Cognitive impairment in Parkinson's disease: impact on quality of life of carers

Background

The quality of life (QoL) of informal caregivers of people with Parkinson's disease (PD) (PwP) can be affected by the caring role. Because of cognitive symptoms and diminished activities of daily living, in addition to the management of motor symptoms, carers of PwP and cognitive impairment may experience increased levels of burden and poorer QoL compared with carers of PwP without cognitive impairment. This study aimed to investigate the impact of cognitive impairment in PD upon QoL of carers.

Methods

Approximately 36 months after diagnosis, 66 dyadic couples of PwP and carers completed assessments. PwP completed a schedule of neuropsychological assessments and QoL measures; carers of PwP completed demographic questionnaires and assessments of QoL. Factor scores of attention, memory/executive function and global cognition, as derived by principal component analysis, were used to evaluate cognitive domains.

Results

Hierarchical regression analysis found lower Montreal Cognitive Assessment was a significant independent predictor of poorer carer QoL, in addition to number of hours spent caregiving, carer depression and PD motor severity. Attentional deficits accounted for the largest proportion of variance of carer QoL. Carers of PwP and dementia (n = 9) had significantly poorer QoL scores compared with PwP and mild cognitive impairment (n = 18) or normal cognition (n = 39) carers (p < 0.01).

Conclusions

Attentional deficits were the strongest predictor of carer QoL compared with other cognitive predictors. Carers for those with PD dementia reported the poorest QoL. Interventions such as respite or cognitive behavioural therapy to improve mood and self‐efficacy in carers may improve carer QoL. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.     

Comparative Evaluation of Two Vaccine Candidates against Experimental Leishmaniasis Due to Leishmania major Infection in Four Inbred Mouse Strains

Experimental leishmaniasis in BALB/c and C57BL/6 mice are the most investigated murine models that were used for the preclinical evaluation of Leishmania vaccine candidates. We have previously described two new inbred mouse strains named PWK and MAI issued from feral founders that also support the development of experimental leishmaniasis due to L. major. In this study, we sought to determine whether different mouse inbred strains generate concordant or discordant results when used to evaluate the potential of Leishmania proteins to protect against experimental leishmaniasis. To this end, two Leishmania proteins, namely, LACK (for Leishmania homolog of receptor for activated C kinase) and LmPDI (for L. major protein disulfide isomerase) were compared for their capacity to protect against experimental leishmaniasis in PWK, MAI, BALB/c, and C57BL/6 inbred mouse strains. Our data show that the capacity of Leishmania proteins to confer protection depends on the mouse strain used, stressing the important role played by the genetic background in shaping the immune response against the pathogen. These results may have important implications for the preclinical evaluation of candidate Leishmania vaccines: rather than using a single mouse strain, a panel of different inbred strains of various genetic backgrounds should be tested in parallel. The antigen that confers protection in the larger range of inbred strains may have better chances to be also protective in outbred human populations and should be selected for clinical trials.The leishmaniasis are parasitic diseases due to a protozoan of the genus Leishmania that are endemic in 88 countries. Three hundred and fifty million people are exposed to the infection risk and 14 million people are known to be infected. Two million new cases, including 1.5 million of the cutaneous leishmaniasis, are estimated to appear annually (39). The leishmaniasis represent a worldwide major public health problem because of several therapeutic challenges such as drug toxicity, parasite resistance to current drugs, and the high cost of the new treatments. The problem is particularly serious since the disease affects the poorest classes of the developing countries. The cutaneous leishmaniasis are among the rare parasitic diseases that might be potentially vaccine preventable. However, even if theoretically feasible, there is still no human Leishmania vaccine available today (17). One serious obstacle facing such a goal is the lack of experimental animal models that tightly mimic the disease as it occurs in humans.The experimental infection of inbred BALB/c and C57BL/6 mice by Leishmania major parasites has established the functionality of the Th1/Th2 dichotomy of CD4⁺ T helper cells and the contrasted pathogenic roles played in protection or disease promotion by the two Th subsets (33). Thus, C57BL/6 mice infected with L. major develop a Th1 response and efficiently control the disease within few weeks. In contrast, susceptible BALB/c mice mount a Th2 response and develop a severe, unremitting, and ultimately lethal disease (37). The susceptibility of BALB/c mice to L. major infection has been ascribed to the occurrence within the lymph nodes draining the inoculation site, of an early burst (at 16 h postinoculation) of interleukin-4 (IL-4) that polarizes the immune response toward the Th2 pathway (15, 24). The contrasted immunopathogenic mechanisms at work in BALB/c and C57BL/6 strains likely reflect differences in their genetic background. Since the majority of studies evaluating vaccine candidates have been conducted in the BALB/c model, it would be hazardous to extrapolate the conclusions drawn from these experiments to other inbred strains of different genetic backgrounds or to out bred animal models (i.e., primates): one given vaccine could be promising in one strain and still fail to protect in another strain (17). Thus, the criteria that would help to select at the preclinical stage a Leishmania antigen as a promising vaccine candidate worth entering the clinical trial stage are still not clearly defined.We have recently identified two new inbred mouse strains derived from feral founders, named PWK and MAI, that are susceptible to L. major infection (1). MAI mice develop an infiltrated lesion at the site of parasite inoculation that enlarges over time in an unremitted way. In this strain, the primary infection does not induce protection against reinfection. Although the immune response to Leishmania antigens in MAI mice was characterized by a Th2 cytokine profile, IL-4 did not seem to play a dominant role in disease phenotype as in BALB/c mice. In PWK mice, the experimental disease induced by L. major infection is featured by a nodule that develops at the site of parasite inoculation. This nodule is larger and of a much longer duration (30 weeks to complete healing) than the one that develops in C57BL/6. PWK mice acquire a solid immunity after a primary infection and are completely refractory to a secondary challenge. They develop during infection a mixed Th1/Th2 cytokine pattern, with IL-10 playing a disease-promoting role.The diverse disease patterns induced by L. major in PWK, MAI, C57BL/6, and BALB/c mice and the heterogeneity in the immunopathogenic mechanisms at work in each strain are likely shaped by the genetic background of the mice. This assumption led us to explore the effect of the genetic diversity of inbred mouse strains on the protection potentially conferred by Leishmania proteins against L major infection. Two Leishmania promising vaccine candidates were used, namely, the Leishmania homolog of receptor for activated C kinase (LACK) (31) and the L. major protein disulfide isomerase (LmPDI) (5).     

