Prostate cancer is for many men a chronic disease with a long life expectancy after treatment. The impact of prostate cancer therapy on men has been well defined, however, explanation of the consequences of cancer treatment has not been modelled against the wider variables of long-term health-care provision. The aim of this study was to explore the parameters of unmet supportive care needs in men with prostate cancer in relation to the experience of nursing care.
A survey was conducted among a volunteer sample of 1001 men with prostate cancer living in seven European countries.
At the time of the survey, 81% of the men had some unmet supportive care needs including psychological, sexual and health system and information needs. Logistic regression indicated that lack of post-treatment nursing care significantly predicted unmet need. Critically, men's contact with nurses and/or receipt of advice and support from nurses, for several different aspects of nursing care significantly had an impact on men's outcomes.
Unmet need is related not only to disease and treatment factors but is also associated with the supportive care men received. Imperative to improving men's treatment outcomes is to also consider the access to nursing and the components of supportive care provided, especially after therapy.
survivorship; consequences of cancer treatment; nursing; supportive care; prostate cancer
Researchers have consistently observed in right-handed individuals across normal and disease states that the ‘dominant’ left hemisphere has greater ipsilateral control of the left side than the right hemisphere has over the right. We sought to determine whether this ipsilateral influence of the dominant hemisphere reported in Parkinson’s disease extends to treatments such as deep brain stimulation (DBS) and whether it affects outcome. We hypothesised that among Parkinson right-handers, unilateral left DBS would provide greater ipsilateral motor improvement compared with the ipsilateral motor improvement experienced on the right side.
A total of 73 Parkinson patients who underwent unilateral DBS of the subthalamic nucleus (STN) or globus palidus internus (GPi) participated. Left and right ‘composite scores’, were computed by separately adding all items on the left and right side from the motor section of the Unified Parkinson Disease Rating Scale. The change in the pre- and 4-month post-implantation score was the primary outcome measure. The mean motor scores improved by 4.96 ± 11.79 points (p < 0.001) post-surgery on the ipsilateral side of the DBS implantation. Regression analyses revealed that the side (left vs. right) and target (STN vs. GPi) did not significantly contribute in the effect of ipsilateral motor improvement (p = 0.3557).
While DBS on the ‘dominant’ left side failed to exert a greater ipsilateral influence compared with DBS on the non-dominant right side, significant ipsilateral motor improvements were observed after unilateral stimulation regardless of site of implantation and laterality.
Unilateral DBS; STN; GPi; Parkinson’s disease; UPDRS
Candidacy for deep brain stimulation (DBS) in Parkinson disease (PD) is typically assessed by the preoperative motor response to levodopa along with an interdisciplinary evaluation. However, recent cases treated at our institution have achieved good outcomes with DBS despite a sub-30% improvement in motor scores. The aim of this study was to examine the outcomes of DBS in a subset of patients who failed to reach the 30% motor improvement threshold.
A review of all DBS patients treated at the University of Florida Movement Disorders Center between 2002 and 2009 was performed utilizing a DBS database. All patients with sub-30% improvement in Unified Parkinson Disease Rating Scale Part III after dopaminergic medication administration were included.
Nine patients were identified; DBS was performed for severe dyskinesia (n = 5), “on/off motor” fluctuations (n = 1) and medication-refractory tremor (n = 3). The target symptoms were improved in all patients. Postoperatively, scores on the Unified Parkinson Disease Rating Scale Part II and III and subscores on Parkinson disease questionnaire-39 improved (P < 0.05).
