Sex-Dependent Improvement in Survival of Parkinson's Disease Patients

Background Advances in the treatment of Parkinson's disease (PD) and changes in general life expectancy may have improved survival in patients with PD.Objective The objective of this study was to investigate recent trends in PD mortality.Methods In total, 1521 patients with PD in local and national registries were followed for 11 years (2006-2016) from diagnosis until exit date or death, and the causes of death were recorded.Results The survival of men with PD improved during the follow-up period, but no change was observed in women (2-year postdiagnosis survival in men, 79.0%-86.3%, P = 0.03; 2-year postdiagnosis survival in women, 82.8%-87.5%, P = 0.42). Pneumonia was the most common immediate cause of death.Discussion The survival of men with PD has improved in Finland without a similar change in women. Because changes in treatment likely affect both sexes similarly, the results may reflect the decreasing sex gap in life expectancy. This phenomenon will likely increase the already high male-to-female prevalence ratio of PD

Molecular Gas Reservoirs of z ∼ 2 Galaxies: A Comparison of CO(1−0) and Dust-based Molecular Gas Masses

We test the use of long-wavelength dust continuum emission as a molecular gas tracer at high redshift, via a unique sample of a dozen z ~ 2 galaxies with observations of both the dust continuum and CO(1−0) line emission (obtained with the Atacama Large Millimeter Array and Karl G. Jansky Very Large Array, respectively). Our work is motivated by recent high-redshift studies that measure molecular gas masses (M_(mol)) via a calibration of the rest-frame 850 μm luminosity (L_(850 μm,rest)) against the CO(1−0)-derived M_(mol) of star-forming galaxies. We therefore test whether this method is valid for the types of high-redshift, star-forming galaxies to which it has been applied. We recover a clear correlation between the rest-frame 850 μm luminosity, inferred from the single-band, long-wavelength flux, and the CO(1−0) line luminosity, consistent with the samples used to perform the 850 μm calibration. The molecular gas masses, derived from L_(850 μm,rest), agree to within a factor of two with those derived from CO(1−0). We show that this factor of two uncertainty can arise from the values of the dust emissivity index and temperature that need to be assumed in order to extrapolate from the observed frequency to the rest-frame at 850 μm. The extrapolation to 850 μm therefore has a smaller effect on the accuracy of M_(mol) derived via single-band dust-continuum observations than the assumed CO(1−0)-to- M_(mol) conversion factor. We therefore conclude that single-band observations of long-wavelength dust emission can be used to reliably constrain the molecular gas masses of massive, star-forming galaxies at z ≳ 2

Symptoms and diagnostic delays in bladder cancer with high risk of recurrence: results from a prospective FinnBladder 9 trial

Purpose: To investigate the symptoms and delays in the clinical pathway of bladder cancer (BC).Methods: This is a substudy of a prospective, randomized, multicenter phase III study (FinnBladder 9, NCT01675219) where the efficacy of photodynamic diagnosis and 6 weekly optimized mitomycin C instillations are studied in pTa bladder cancer with high risk for recurrence. The data of presenting symptoms and critical time points were prospectively collected, and the effect of factors on delays was analyzed.Results: At the time of analysis, 245 patients were randomized. Analysis included 131 patients with primary bladder cancer and their complete data. Sixty-nine percent had smoking history and 67% presented with macroscopic hematuria. Median patient delay (from symptoms to health-care contact) was 7 days. The median general practice delay (from health-care contact to urology referral) was 8 days. Median time from urology referral to cystoscopy was 23 days and from cystoscopy to TUR-BT 21 days. Total time used in the clinical pathway (from symptom to TUR-BT) was 78 days. Current and former smokers had non-significantly shorter patient-related and general practice delays compared to never smokers. TUR-BT delay was significantly shorter in patients with malignant cytology (16 days) compared to patients with benign cytology (21 days, p = 0.03).Conclusions: Patient-derived delay was short and most of the delay occurred in the referral centers. The majority had macroscopic hematuria as the initial symptom. Surprisingly, current and past smokers were more prone to contact the health-care system compared to never smokers.</p

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular. © 2018 The Authors. Published under the terms of the CC BY 4.0 licensePeer reviewe

Striatal Pre- and Postsynaptic Profile of Adenosine A2A Receptor Antagonists

Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively

The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. In FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [I-123]IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs. The HV subjects comprised 12 women and 8 men (mean age 31 +/- 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 +/- 5 years). The FD patients had a lower left plus right average striatal binding potential (BPNP) for the caudate nucleus (p = 0.02), but not for putamen (p = 0.15), which in the FD patients was correlated with maximal ingested volume (r = 0.756, p = 0.03). The D2R BPNP in the putamen was correlated with nausea (r = 0.857, p = 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects. These preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathway

Altered orbitofrontal sulcogyral patterns in gambling disorder: a multicenter study

Gambling disorder is a serious psychiatric condition characterized by decision-making and reward processing impairments that are associated with dysfunctional brain activity in the orbitofrontal cortex (OFC). However, it remains unclear whether OFC functional abnormalities in gambling disorder are accompanied by structural abnormalities. We addressed this question by examining the organization of sulci and gyri in the OFC. This organization is in place very early and stable across life, such that OFC sulcogyral patterns (classified into Types I, II, and III) can be regarded as potential pre-morbid markers of pathological conditions. We gathered structural brain data from nine existing studies, reaching a total of 165 individuals with gambling disorder and 159 healthy controls. Our results, supported by both frequentist and Bayesian statistics, show that the distribution of OFC sulcogyral patterns is skewed in individuals with gambling disorder, with an increased prevalence of Type II pattern compared with healthy controls. Examination of gambling severity did not reveal any significant relationship between OFC sulcogyral patterns and disease severity. Altogether, our results provide evidence for a skewed distribution of OFC sulcogyral patterns in gambling disorder and suggest that pattern Type II might represent a pre-morbid structural brain marker of the disease. It will be important to investigate more closely the functional implications of these structural abnormalities in future work

AMPT-induced monoamine depletion in humans: evaluation of two alternative [123I]IBZM SPECT procedures

Purpose Acute monoamine depletion paradigms using alpha-methyl-para-tyrosine (AMPT) combined with single photon emission computed tomography (SPECT) have been used successfully to evaluate disturbances in central dopaminergic neurotransmission. However, severe side effects due to relatively high doses (4,500 to 8,000 mg) of AMPT have been reasons for study withdrawal. Thus, we assessed the effectiveness and tolerability of two alternative procedures, using lower doses of AMPT. Methods Six healthy subjects underwent three measurements of striatal dopamine D2 receptor (D2R)-binding potential (BPND) with SPECT and the selective radiolabeled D2R antagonist [123I]IBZM. All subjects were scanned in the absence of pharmacological intervention (baseline) and after two different depletion procedures. In the first depletion session, over 6 h, subjects were administered 1,500 mg of AMPT before scanning. In the second depletion session, over 25 h, subjects were administered 40 mg AMPT/kg body weight. We also administered the Subjective Well-being Under Neuroleptic Treatment Scale, a self-report instrument designed to measure the subjective experience of patients on neuroleptic medication. Results We found no change of mean D2R BPND after the first and short AMPT challenge compared to the baseline. However, we found a significant increase in striatal D2R BPND binding after the AMPT challenge adjusted for bodyweight compared to both other regimen. Although subjective well-being worsened after the prolonged AMPT challenge, no severe side effects were reported. Conclusions Our results imply a low-dosage, suitable alternative to the common AMPT procedure. The probability of side effects and study withdrawal can be reduced by this procedure