was 26 (10.3–42) in the sepsis group and 9.8 (4.8–17.3) in the non-infected group (p < 0.001) per field. Among the patients with sepsis (n = 64), there was an increased number of adhered leukocytes in non-survivors compared to survivors (3.0 (1–5.5) vs. 1.0 (0–3.0)) (p < 0.05); however, there was no difference in rolling leukocytes (35 (20–48) vs. 26 (10–41)) (p = 0.31). Conclusions Our results demonstrated a higher number of rolling and adhered leukocytes in patients with septic shock when compared to non-infected controls, and an increased number of adhered leukocytes in non-survivors. Trial registration ClinicalTrials.gov, NCT00793442; Registered on 19 November 2008 PG0GM076659 (US NIH Grant/Contract). First submitted 18 July 2007. First posted 2 August 2007

Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14

Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia.Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations.We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11.We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Capillary Leukocytes, Microaggregates, and the Response to Hypoxemia in the Microcirculation of Coronavirus Disease 2019 Patients

OBJECTIVES In this study, we hypothesized that coronavirus disease 2019 patients exhibit sublingual microcirculatory alterations caused by inflammation, coagulopathy, and hypoxemia. DESIGN Multicenter case-controlled study. SETTING Two ICUs in The Netherlands and one in Switzerland. PATIENTS Thirty-four critically ill coronavirus disease 2019 patients were compared with 33 healthy volunteers. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The microcirculatory parameters quantified included total vessel density (mm × mm-2), functional capillary density (mm × mm-2), proportion of perfused vessels (%), capillary hematocrit (%), the ratio of capillary hematocrit to systemic hematocrit, and capillary RBC velocity (μm × s-1). The number of leukocytes in capillary-postcapillary venule units per 4-second image sequence (4 s-1) and capillary RBC microaggregates (4 s-1) was measured. In comparison with healthy volunteers, the microcirculation of coronavirus disease 2019 patients showed increases in total vessel density (22.8 ± SD 5.1 vs 19.9 ± 3.3; p < 0.0001) and functional capillary density (22.2 ± 4.8 vs 18.8 ± 3.1; p < 0.002), proportion of perfused vessel (97.6 ± 2.1 vs 94.6 ± 6.5; p < 0.01), RBC velocity (362 ± 48 vs 306 ± 53; p < 0.0001), capillary hematocrit (5.3 ± 1.3 vs 4.7 ± 0.8; p < 0.01), and capillary-hematocrit-to-systemic-hematocrit ratio (0.18 ± 0.0 vs 0.11 ± 0.0; p < 0.0001). These effects were present in coronavirus disease 2019 patients with Sequential Organ Failure Assessment scores less than 10 but not in patients with Sequential Organ Failure Assessment scores greater than or equal to 10. The numbers of leukocytes (17.6 ± 6.7 vs 5.2 ± 2.3; p < 0.0001) and RBC microaggregates (0.90 ± 1.12 vs 0.06 ± 0.24; p < 0.0001) was higher in the microcirculation of the coronavirus disease 2019 patients. Receiver-operating-characteristics analysis of the microcirculatory parameters identified the number of microcirculatory leukocytes and the capillary-hematocrit-to-systemic-hematocrit ratio as the most sensitive parameters distinguishing coronavirus disease 2019 patients from healthy volunteers. CONCLUSIONS The response of the microcirculation to coronavirus disease 2019-induced hypoxemia seems to be to increase its oxygen-extraction capacity by increasing RBC availability. Inflammation and hypercoagulation are apparent in the microcirculation by increased numbers of leukocytes and RBC microaggregates

Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14

Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia.Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations.We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11.We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society