Although motor response to levodopa remains the primary selection criteria for DBS candidacy in Parkinson disease, patients who do not meet the 30% threshold and have disabling symptoms may still benefit from DBS. Select patients with severe dyskinesia, “on/off” motor fluctuations, and/or medication-refractory tremor may experience significant benefits from DBS and should be considered on a case by case basis through an interdisciplinary team evaluation.
deep brain stimulation; Parkinson disease; levodopa challenge test; dyskinesia; on-off motor fluctuations; tremor; quality of life
The purpose of this review is to assess the current state of the literature on the topic of deep brain stimulation (DBS) and its effects on swallowing function in Parkinson’s disease (PD). Pubmed, Cochrane review, and web of science searches were completed on all articles addressing DBS that contained a swallowing outcome measure. Outcome measures included the penetration/aspiration scale, pharyngeal transit time, oropharyngeal residue, drooling, aspiration pneumonia, death, hyolaryngeal excursion, epiglottic inversion, UPDRS scores, and presence of coughing/throat clearing during meals. The search identified 13 studies specifically addressing the effects of DBS on swallowing. Critical assessment of the 13 identified peer-reviewed publications revealed nine studies employing an experimental design, (e.g. “on” vs. “off”, pre- vs. post-DBS) and four case reports. None of the nine experimental studies were found to identify clinically significant improvement or decline in swallowing function with DBS. Despite these findings, several common threads were identified across experimental studies and will be examined in this review. Additionally, available data demonstrate that, although subthalamic nucleus (STN) stimulation has been considered to cause more impairment to swallowing function than globus pallidus internus (GPi) stimulation, there are no experimental studies directly comparing swallowing function in STN vs. GPi. Moreover, there has been no comparison of unilateral vs. bilateral DBS surgery and the coincident effects on swallowing function. This review includes a critical analysis of all experimental studies and discusses methodological issues that should be addressed in future studies.
DBS; Dysphagia; Swallow; Aspiration pneumonia; Parkinson’s disease; Review
Conidiogenesis is the primary process for asexual reproduction in filamentous fungi. As the conidia resulting from the conidiogenesis process are primarily disseminated via air currents and/or water, an outstanding question has been how fungi recognize aerial environments suitable for conidial development. In this study, we documented the somewhat complex development of the conidia-bearing structures, termed conidiophores, from several Aspergillus species in a subsurface (gel-phase) layer of solid media. A subset of the isolates studied was able to develop conidiophores in a gel-phase environment, but exposure to the aeriform environment was required for the terminal developmental transition from phialide cells to conidia. The remaining Aspergilli could not initiate the conidiogenesis process until they were exposed to the aeriform environment. Our observations of conidiophore development in high or low oxygen conditions in both aeriform and gel-phase environments revealed that oxygen and the aeriform state are positive environmental factors for inducing conidiogenesis in most of the aspergilli tested in this study. Transcriptional analysis using A. fumigatus strain AF293 confined to either the aeriform or gel-phase environments revealed that expression of a key regulatory gene for conidiophore development (AfubrlA) is facilitated by oxygen while expression of another regulatory gene controlling conidia formation from phialides (AfuabaA) was repressed regardless of oxygen levels in the gel-embedded environment. Furthermore, by comparing the developmental behavior of conidiation-defective mutants lacking genes controlling various regulatory checkpoints throughout the conidiogenesis pathway, we propose that this aerial response by the fungus requires both oxygen and the phase transition (solid to aeriform), with these environmental signals integrating into the upstream regulatory pathway and central regulatory pathway of conidiogenesis, respectively. Our findings provide not only novel insight into how fungi respond to an aerial environment to trigger development for airborne conidia production but also the relationship between environmental factors and conidiogenesis regulation in aspergilli.
Childhood ataxia is characterized by impaired balance and coordination primarily due to cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies.
cardiomyopathy; cerebellar ataxia; childhood ataxia; frataxin; Friedreich ataxia; GAA repeat expansion; hypertrophy; iron accumulation; iron-sulfur clusters; mitochondria; oxidative stress
Salmonella enterica serovar Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is required for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by at least two independent pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems for host defense against wild type Salmonella infection is complex, and innate immune detection of flagellin contributes to both protection and susceptibility. We hypothesized that efficient modulation of flagellin expression in vivo permits Salmonella to evade innate immune detection and limit the functional role of flagellin-specific host innate defenses. To test this hypothesis, we used Salmonella deficient in the anti-sigma factor flgM, which overproduce flagella and are attenuated in vivo. In this study we demonstrate that flagellin recognition by the innate immune system is responsible for the attenuation of flgM− S. Typhimurium, and dissect the contribution of each flagellin recognition pathway to bacterial clearance and inflammation. We demonstrate that caspase-1 controls mucosal and systemic infection of flgM− S. Typhimurium, and also limits intestinal inflammation and injury. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum and systemic infection, but attenuates intestinal inflammation. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing infection and that evasion of TLR5 and caspase-1 dependent flagellin recognition helps Salmonella induce intestinal inflammation and establish a niche in the inflamed gut.
