Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology

The deposition of alpha-synuclein in the brain, the neuropathological hallmark of Parkinson’s disease (PD), follows a distinct anatomical and temporal sequence. This study aimed to characterize alpha-synuclein deposition in cutaneous nerves from patients with PD. We further strived to explore whether peripheral nerve involvement is intrinsic to PD and reflective of known features of brain pathology, which could render it a useful tool for pathogenetic studies and pre-mortem histological diagnosis of PD. We obtained skin biopsies from the distal and proximal leg, back and finger of 31 PD patients and 35 controls and quantified the colocalization of phosphorylated alpha-synuclein in somatosensory and autonomic nerve fibers and the pattern of loss of different subtypes of dermal fibers. Deposits of phosphorylated alpha-synuclein were identified in 16/31 PD patients but in 0/35 controls (p < 0.0001). Quantification of nerve fibers revealed two types of peripheral neurodegeneration in PD: (1) a length-dependent reduction of intraepidermal small nerve fibers (p < 0.05) and (2) a severe non-length-dependent reduction of substance P-immunoreactive intraepidermal nerve fibers (p < 0.0001). The latter coincided with a more pronounced proximal manifestation of alpha-synuclein pathology in the skin. The histological changes did not correlate with markers of levodopa toxicity such as vitamin B12 deficiency. Our findings suggest that loss of peripheral nerve fibers is an intrinsic feature of PD and that peripheral nerve changes may reflect the two types of central alpha-synuclein-related PD pathology, namely neuronal death and axonal degeneration. Detection of phosphorylated alpha-synuclein in dermal nerve fibers might be a useful diagnostic test for PD with high specificity but low sensitivity.     

Atypical language representation is unfavorable for language abilities following childhood stroke

Brain plasticity has often been quoted as a reason for the more favorable outcome in childhood stroke compared to adult stroke. We investigated the relationship between language abilities and language localization in childhood stroke. Seventeen children and adolescents with left- or right-sided ischemic stroke and 18 healthy controls were tested with a comprehensive neurolinguistic test battery, and the individual neural representation of language was measured with an fMRI language paradigm. Overall, 12 of 17 stroke patients showed language abilities below average, and five patients exhibited impaired language performance. fMRI revealed increased activity in right hemisphere areas homotopic to left hemisphere language regions. In sum, seven stroke patients revealed atypical, i.e. bilateral or right lateralized language representation. Typical left hemispheric language lateralization was associated with better performance in naming and word fluency, whereas increased involvement of right homologues was accompanied by worse language outcome. In contrast, lesion lateralization or lesion volume did not correlate with language outcome or atypical language lateralization. Thus, atypical language lateralization is unfavorable for language outcome, and right homologues do not have the same cognitive capacity, even in young children.     

Comparison between Upfront Transplantation and different Pretransplant Cytoreductive Treatment Approaches in Patients with High-Risk Myelodysplastic Syndrome and Secondary Acute Myelogenous Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with advanced myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (sAML), but in the absence of prospective trials the impact of pretransplant cytoreduction is controversially discussed. We retrospectively analyzed the outcome of 165 patients with MDS and excess blasts (n = 126, 76%) and sAML (n = 39, 24%) according to a pretransplant strategy. Sixty-seven patients (41%) were directly transplanted (upfront group), whereas 98 patients (59%) had received pretransplant cytoreductive treatment (induction chemotherapy [CTX], n = 64; hypomethylating agents [HMAs], n = 34) resulting in a significantly higher complete remission rate in the CTX group (59% versus HMA 18%, P < .0001). Estimated rates of 5-year overall survival (OS) and relapse-free survival (RFS) for the entire group were 54% and 39%, respectively. The 5-year OS rates of the upfront, CTX, and HMA groups were 61%, 50%, and 45%, respectively (P = .116), whereas RFS rates were 38%, 41%, and 38% (P = .926). Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) did not differ between treatment groups. In the upfront group no difference regarding OS and RFS was seen with respect to pretransplant blast count (>10% versus <10%). In multivariate analyses type of pretransplant strategy did not have an effect on OS, RFS, CIR, and NRM, whereas cytogenetics (OS, RFS, CIR), reduced-intensity conditioning (OS, RFS, CIR), and an unrelated donor (RFS, CIR) were identified as negative predictors. When compared with the upfront group, 5-year OS was significantly lower in patients with CTX-refractory disease (34% versus 64%, P = .0346) and by clear trend in HMA nonresponders (42% versus 61%, P = .073), whereas RFS did not differ significantly. In further support of the concept, that pretransplant therapy may favor the selection of resistant clones, patients in the upfront group had a higher likelihood to respond to HMAs as salvage therapy for relapse in comparison with pretreated patients (complete remission, 58% versus 10%; P = .0005) and a higher 2-year OS rate after relapse (59% versus 19%, P = .0001). These data suggest that an upfront transplant strategy is at least not inferior to pretransplant cytoreduction and may be augmented by HMAs + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT.     

