Neuronal and glial characterization in the rostrocaudal axis of the human anterior olfactory nucleus: Involvement in Parkinson’s disease

Hyposmia is one of the prodromal symptoms of Parkinson’s disease (PD) and a red flag in clinical diagnosis. Neuropathologically, this sign correlates with α-synuclein involvement in the anterior olfactory nucleus (AON). Neurodegeneration, microgliosis, and astrogliosis in AON are poorly studied, and bulbar AON is the focus of these studies with contradictory results. Additionally, male sex is a risk marker for developing PD, but sexual dimorphism of neural and glial populations in the AON has rarely been considered. The aim of this study was to analyze the density of NeuN, Iba-1, GFAP, and Lewy bodies (LBs), as well as the relationship of these cell type markers with pathology along the rostrocaudal axis of the AON (bulbar, retrobulbar, cortical anterior, and posterior divisions). Cavalieri, optical fractionator, and area fraction fractionator stereological approaches were used for the volume, cell populations and LBs densities, area fraction, and percentage of overlap. Iba-1 and α-syn intensities were measured using ImageJ. In non-PD (NPD) cases, the volume was lower in the AON at the extremes of the rostrocaudal axis than in the intermediate divisions. Cortical anterior AON volume decreased in PD compared with NPD cases. NeuN density decreased rostrocaudally in AON portions in NPD and PD cases. This occurred similarly in Iba-1 but only in PD samples. Iba-1 intensity significantly increased in bulbar AON between PD and NPD. No changes were found in astrocytes. Eight percent of NeuN, 0.1% of Iba-1, and 0.1% of GFAP areas overlapped with LBs area along the AON portions. The data indicate that bulbar AON, which is the most rostral portion in this axis, could play a major role in the pathology. This could be related to the larger area occupied by LBs in these divisions

Cognitive Improvement After Cochlear Implantation in Older Adults With Severe or Profound Hearing Impairment: A Prospective, Longitudinal, Controlled, Multicenter Study

Objective: To compare the cognitive evolution of older adults with severe or profound hearing impairment after cochlear implantation with that of a matched group of older adults with severe hearing impairment who do not receive a cochlear implant (CI).Design: In this prospective, longitudinal, controlled, and multicenter study, 24 older CI users were included in the intervention group and 24 adults without a CI in the control group. The control group matched the intervention group in terms of gender, age, formal education, cognitive functioning, and residual hearing. Assessments were made at baseline and 14 months later. Primary outcome measurements included the change in the total score on the Repeatable Battery for the Assessment of Neuropsychological Status for Hearing impaired individuals score and on its subdomain score to assess cognitive evolution in both groups. Secondary outcome measurements included self-reported changes in sound quality (Hearing Implant Sound Quality Index), self-perceived hearing disability (Speech, Spatial, and Qualities of Hearing Scale), states of anxiety and depression (Hospital Anxiety and Depression Scale), and level of negative affectivity and social inhibition (Type D questionnaire).Results: Improvements of the overall cognitive functioning (p = 0.05) and the subdomain “Attention” (p = 0.02) were observed after cochlear implantation in the intervention group; their scores were compared to the corresponding scores in the control group. Significant positive effects of cochlear implantation on sound quality and self-perceived hearing outcomes were found in the intervention group. Notably, 20% fewer traits of Type D personalities were measured in the intervention group after cochlear implantation. In the control group, traits of Type D personalities increased by 13%.Conclusion: Intervention with a CI improved cognitive functioning (domain Attention in particular) in older adults with severe hearing impairment compared to that of the matched controls with hearing impairment without a CI. However, older CI users did not, in terms of cognition, bridge the performance gap with adults with normal hearing after 1 year of CI use. The fact that experienced, older CI users still present subnormal cognitive functioning may highlight the need for additional cognitive rehabilitation in the long term after implantation

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

¿Se endeudan más los partidos progresistas? ciclo partidista vs. ciclo electoral: Do progressive goverments undertake different debt burdens? partisan vs. electoral cycles

Public debt has traditionally been explained mainly by two political factors: a progressive ideology and the electoral cycle. The aim of this paper is to demonstrate how these two factors influence the behavior of Spanish local governments as regards indebtedness, and also how indebtedness is influenced by the interaction of ideology and the electoral cycle. Different dependence models were estimated using panel data methodology based on a sample comprised of Spanish provincial capitals and towns with populations over 50,000, for a total of 148 town councils. The time frame corresponds to the fiscal years 1988 to 2008, inclusive. The results show that in an electoral year all politicians behave opportunistically, giving rise to an important increase in public debt in relation to municipal revenue, although progressive incumbents incur three times more debt than those of the opposite ideology. Moreover, the presence of conservative parties in government has tended to significantly attenuate this behavior in years prior to elections, whereas progressive or left-wing parties have not. It must also be noted that partisan and electoral business cycles have been mitigated since 2002, when the Budgetary Stability Law came into effect, imposing limits on the debt of subnational administrations. The empirical evidence obtained points to the need to perfect internal and external control mechanisms in order to avoid a breakdown in the stability policy and the risk of debt becoming untenable, thus achieving greater budgetary discipline.El nivel de endeudamiento público ha sido explicado mediante dos factores políticos, principalmente, la ideología progresista y el ciclo electoral. El objetivo de este trabajo es evidenciar como influyen ambos factores en el comportamiento de los municipios españoles en relación con la deuda que estos asumen dada su capacidad, y como este esfuerzo se ve influenciado por la interacción entre los ciclos partidista y electoral. Se han estimado diversos modelos de dependencia, mediante metodologías de datos de panel, a partir de una muestra integrada por las capitales de provincia y los municipios españoles con una población superior a 50.000 habitantes, incluyendo un total de 148 ayuntamientos. El ámbito temporal analizado es el correspondiente a los ejercicios 1988 a 2008, ambos inclusive. Los resultados ponen de manifiesto que durante el año electoral, los políticos se comportan de manera oportunista, lo que conlleva un importante incremento de la deuda pública en relación con los ingresos municipales, aunque los partidos de ideología progresista realizan un esfuerzo tres veces mayor que los conservadores. Además, los gobiernos locales conservadores tienden a atenuar significativamente este comportamiento en los años previos a los comicios, mientras que los partidos de izquierdas no. Igualmente, se ha observado que los ciclos partidista y electoral han sido mitigados desde 2002 con la entrada en vigor de la Ley de estabilidad presupuestaria que impuso límites al endeudamiento que pueden asumir las administraciones subnacionales. La evidencia empírica obtenida pone de manifiesto la necesidad de perfeccionar los mecanismos de control internos y externos con el objetivo de evitar la ruptura de la política de estabilidad y el riesgo de insostenibilidad de la deuda, logrando una mayor disciplina presupuestaria