Legionella pneumophila (Lp) flagellin activates signaling pathways in murine macrophages that control Lp replication. Nucleotide-binding oligomerization domain (NOD) containing-like receptor (NLR) family, caspase recruitment domain (CARD) containing 4 (NLRC4) and Toll-like Receptor (TLR5) both recognize Lp flagellin in vitro, but whether these two receptors play redundant or separate functional roles in vivo is unknown.
The immune response of Nlrc4−/−, Nlrc4−/−/Tlr5−/−, and wild type C57Bl/6 mice was analyzed after in vivo infection with aerosolized Lp.
Lp clearance from the lungs was delayed in Nlrc4−/− mice over seven days in comparison to wild type controls. Nlrc4−/−/Tlr5−/− mice had no additional defect. In contrast to TLR5, NLRC4 did not regulate recruitment of neutrophils to the lung. Although there were no differences among the mouse strains in the lung transcriptome at 4 hours, Nlrc4−/− and Nlrc4−/−Tlr5−/− mice had increased lung inflammation at 72 hours in comparison to WT. Nlrc4−/−/Tlr5−/− mice also had altered cytokine production at both 4 and 24 hours post infection when compared to wild-type (WT) and Nlrc4−/− mice. Lp replication in murine alveolar macrophages was NLRC4-dependent and TLR5-independent.
These studies reveal that NLRC4 and TLR5 mediate different roles in the inflammatory response to Lp flagellin in an aerosolized infection model and NLRC4 regulates replication in both lungs and alveolar macrophages.
Legionella pneumophila; Pneumonia; Alveolar macrophage; NLRC4; TLR5
Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G1-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored.
Cytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2.
Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.
Dystonia; Chromosome 13q34; Duplication; TFDP1; Breast cancer; G1-S Checkpoint pathway
Our research aims to understand the consequences of inadequate workplace flexibility through the lens of daily stress processes. Using a sample of hourly hotel employees with children aged 10 to 18 who participated in a daily diary study, we compared workers with low and high flexibility on stressor exposure, reactivity, and transmission. Our findings showed a consistent pattern of hourly workers with low flexibility having greater exposure to work stressors in general and to work place arguments in particular. Workers with low flexibility were also more emotional and physically reactive to work stressors. There was some evidence of stressor transmission to children when parents had low flexibility. Increasing workplace flexibility could serve as a protective factor in exposure and reactivity to stressors that are experienced in daily life.
Workplace Flexibility; Daily Stress; Stressor Exposure; Stressor Reactivity; Stress transmission
The success of cellular therapies for Parkinson’s disease (PD) will depend not only a conducive growth environment in vivo, but also on the ex vivo amplification and targeted neural differentiation of stem/progenitor cells. Here, we demonstrate the in vitro proliferative and differentiation potential of stem/progenitor cells, adult human neural progenitor cells (“AHNPs”) isolated from idiopathic PD postmortem tissue samples and, to a lesser extent, discarded deep brain stimulation electrodes. We demonstrate that these AHNPs can be isolated from numerous structures (e.g. substantia nigra, “SN”) and are able to differentiate into both glia and neurons, but only under particular growth conditions including co-culturing with embryonic stem cell-derived neural precursors; this suggests that PD multipotent neural stem/progenitor cells do reside with the SN and other areas, but by themselves appear to lack key factors required for neural differentiation. AHNPs engraft following ex vivo expansion and transplantation into the rodent brain, demonstrating their regenerative potential. Our data demonstrate the presence and capacity of endogenous stem/progenitor cells in the PD brain.