The Therapy Process Questionnaire ‐ Factor analysis and psychometric properties of a multidimensional self‐rating scale for high‐frequency monitoring of psychotherapeutic processes

Many outcome measures and session‐related questionnaires in psychotherapy are designed for weekly or biweekly administration. Yet, today, technical developments allow for higher frequency assessments to monitor human change dynamics more closely by daily assessments. For this purpose, the Therapy Process Questionnaire (TPQ) was developed, with a specific focus on inpatient psychotherapy. In this article, we present an explorative and confirmative factor analysis of the TPQ on the basis of the time series data of 150 patients collected during their hospital stay (mean time series length: 69.1 measurement points). A seven‐factor solution was identified, which explains 68.7% of variance and associates 43 items onto the factors, which are “well‐being and positive emotions,” “relationship with fellow patients,” “therapeutic relationship and clinical setting,” “emotional and problem intensity,” “insight/confidence/therapeutic progress,” “motivation for change,” and “mindfulness/self‐care.” The internal consistency (Cronbach's α), the inter‐item correlations of the subscales, and the discriminative power of the items are excellent. The TPQ can be applied in practice and research for creating time series with equidistant measurement points and time series lengths, which are appropriate for the application of nonlinear analysis methods. Especially in clinical practice, it is important to identify precursors of phase transitions, changing synchronization patterns, and critical or instable periods of a process, which now is possible by internet‐ or app‐based applications of this multidimensional questionnaire.     

Interleukin-12 Is Essential for a Protective Th1 Response in Mice Infected with Cryptococcus neoformans

To analyze the roles of interleukin-12 (IL-12) and the IL-12-dependent Th1 response in resistance to Cryptococcus neoformans, we have established a chronic infection model in wild-type mice and in mice with targeted disruptions of the genes for the IL-12p35 and IL-12p40 subunits (IL-12p35^−/− and IL-12p40^−/− mice, respectively) as well as in mice with a targeted disruption of the IL-4 gene. Long-term application of exogenous IL-12 prevented death of infected wild-type mice for the entire period of the experiment (up to 180 days) but did not resolve the infection. Infected IL-12p35^−/− and IL-12p40^−/− mice died significantly earlier than infected wild-type mice, whereas infection of IL-4-deficient mice led to prolonged survival. Interestingly, infected IL-12p40^−/− mice died earlier and developed higher organ burdens than IL-12p35^−/− mice, which, for the first time in an infection model, suggests a protective role of the IL-12p40 subunit independent of the IL-12 heterodimer. The fungal organ burdens of IL-4-deficient mice and IL-12-treated wild-type mice were significantly reduced compared to those of untreated wild-type mice and IL-12-deficient mice. Histopathological analysis revealed reduction of the number of granulomatous lesions following treatment with IL-12. Susceptibility of both IL-12p35^−/− and IL-12p40^−/− mice was associated with marginal production of gamma interferon and elevated levels of IL-4 from CD4⁺ T cells, which indicates Th2 polarization in the absence of IL-12, whereas wild-type mice developed a Th1 response. Taken together, our data emphasize the essential role of IL-12 for protective Th1 responses against C. neoformans.     

Childbirth Fear: Relation to Birth and Care Provider Preferences

Introduction

The purpose of this study was to assess how preferences for place of birth and mode of birth relate to different dimensions of childbirth fear and whether there is an association between Canadian women's prenatal fear of childbirth and the type and quality of prenatal care they received.

Methods

A link to an online survey was posted on Canadian pregnancy and birth websites; 409 women completed the survey that included sociodemographic questions, questions about the current pregnancy and previous pregnancy experiences (if applicable), and the Childbirth Fear Questionnaire, a validated 40‐item scale that measures 9 dimensions of childbirth fear.

Results

Women under physician care and those with a preference for cesarean birth were generally more fearful of pain associated with vaginal birth, fear of loss of sexual pleasure and attractiveness, and fear of harm to themselves or their infant. Conversely, women under the care of midwives and women who preferred to give birth vaginally were more fearful of interventions. Women who preferred a cesarean birth were significantly more likely to report that fear of childbirth interfered with daily functioning, compared to women who preferred a vaginal birth. Satisfaction with care was associated with lower scores on the Childbirth Fear Questionnaire full and subscales, especially among midwifery clients.

Discussion

At present there are no guidelines in Canada or the United States for the treatment and/or referral of pregnant women who suffer from childbirth fear. Until such guidelines are developed, findings from the current study can help maternity care providers identify and address specific fears among women in their care and understand how different fear domains relate to care provider choice, satisfaction with care, and women's preferences for place and mode of birth.     

Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction,but 2‐deoxy‐glucose affects effector functions

The strong link between T‐cell metabolism and effector functions is well characterized in the murine system but hardly investigated in human T cells. Therefore, we analyzed glycolytic and mitochondrial activity in correlation to function in activated human CD4 and CD8 T cells. Glycolysis was barely detectable upon stimulation but accelerated beyond 24 h, whereas mitochondrial activity was elevated immediately in both T‐cell populations. Glucose deprivation or mitochondrial restriction reduced proliferation, had only a transient impact on “on‐blast formation” and no impact on viability, IFN‐γ, IL‐2, IL‐4, and IL‐10 production, whereas TNF was reduced. Similar results were obtained in bulk T cells and T‐cell subsets. Elevated respiration under glucose restriction demonstrated metabolic flexibility. Administration of the glycolytic inhibitor 2‐deoxy‐glucose suppressed both glycolysis and respiration and exerted a strong impact on cytokine production that persisted for IFN‐γ after removal of 2‐deoxy‐glucose. Taken together, glycolytic or mitochondrial restriction alone compromised proliferation of human T cells, but barely affected their effector functions. In contrast, effector functions were severely affected by 2‐deoxy‐glucose treatment.