Early hyperdopaminergic state following sub-thalamic nucleus deep brain stimulation in Parkinson disease.

BACKGROUND: Hyperdopaminergic state (HS), especially impulse control behaviors (ICBs), are not rare in Parkinson's disease (PD). Controversial data regarding HS prevalence one year following sub-thalamic nucleus deep brain stimulation (STN-DBS) are reported. OBJECTIVE: Our objectives were to describe early postoperative HS (PoOHS) including ICBs, hypomania and psychotic symptoms during the first 3 months following STN-DBS (V1) and their prognosis at 1 year (V2). METHODS: This descriptive study included 24 PD patients treated successively with bilateral STN-DBS between 2017 and 2019. The primary endpoint was prevalence of PoOHS at V1 according to the Ardouin Scale of Behaviour in Parkinson's Disease. RESULTS: Prior to STN-DBS (V0), 25% patients had HS (only ICBs) whereas at V1 (during the 3 first months), 10 patients (41.7%) had one or several HS (P=0.22) (de novo in 29.2%): 7 (29.2%) ICBs, 4 (16.7%) hypomanic mood, 1 (4.7%) psychotic symptoms. At V2, all V0 and V1 HS had disappeared, while 1 patient (4.2%) presented de novo HS (P<0.01). No correlation was found between the occurrence of PoOHS at V1 and any V0 data. Higher levodopa equivalent dose of dopamine agonists at V1 was correlated with ICB at V1 (P=0.04). CONCLUSION: We found that early PoOHS are frequent in PD after STN-DBS, mostly de novo, with ICBs and hypomania being the most frequent. Despite a good prognosis of PoOHS at one year, our work emphasizes the importance of both a cautious adjustment of dopamine agonist doses and a close non-motor monitoring pre- and post-STN-DBS in PD.

Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study.

BACKGROUND: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. METHODS: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. RESULTS: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). CONCLUSION: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

Survey on patients' organisations' knowledge and position paper on screening for inherited neuromuscular diseases in Europe.

BACKGROUND: The development of new genetic testing methods and the approval of the first treatments raises questions regarding when and how to perform screening for inherited neuromuscular conditions. Screening directives and access to the different techniques is not uniform across Europe. The patient advisory board of the European reference network for rare neuromuscular diseases (NMD) conducted a qualitative study to understand the state of play of screening for inherited NMD in Europe and patients' needs. RESULTS: We collected answers from 30 patient organisations (POs) from 18 European countries. Fifteen acknowledge the existence of pre-implantation genetic diagnosis in their country. Regarding prenatal screening, we had 25 positive answers and 5 negative ones. Twenty-four POs mentioned that newborn screening was available in their country. We had some contradictory answers from POs from the same country and in some cases; diseases said to be part of the screening programmes were not hereditary disorders. Twenty-eight organisations were in favour of screening tests. The reasons for the two negative answers were lack of reimbursement and treatment, religious beliefs and eventual insurance constrains. Most POs (21) were in favour of systematic screening with the option to opt-out. Regarding the timing for screening, "at birth", was the most consensual response. The main priority to perform screening for NMDs was early access to treatment, followed by shorter time to diagnostic, preventive care and genetic counselling. CONCLUSIONS: This is the first study to assess knowledge and needs of POs concerning screening for NMDs. The knowledge of POs regarding screening techniques is quite uneven. This implies that, even in communities highly motivated and knowledgeable of the conditions they advocate for, there is a need for better information. Differences in the responses to the questions "how and when to screen" shows that the screening path depends on the disease and the presence of a disease modifying treatment. The unmet need for screening inherited NMDs should follow an adaptive pathway related to the fast moving medical landscape of NMDs. International coordination leading to a common policy would certainly be a precious asset tending to harmonize the situation amongst European countries.

Bacteriohopanepolyols along redox gradients in the Humboldt Current System off northern Chile.