Distinct molecular requirements for activation or stabilization of soluble guanylyl cyclase upon haem oxidation-induced degradation

Background and purpose:

In endothelial dysfunction, signalling by nitric oxide (NO) is impaired because of the oxidation and subsequent loss of the soluble guanylyl cyclase (sGC) haem. The sGC activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino)methyl[benzoic]acid (BAY 58-2667) is a haem-mimetic able to bind with high affinity to sGC when the native haem (the NO binding site) is removed and it also protects sGC from ubiquitin-triggered degradation. Here we investigate whether this protection is a unique feature of BAY 58-2667 or a general characteristic of haem-site ligands such as the haem-independent sGC activator 5-chloro-2-(5-chloro-thiophene-2-sulphonylamino-N-(4-(morpholine-4-sulphonyl)-phenyl)-benzamide sodium salt (HMR 1766), the haem-mimetic Zn-protoporphyrin IX (Zn-PPIX) or the haem-dependent sGC stimulator 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272).

Experimental approach:

The sGC inhibitor 1H-(1,2,4)-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) was used to induce oxidation-induced degradation of sGC. Activity and protein levels of sGC were measured in a Chinese hamster ovary cell line as well as in primary porcine endothelial cells. Cells expressing mutant sGC were used to elucidate the molecular mechanism underlying the effects observed.

Key results:

Oxidation-induced sGC degradation was prevented by BAY 58-2667 and Zn-PPIX in both cell types. In contrast, the structurally unrelated sGC activator, HMR 1766, and the sGC stimulator, BAY 41-2272, did not protect. Similarly, the constitutively haem-free sGC mutant β₁H105F was stabilized by BAY 58-2667 and Zn-PPIX.

Conclusions:

The ability of BAY 58-2667 not only to activate but also to stabilize oxidized/haem-free sGC represents a unique example of bimodal target interaction and distinguishes this structural class from non-stabilizing sGC activators and sGC stimulators such as HMR 1766 and BAY 41-2272, respectively.     

The negative inotropic action of canrenone is mediated by L-type calcium current blockade and reduced intracellular calcium transients

Background and purpose:

Adding spironolactone to standard therapy in heart failure reduces morbidity and mortality, but the underlying mechanisms are not fully understood. We analysed the effect of canrenone, the major active metabolite of spironolactone, on myocardial contractility and intracellular calcium homeostasis.

Experimental approach:

Left ventricular papillary muscles and cardiomyocytes were isolated from male Wistar rats. Contractility of papillary muscles was assessed with force transducers, Ca²⁺ transients by fluorescence and Ca²⁺ fluxes by electrophysiological techniques.

Key results:

Canrenone (300–600 µmol·L⁻¹) reduced developed tension, maximum rate of tension increase and maximum rate of tension decay of papillary muscles. In cardiomyocytes, canrenone (50 µmol·L⁻¹) reduced cell shortening and L-type Ca²⁺ channel current, whereas steady-state activation and inactivation, and reactivation curves were unchanged. Canrenone also decreased the Ca²⁺ content of the sarcoplasmic reticulum, intracellular Ca²⁺ transient amplitude and intracellular diastolic Ca²⁺ concentration. However, the time course of [Ca²⁺]_i decline during transients evoked by caffeine was not affected by canrenone.