Parkinson’s disease; neurogenesis; neural stem cell; neural progenitor cell; cell culture
Bi-directional trafficking of cells between the mother and the fetus is routine in pregnancy and a component of maternal-fetal tolerance. Changes in fetal-to-maternal cellular trafficking have been reported in prenatal complications, but maternal-to-fetal trafficking has never been studied in the context of fetal intervention. We hypothesized that patients undergoing open fetal surgery would have altered maternal-fetal cellular trafficking.
Cellular trafficking was analyzed in patients with myelomeningocele (MMC) who underwent open fetal surgical repair (n=5), MMC patients who had routine postnatal repair (n=6), and normal term patients (n=9). As a control for the fetal operation, trafficking was also analyzed in patients who were delivered by an ex utero intrapartum treatment (EXIT) procedure (n=6). Microchimerism in maternal and cord blood was determined using quantitative real-time PCR for non-shared alleles.
Maternal-to-fetal trafficking was significantly increased in patients who underwent open fetal surgery for MMC compared to normal controls, postnatal MMC repair, and EXIT patients. There were no differences in fetal-to-maternal cell trafficking between groups.
Patients undergoing open fetal surgery for MMC have elevated levels of maternal microchimerism. These results suggest altered trafficking and/or increased proliferation of maternal cells in fetal blood and may have important implications for preterm labor.
Fetal surgery; myelomeningocele; spina bifida; maternal-fetal cellular trafficking; microchimerism; preterm labor; EXIT
Hyphal anastomosis, or vegetative hyphal fusion, establishes the interconnection of individual hyphal strands into an integrated network of a fungal mycelium. In contrast to recent advances in the understanding of the molecular basis for hyphal anastomosis, knowledge of the physiological role of hyphal anastomosis in the natural habitats of filamentous fungi is still very limited. To investigate the role of hyphal anastomosis in fungal endophyte-plant interactions, we generated mutant strains lacking the Epichloë festucae soft (so) gene, an ortholog of the hyphal anastomosis gene so in the endophytic fungus E. festucae. The E. festucae Δso mutant strains grew similarly to the wild-type strain in culture but with reduced aerial hyphae and completely lacked hyphal anastomosis. The most striking phenotype of the E. festucae Δso mutant strain was that it failed to establish a mutualistic symbiosis with the tall fescue plant host (Lolium arundinaceum); instead, it killed the host plant within 2 months after the initial infection. Microscopic examination revealed that the death of the tall fescue plant host was associated with the distortion and disorganization of plant cells. This study suggests that hyphal anastomosis may have an important role in the establishment/maintenance of fungal endophyte-host plant mutualistic symbiosis.
This pilot study adapted a well-established drug self-administration paradigm to examine the effects of mood induction on the ability to resist high-calorie foods and subsequent food consumption differently in 15 obese individuals (40.0% women, BMI: 35.1±3.70) and 15 non-obese individuals (46.7% women, BMI: 23.0±1.96). Participants completed two laboratory sessions (positive vs. negative mood conditions) consisting of 3-hour food deprivation, followed by mood induction, and a 3-hour ad-lib eating period, where they were asked to choose between favorite high-calorie snacks and monetary reinforcement. Obese individuals were less able to resist eating and increased high-calorie food consumption during the positive mood condition than the negative condition. Non-obese individuals were less able to resist eating during the negative mood condition than the positive condition, but their total consumption was not affected by the mood conditions. In obese individuals, food craving was associated with less ability to resist eating and greater calorie consumption during the negative mood condition. This is the first study to experimentally demonstrate that mood state may increase vulnerability to food consumption by reducing the ability to resist eating. The ability to resist eating may be a novel dimension of eating behaviors that has a significant contribution to understanding mood-eating relationships.