Differential Effects of Parkinson’s Disease on Interneuron Subtypes within the Human Anterior Olfactory Nucleus

Synucleinopathies (including α-synucleinopathies), which include Parkinson’s disease (PD), manifest themsevles early on (stage 1) in the olfactory system; preferentially in the anterior olfactory nucleus (AON). In particular, the non-motor, early manifestations of PD include hyposmia, which is the partial loss of the sense of smell. The neural basis of hyposmia in PD, however, is poorly understood; but the AON appears to be a key structure in the disease’s progression. We analyzed whether α-synuclein was involved in the differential interneuron vulnerability associated with PD in the retrobulbar, cortical anterior and cortical posterior divisions of the AON. First, we determined the expression of the calcium binding interneuron markers, calretinin, calbindin and parvalbumin, as well as non-calcium binding interneuron marker, somatostatin, in neuronal cell bodies alone (cells/mm2) and in neuronal cell bodies and neurites (% of area fraction) of post-mortem tissue from PD cases and age-matched controls (n = 4 for each) by immunofluorescent confocal microscopy. Results indicated that parvalbumin expression was upregulated in neuronal cell bodies throughout the anterior olfactory nucleus of PD cases compared with controls. Furthermore, there was increased calbindin, calretinin and parvalbumin expression in the cell bodies and neurites of neurons in the retrobulbar division and also increased parvalbumin expression in the neurites of neurons in the cortical division; calretinin expression was also increased in neuronal cell bodies and neurites in the cortical posterior division. Second, we analyzed the co-localization of the above markers with α-synuclein, with results indicating that α-synuclein co-localized with the calcium-binding proteins, but only partially with somatostatin. Taken together, these results indicate differential expression levels among different neural markers in the divisions of the AON in PD cases and point to several possibilities, among them: possible neuroprotective mechanisms of calcium-binding proteins against α-synuclein; and the differential involvement of somatostatin in α-synuclein-positive cell bodies and neurites

Neurodegeneration and contralateral α-synuclein induction after intracerebral α-synuclein injections in the anterior olfactory nucleus of a Parkinson’s disease A53T mouse model

Abstract Parkinson’s disease is characterized by a proteinopathy that includes aggregates of α-synuclein. A recent hypothesis proposes a prion-like spreading mechanism for this α-synucleinopathy. Early neuropathological deposits occur, among others, in the anterior olfactory nucleus (AON). This study investigates the anterograde and/or retrograde transmissibility of exogenous α-synuclein inoculated in the right AON of the A53T model of Parkinson’s disease and wild-type mice as well as neuronal and glial involvement. Seven experimental groups were established: wild-type injected with tracers; A53T mice injected with either α-synuclein or saline 2 months beforehand; wild-type injected with either α-synuclein or saline 2 months beforehand; and wild-type injected with either α-synuclein or saline 4 months beforehand. Weight and behavioral changes were analyzed. Immunohistochemistry against α-synuclein, NeuN, Iba-1 and GFAP was performed. Volume and marker distributions in the olfactory bulb (OB), AON and piriform cortex were analyzed using unbiased stereology. The behavioral analyses reveal higher levels of hyperactivity in transgenic as compared to wild-type mice. Tract-tracing experiments show that the main contralateral afferent projections to the dorsal AON come from the AON and secondarily from the OB. In saline-injected transgenic animals, α-synuclein expression in the OB and the AON is higher in the left hemisphere than in the right hemisphere, which could be due to basal interhemispheric differences. α-synuclein injection could provoke a significant increase in the left hemisphere of the transgenic mice’s OB, compared to saline-injected animals. Neuronal loss was observed in saline-injected transgenic mice relative to the saline-injected wild-type group. There were no overall differences in neuron number following injection of α-synuclein into either wild-type or transgenic mice, however some neuron loss was apparent in specific regions of α-synuclein injected wild-types. Microglia labeling appeared to be correlated with surgery-induced inflammation. Astroglial labeling was higher in transgenic animals, which could be due to endogenous α-synucleinopathy. This study suggests α-synucleinopathy induction, via retrograde and contralateral projections, within the olfactory system of transgenic animals