Conclusion and implications:

Canrenone reduced L-type Ca²⁺ channel current, amplitude of intracellular Ca²⁺ transients and Ca²⁺ content of sarcoplasmic reticulum in cardiomyocytes. These changes are likely to underlie the negative inotropic effect of canrenone.     

Biochemical Stress Responses in Tissues of the Cichlid Fish Cichlasoma dimerus Exposed to a Commercial Formulation of Endosulfan

Median lethal concentration (LC(50)) and sublethal effects of the commercial endosulfan formulation Zebra Ciagro(?) on the fish Cichlasoma dimerus were studied. The 96-h LC(50) was estimated as 17.7 μg/L. In order to investigate sublethal effects, fish were exposed to 25% and 50% LC(1) (3.4 and 6.8 μg/L, respectively). Endosulfan (ED) significantly increased the hemoglobin concentration and white blood cell count after 96 h. Differential leukocytes count was also altered, due to an increase in the percentage of neutrophils in exposed fish. The hepatopancreatic tissue of fish under ED treatment showed a decrease in aspartate aminotransferase and alanine aminotransferase and an increase in alkaline phosphatase. Lipid peroxidation levels in the 6.8-μg/L ED-containing group were higher than those in control fish for all organs tested (gills, hepatopancreas, and brain).     

High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group

Relapse is a major cause of treatment failure following allogeneic bone marrow transplantation (BMT) for acute myeloid leukemia (AML). To reduce the risk of relapse following BMT for patients with hematologic malignancy, our group developed a novel preparative regimen which combines high-dose etoposide with cyclophosphamide and total body irradiation (VPCyTBI). We now report the outcome of therapy with VPCyTBI followed by allogeneic BMT for 40 patients with AML in untreated first relapse. With the exception of increased stomatitis, the toxicity of this regimen was similar to that reported by others for CyTBI. Forty-four months after transplant the actuarial probabilities of disease-free survival (DFS), persistent or recurrent leukemia, and transplant related mortality were .29, .44, and .47 respectively. DFS was improved (P < .01) and risk of persistent or recurrent leukemia reduced (P = .005) among patients with significant (grade > or = 2) acute GVHD. Patients with 30% or more blasts on pre-BMT bone marrow examination were not at increased risk for persistent or recurrent leukemia. We conclude that VPCyTBI with allogeneic BMT is effective therapy for AML in untreated first relapse and that a randomized trial comparing this regimen with CyTBI is warranted.     

High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.     

Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis

Between December 1990 and January 1994, bone marrow (BM) samples from 151 patients with multiple myeloma (MM), including 117 patients evaluated at diagnosis, were collected for cytogenetic analysis. A total of 129 patients had assessable metaphases (100 patients at diagnosis). Cytogenetic studies were performed on BM cells after longterm cultures (6 days) with stimulation of cultures by granulocyte- macrophage colony-stimulating factor (GM-CSF), GM-CSF plus interleukin (IL)-6, IL-3 plus IL-6, or GM-CSF plus IL-3 plus IL-6 to improve myeloma cell growth, and 91 patients had an additional unstimulated culture. Sixty-six patients (51%) had cytogenetic abnormalities, including 47 of 100 patients at diagnosis (47%) and 17 of 24 patients at relapse (71%; P = .04). The aberration rate increased with stage (P = .007), BM plasmacytosis (P = .003), beta 2 microglobulin level (P = .001), C-reactive protein (CRP) level (P = .001), and Ki-67 (P = .007). The abnormality detection rate was higher in stimulated than unstimulated cultures, and the difference was statistically significant (P < .01). Hyperdiploidy was observed in 39 patients (30% of patients with an assessable karyotype) and hypodiploidy in 19 patients (15%). Among numeric changes, gains predominantly involved chromosomes 3, 5, 7, 9, 11, 15, 19 and losses, chromosomes 8, 13, 14, and X. The most frequent loss was loss of chromosome 13, observed in 22 patients (15%), including 18 patients at diagnosis (12%). We observed frequent structural changes of chromosomes 1 (15%) and 14 (10%) but also a 5% incidence of 19q13 abnormality and two patients with translocation t(1;16)(p11;p11). By using the proportional hazard univariate model, patients with abnormal karyotypes were demonstrated to have 2.5-fold greater chance of death than patients with normal karyotypes (P < .014). Despite a multivariate approach with the same model, the respective roles of karyotype abnormality, age, stage, and beta 2 microglobulin level could not be clearly ascertained. From these results we conclude that cytogenetic analysis using stimulation of cultures by cytokine(s) may be a promising method to identify about 50% of cytogenetic abnormalities in patients with newly diagnosed MM. Cytogenetic analysis may help to define a high-risk population that would benefit from intensive therapeutic approaches.     