Marine oxygen minimum zones (OMZs) are characterized by the presence of subsurface suboxic or anoxic waters where diverse microbial processes are responsible for the removal of fixed nitrogen. OMZs have expanded over past decades and are expected to continue expanding in response to the changing climate. The implications for marine biogeochemistry, particularly nitrogen cycling, are uncertain. Cell membrane lipids (biomarkers), such as bacterial bacteriohopanepolyols (BHPs) and their degradation products (hopanoids), have distinctive structural attributes that convey information about their biological sources. Since the discovery of fossil hopanoids in ancient sediments, the study of BHPs has been of great biogeochemical interest due to their potential to serve as proxies for bacteria in the geological record. A stereoisomer of bacteriohopanetetrol (BHT), BHT II, has been previously identified in OMZ waters and has as been unequivocally identified in culture enrichments of anammox bacteria, a key group contributing to nitrogen loss in marine OMZs. We tested BHT II as a proxy for suboxia/anoxia and anammox bacteria in suspended organic matter across OMZ waters of the Humboldt Current System off northern Chile, as well as in surface and deeply buried sediments (125-150 ky). The BHT II ratio (BHT II/total BHT) increases as oxygen content decreases through the water column, consistent with previous results from Perú, the Cariaco Basin and the Arabian Sea, and in line with microbiological evidence indicating intense anammox activity in the Chilean OMZ. Notably, BHT II is transported from the water column to surface sediments, and preserved in deeply buried sediments, where the BHT II ratio correlates with changes in δ15 N sediment values during glacial-interglacial transitions. This study suggests that BHT II offers a proxy for past changes in the relative importance of anammox, and fluctuations in nitrogen cycling in response to ocean redox changes through the geological record.

The use of adjunctive antipsychotics to treat depression in UK primary care.

OBJECTIVE: Adjunctive antipsychotic therapy can be prescribed to patients with depression who have inadequate response to antidepressants. This study aimed to describe the use of adjunctive antipsychotics over a time period that includes the authorization in 2010 of prolonged-release quetiapine as the first adjunct antipsychotic to be used in major depressive disorder in the UK. RESEARCH DESIGN AND METHODS: Adults with an episode of depression between January 1, 2005 and July 31, 2013 were identified from antidepressant prescriptions and depression diagnoses in the UK Clinical Practice Research Datalink. Patients with prior records of bipolar disorder, schizophrenia, or antipsychotic prescriptions were excluded. MAIN OUTCOME MEASURES: Rates of adjunct antipsychotic initiation and characteristics and management of patients with adjunct antipsychotics. RESULTS: Of 224,353 adults with depression, 5,807 (2.6%) initiated adjunct antipsychotic therapy. Overall incidence of antipsychotic initiation was 7.4 per 1,000 patient-years (95% CI = 7.2-7.6). Between 2005-2013, the overall rate did not change, although initiation of typical antipsychotic prescribing decreased (57.7% to 29.1%), while atypical antipsychotics, especially quetiapine (14.1% to 49.7%), increased. Of those who initiated antipsychotics, 59.4% were women (typical antipsychotics = 62.8%, atypical antipsychotics = 56.1%) and median age was 46 years (typicals = 49 years, atypicals = 44 years). CONCLUSIONS: Antipsychotics were rarely used to treat depression between 2005-2013 in UK primary care. The choice of adjunctive antipsychotic therapy changed over this time, with atypical antipsychotics now representing the preferred treatment choice. However, information on patients strictly cared for in other settings, such as by psychiatrists or in hospitals, potentially more severe patients, was unavailable and may differ. Nonetheless, the high off-label use in primary care, even after the authorization of quetiapine, suggests that there is a need for more licensed treatment options for adjunctive antipsychotic therapy in major depressive disorder.

Radiocarbon constraints on the extent and evolution of the South Pacific glacial carbon pool.

During the last deglaciation, the opposing patterns of atmospheric CO2 and radiocarbon activities (Δ(14)C) suggest the release of (14)C-depleted CO2 from old carbon reservoirs. Although evidences point to the deep Pacific as a major reservoir of this (14)C-depleted carbon, its extent and evolution still need to be constrained. Here we use sediment cores retrieved along a South Pacific transect to reconstruct the spatio-temporal evolution of Δ(14)C over the last 30,000 years. In ∼2,500-3,600 m water depth, we find (14)C-depleted deep waters with a maximum glacial offset to atmospheric (14)C (ΔΔ(14)C=-1,000‰). Using a box model, we test the hypothesis that these low values might have been caused by an interaction of aging and hydrothermal CO2 influx. We observe a rejuvenation of circumpolar deep waters synchronous and potentially contributing to the initial deglacial rise in atmospheric CO2. These findings constrain parts of the glacial carbon pool to the deep South Pacific.