Obesity; mood; eating behaviors; high-calorie foods; food craving
Variation in testosterone (T) is thought to affect the allocation of effort between reproductive and parenting strategies. Here, using a large sample of elderly American men (n = 754) and women (n = 669) we examined the relationship between T and self-reported parenthood, as well as the relationship between T and number of reported children. Results supported previous findings from the literature, showing that fathers had lower T levels than men who report no children. Furthermore, we found that among fathers T levels were positively associated with the number of children a man reports close to the end of his lifespan. Results were maintained when controlling for a number of relevant factors such as time of T sampling, participant age, educational attainment, BMI, marital status and reported number of sex partners. In contrast, T was not associated with either motherhood or the number of children women had, suggesting that, at least in this sample, T does not influence the allocation of effort between reproductive and parenting strategies among women. Findings from this study contribute to the growing body of literature suggesting that, among men, pair bonding and paternal care are associated with lower T levels, while searching and acquiring sex partners is associated with higher T levels.
The p53 tumor suppressor is embedded in a large gene network controlling diverse cellular and organismal phenotypes. Multiple signaling pathways converge onto p53 activation, mostly by relieving the inhibitory effects of its repressors, MDM2 and MDM4. In turn, signals originating from increased p53 activity diverge into distinct effector pathways to deliver a specific cellular response to the activating stimuli. Much attention has been devoted to dissecting how the various input pathways trigger p53 activation and how the activity of the p53 protein itself can be modulated by a plethora of co-factors and post-translational modifications. In this review we will focus instead on the multiple configurations of the effector pathways. We will discuss how p53-generated signals are transmitted, amplified, resisted and eventually integrated by downstream gene circuits operating at the transcriptional, post-transcriptional and post-translational level. We will also discuss how context-dependent variations in these gene circuits define the cellular response to p53 activation and how they may impact the clinical efficacy of p53-based targeted therapies.
gene network; PUMA; p21; apoptosis; cell cycle arrest; personalized medicine; functional genomics; molecular diagnostics
Candida albicans is a normal member of the gastrointestinal (GI) tract microbiota of healthy humans, but during host immunosuppression or alterations in the bacterial microbiota, C. albicans can disseminate and cause life-threatening illness. The bacterial microbiome of the GI tract, including lactic acid bacteria (LAB), plays a vital role in preventing fungal invasion. However, little is known about the role of C. albicans in shaping the bacterial microbiota during antibiotic recovery. We investigated the fungal burdens in the GI tracts of germfree mice and mice with a disturbed microbiome to demonstrate the role of the microbiota in preventing C. albicans colonization. Histological analysis demonstrated that colonization with C. albicans during antibiotic treatment does not trigger overt inflammation in the murine cecum. Bacterial diversity is reduced long term following cefoperazone treatment, but the presence of C. albicans during antibiotic recovery promoted the recovery of bacterial diversity. Cefoperazone diminishes Bacteroidetes populations long term in the ceca of mice, but the presence of C. albicans during cefoperazone recovery promoted Bacteroidetes population recovery. However, the presence of C. albicans resulted in a long-term reduction in Lactobacillus spp. and promoted Enterococcus faecalis populations. Previous studies have focused on the ability of bacteria to alter C. albicans; this study addresses the ability of C. albicans to alter the bacterial microbiota during nonpathogenic colonization.
Deep brain stimulation (DBS) has been associated with mood sequelae in a subset of patients operated on in either the subthalamic nucleus or the globus pallidus internus for the treatment of Parkinson disease.
To compare mood and motor outcomes in those with and without a presurgical history of depression.
Unilateral subthalamic nucleus or unilateral globus pallidus internus DBS patients followed up for a minimum of 6 months were included. All patients underwent a comprehensive outpatient psychiatric evaluation by a board-certified psychiatrist. Psychiatric diagnoses were based on Diagnostic and Statistical Manual, fourth edition, text revision, nomenclature (American Psychiatric Association, 2000). Motor and mood outcomes were compared.