Overexpression of cyclin D2 in chronic B-cell malignancies

Tumor progression in B-cell chronic lymphocytic leukemia (B-CLL) is thought to result from the gradual accumulation of small resting G0/G1 phase lymphoid cells rather than the proliferation of actively dividing cells. The recent identification of G1 cyclins that are likely to control both the progression through G0 and G1 phase and the G1/S transition prompted us to study the mRNA expression of D-type cyclins in the peripheral blood lymphocytes from 34 patients with B-CLL, 7 patients with lymphoplasmacytic lymphoma (LPL), and 2 patients with mantle cell lymphoma (MCL). Cyclin D2 mRNA was, on average, 5- to 10- fold overexpressed in most of the samples studied (B-CLL, 29/34; LPL, 7/7; MCL, 0/2) as compared with normal resting B lymphocytes, in which cyclin D2 mRNA was barely detectable. In situ hybridization with cyclin D2 digoxigenin-labeled mRNA probe showed that all the cells from a given sample were stained with approximately the same intensity. Cyclin D3 was never detected in any of the samples tested, whereas cyclin D1 was expressed in only the 3 cases (1 LPL and 2 MCL) bearing a t(11;14) translocation. A trisomy 12 was found in 4 of 19 (21%) B-CLL or LPL cases for which cytogenetic analysis was available. Although the cyclin D2 gene has been mapped to chromosome 12p13, there was no apparent correlation between trisomy 12 and the level of cyclin D2 expression. Cell cycle analysis by flow cytometry after staining with propidium iodide consistently showed that more than 96% of the cells were in G0/G1 phase, whatever the importance of cyclin D2 overexpression was, and that cyclin D2 overexpression in B-CLL was not associated with any modifications of the cell cycle repartition. No consistent overexpression of cyclin D2 was found in acute myeloid leukemias. In conclusion, overexpression of cyclin D2 mRNA was found to be an almost constant feature in B-CLL and LPL. Therefore, it led us to hypothesize, with the support of data from some transfection experiments previously reported in murine hematopoietic cell lines, that cyclin D2 might play a role in B-CLL pathogenesis, possibly by preventing cells from programmed cell death.     

温固化水凝胶复合细胞外基质与膀胱平滑肌细胞的相容性

目的:选用膀胱平滑肌细胞为实验细胞,评估细胞外基质/温度敏感性水凝胶复合支架材料的生物相容性。方法:实验于2005-02/05在武汉大学人民医院泌尿外科研究室完成。①实验分组:实验分为4组。细胞外基质/温度敏感性水凝胶复合支架组:细胞外基质/温度敏感性水凝胶复合支架种植平滑肌细胞;单纯细胞外基质组:单纯细胞外基质种植平滑肌细胞;阴性对照组:单纯培养平滑肌细胞;空白对照组:无细胞培养液。②实验操作:种植细胞前先用培养液将支架材料预湿,取第3代兔膀胱平滑肌细胞悬液(1×108L-1)50μL缓慢接种于材料上。③实验评估:培养2d后倒置相差显微镜下观察细胞黏附、生长情况以及扫描电镜下观察细胞在材料上的空间生长情况;培养5,10d取细胞外基质/温度敏感性水凝胶复合支架组、单纯细胞外基质组材料,进行细胞计数,观察细胞黏附数量;培养1,3,5,7d时MTT法检测细胞的活力。结果:①相差显微镜下可见细胞外基质/温度敏感性水凝胶复合材料为红染的网状结构,纤维较粗,网孔直径较小,未见到细胞碎片;种植平滑肌细胞后6h,可见细胞紧密黏附于材料表面;种植平滑肌细胞后12h,可见细胞已伸展,有多个突起;培养3d时,贴附于材料的细胞数量增加,细胞增殖明显。②扫描电镜下可见发育良好的细胞附于材料上,伪足沿纤维伸展,附着牢固,细胞间连接紧密,可见到细胞外基质分泌。③膀胱平滑肌细胞在单纯细胞外基质上黏附性良好,黏附率为87.6%,复合温度敏感性水凝胶后的细胞外基质表面黏附能力较之增强,黏附率为96.7%。④细胞活力:细胞外基质/温度敏感性水凝胶复合支架组、阴性对照组细胞活力(A)高于单纯细胞外基质组,差异有显著性意义(P<0.05,0.01),培养1,3,5d细胞外基质/温度敏感性水凝胶复合支架组细胞活力(A)低于阴性对照组,培养7d高于阴性对照组,差异有显著性意义(P<0.05,0.01)。结论:细胞外基质/温度敏感性水凝胶复合材料具有便于细胞黏附和生长的微孔结构,生物相容性好,并且保留的某些成分具有良好的促组织再生作用,是一种理想的组织工程材料。