Pharmacotherapeutic strategies for patients treated for depression in UK primary care: a database analysis.

OBJECTIVE: To investigate long-term patterns of antidepressant treatment in patients in primary care in the UK, and to assess their healthcare resource use and disease outcomes. RESEARCH DESIGN AND METHODS: A retrospective longitudinal cohort study was conducted using the Clinical Practice Research Datalink. The study population comprised patients aged ≥18 years with depression receiving a prescription for antidepressant monotherapy between 1 January 2006 and 31 December 2011 with no antidepressants within the preceding 6 months. Recovery was defined by timing of antidepressant prescriptions (≥6 months without treatment). Treatment lines and strategies (switching, combining, augmenting and resuming medication) were analyzed. Healthcare resource use for the different treatment strategies and periods of no therapy was assessed. RESULTS: Data from 123,662 patients (287,564 treatment lines) were analyzed. Switching and resumption of treatment were more frequent than other strategies. Recovery was highest with first-line monotherapy (45% of patients), while as a second-line strategy switching was more successful (43%) than combination or augmentation. In subsequent lines of treatment, switching was associated with successively lower rates of recovery (31% in the third line and 24% from the fourth line onwards). Similar rates were observed for resumption. Healthcare resource use was greater during antidepressant use than treatment-free periods. Augmentation was associated with the highest proportions of patients with a psychiatrist referral, psychologist referral and psychiatric hospitalization. CONCLUSIONS: This study provides extensive real-world information on the prescribing patterns and treatment outcomes for a large cohort of patients treated for depression with antidepressants in primary care. Switching is more frequently used than augmentation or combination treatment, with decreasing effectiveness across successive lines. Key limitations of the study were: (i) risk of selection bias due to the use of inclusion criteria based on depression diagnoses recorded by the practitioner; and (ii) reliance on prescribing patterns as proxies for clinical outcomes, such as recovery.

Increased dust deposition in the Pacific Southern Ocean during glacial periods.

Dust deposition in the Southern Ocean constitutes a critical modulator of past global climate variability, but how it has varied temporally and geographically is underdetermined. Here, we present data sets of glacial-interglacial dust-supply cycles from the largest Southern Ocean sector, the polar South Pacific, indicating three times higher dust deposition during glacial periods than during interglacials for the past million years. Although the most likely dust source for the South Pacific is Australia and New Zealand, the glacial-interglacial pattern and timing of lithogenic sediment deposition is similar to dust records from Antarctica and the South Atlantic dominated by Patagonian sources. These similarities imply large-scale common climate forcings, such as latitudinal shifts of the southern westerlies and regionally enhanced glaciogenic dust mobilization in New Zealand and Patagonia.

Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas.

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.

[The role of the French Agence de la biomédecine in lung transplantation]. / Le rôle de l'Agence de la biomédecine dans la greffe pulmonaire.

The Agence de la biomédecine is a public institution in charge of organs tissues cells transplantation, reproduction, embryology and genetics. It interacts with the hospital coordinators and the transplant teams and ensure the regulation of organ retrieval and allocation. Its strategic missions are the revision of the graft allocation rules and the optimization of transplant organization. These last years, after redefining the graft selection criteria, the activity of lung transplantation increased drastically. The lung procurement efficacy must be still improved, while various machines of perfusion are going to be available. In July 2007, a national priority status for the patients with a life-threatening condition in the very short-term was put in place. The use of a graft allocation score taking into account the urgency and the individual benefit from transplantation is in evaluation. The optimization of the patient access to the waiting list needs a network approach of the end-stage lung diseases.

[Epidermolysis bullosa acquisita of childhood]. / Epidermolyse bulleuse acquise de l'enfant.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a subepidermal autoimmune blistering disease characterized immunologically by autoantibodies to type VII collagen. Its occurrence in childhood is rare. Thirty-five cases have been described to date in the literature. PATIENTS AND METHODS: We report the case of an 8-year-old girl presenting blistering lesions on the cheeks, extremities and limb extension areas. The diagnosis of EBA was confirmed by histology, direct immunofluorescence of a perilesional skin biopsy specimen, indirect immunofluorescence on salt-split skin substrate and direct electron microscopy. The patient was controlled clinically under treatment with dapsone alone. DISCUSSION: This 36th childhood case of EBA presented typical clinical features, a similar prognosis and comparable treatment response to other paediatric cases. Clinical presentation is inflammatory and affects the face. As in our case, in childhood, prognosis is often better than in adults without the need for immunosuppressive agents.

[Surgical treatment of hidradenitis suppurativa: a retrospective study of 93 cases]. / Maladie de Verneuil: étude rétrospective chez 93 malades traités chirurgicalement.

INTRODUCTION: Hidradenitis suppurativa is a chronic disease, severe forms of which may be highly invalidating. Although wide surgery is usually considered the most effective curative therapy, few medical teams in France have extensive experience of this approach. Our aim was to evaluate the clinical history and the results of surgery in all patients operated with curative intent in an experienced centre. PATIENTS AND METHODS: Medical records were reviewed for all patients operated between January 1985 and January 2007. In addition, the patients were contacted by telephone and/or letter and asked about their clinical history, the repercussions of their disease on their daily lives, postsurgical relapse and their overall satisfaction regarding surgery. Separate analyses were carried out for patients and for individual operated sites. RESULTS: Of 93 patients followed-up for between one and 205 months (mean: 30 months), 209 anatomical sites were operated with curative intent, using either limited excision (i.e. including all visible lesions without margins) or wide excision (i.e. including all lesions with a significant margin). The disease had been present for an average of 7.6 years before surgical treatment, with onset seven years earlier in women. Most patients had previously received multiple and often unsuitable medical treatments. Patients' personal and professional lives were highly affected. Surgery required hospitalization for an average duration of 6.6 days, caused complications in 21% of cases and was often perceived as trying. Relapse in the operated areas occurred in 33% of cases and this was more frequent after limited excision. Nevertheless, 74% of patients were ultimately satisfied with their surgical treatment and most regarded surgery as the only really effective therapy. DISCUSSION: Our study confirms the heavy repercussions of hidradenitis suppurativa on patients' day-life as well as the value of surgical management by experienced surgeons. CONCLUSION: Wide excision remains the mainstay of therapy in extensive forms of hidradenitis suppurativa. However, this chronic, disseminated and recurrent disease continues to be insufficiently understood and innovative medical approaches, including the development of clinical trials, are required.

Methotrexate and liver function: a study of 13 psoriasis cases treated with different cumulative dosages.

BACKGROUND: The need and frequency of hepatic biopsies during methotrexate (MTX) therapy are still controversial. OBJECTIVES: The purpose of this investigation is to assess MTX liver toxicity in patients with psoriasis through percutaneous liver biopsy, and compare liver morphology changes with increasing cumulative dosages (1, 2, 3 and 4 g) of MTX. RESULTS: Cumulative dosages of 1 to 2 g MTX did not cause significant liver toxicity. From a cumulative dosage of 3 to 4 g, there is fibrosis formation, inflammation enhancement in the portal area and fibrous septa, configuring regenerative nodes. CONCLUSION: In patients with no risk factors for liver disease, with normal physical examination and liver tests, biopsy can be done after a cumulative MTX dosage of approximately 1 to 1.5 g and repeated for each gram. In patients with risk factors, liver biopsy should be done before use of MTX, or within the first 2 months of treatment at the most, and repeated for each gram of cumulative dosage.

Genomic paleontology provides evidence for two distinct origins of Asian rice (Oryza sativa L.).

The origin of rice domestication has been the subject of debate for several decades. We have compared the transpositional history of 110 LTR retrotransposons in the genomes of two rice varieties, Nipponbare (Japonica type) and 93-11 (Indica type) whose complete sequences have recently been released. Using a genomic paleontology approach, we estimate that these two genomes diverged from one another at least 200,000 years ago, i.e., at a time which is clearly older than the date of domestication of the crop (10,000 years ago, during the late Neolithic). In addition, we complement and confirm this first in silico analysis with a survey of insertion polymorphisms in a wide range of traditional rice varieties of both Indica and Japonica types. These experimental data provide additional evidence for the proposal that Indica and Japonica rice arose from two independent domestication events in Asia.