A total of 110 patients were included. There were no significant differences in baseline variables between the 2 groups. Those with a preoperative history of depression had significantly higher Beck Depression Inventory scores than the nondepression group after DBS (8.97 ± 7.55 vs 5.92 ± 5.71; P = .04). Patients with a depression history had less improvement (11.6%) in pre/post-DBS change when Unified Parkinson Disease Rating Scale motor scores were compared (P = .03) after adjustment for stimulation site and baseline demographic and clinical variables. Patients with a higher levodopa equivalent dose had a worse clinical motor outcome.
Patients with a preoperative depression history had higher Beck Depression Inventory scores after DBS and significantly less (albeit small) improvement in pre/post-DBS change in Unified Parkinson Disease Rating Scale motor scores than patients without a history of depression.
DBS; Deep brain stimulation; Depression; DSM; Outcomes; Psychiatry; Psychology
We aimed in this investigation to study deep brain stimulation (DBS) battery drain with special attention directed toward patient symptoms prior to and following battery replacement.
Previously our group developed web-based calculators and smart phone applications to estimate DBS battery life (http://mdc.mbi.ufl.edu/surgery/dbs-battery-estimator).
A cohort of 320 patients undergoing DBS battery replacement from 2002–2012 were included in an IRB approved study. Statistical analysis was performed using SPSS 20.0 (IBM, Armonk, NY).
The mean charge density for treatment of Parkinson’s disease was 7.2 µC/cm2/phase (SD = 3.82), for dystonia was 17.5 µC/cm2/phase (SD = 8.53), for essential tremor was 8.3 µC/cm2/phase (SD = 4.85), and for OCD was 18.0 µC/cm2/phase (SD = 4.35). There was a significant relationship between charge density and battery life (r = −.59, p<.001), as well as total power and battery life (r = −.64, p<.001). The UF estimator (r = .67, p<.001) and the Medtronic helpline (r = .74, p<.001) predictions of battery life were significantly positively associated with actual battery life. Battery status indicators on Soletra and Kinetra were poor predictors of battery life. In 38 cases, the symptoms improved following a battery change, suggesting that the neurostimulator was likely responsible for symptom worsening. For these cases, both the UF estimator and the Medtronic helpline were significantly correlated with battery life (r = .65 and r = .70, respectively, both p<.001).
Battery estimations, charge density, total power and clinical symptoms were important factors. The observation of clinical worsening that was rescued following neurostimulator replacement reinforces the notion that changes in clinical symptoms can be associated with battery drain.
Deep brain stimulation is a treatment for select cases of medication refractory movement disorders including Parkinson’s disease. Deep brain stimulation has not been recommended for treatment in multiple system atrophy patients. However, the paucity of literature documenting the effects of deep brain stimulation in multiple system atrophy patients and the revelation of a levodopa-responsive subtype of multiple system atrophy suggests further investigation is necessary.
This study summarizes the positive and negative effects of deep brain stimulation treatment in two pathologically confirmed multiple system atrophy patients from the University of Florida Deep Brain Stimulation-Brain Tissue Network. Clinical diagnosis for the two patient cases did not match the neuropathological diagnosis. We noted that in both pathologically confirmed multiple system atrophy patients, death occurred as a result of myocardial infarction. Importantly, there was reported transient benefit in levodopa responsive features that indicate deep brain stimulation may be an option for select multiple system atrophy patients.
Deep Brain Stimulation; Pathology; Multiple System Atrophy
The relative reinforcing value of food (RRVfood) provides an index of the motivation to eat. Research has shown that RRVfood is higher in obese individuals than their non-obese peers, is associated with greater energy intake, predicts weight gain and interacts with impulsivity to predict energy intake. This study was designed to determine whether dietary restraint, dietary disinhibition or hunger moderate the effect of RRVfood on the weight status and energy intake in 273 adults of various body mass index (BMI) levels. Hierarchical regression was used to assess the independent effects of RRVfood on BMI and energy intake, controlling for age, sex, income, education, minority status and RRVreading. Results showed that greater RRVfood, but not RRVreading, was associated with greater BMI and energy intake. Dietary disinhibition and dietary restraint moderated the relationship between RRVfood and BMI, with dietary disinhibition being a stronger moderator of this relationship (r2 = 0.20) than dietary restraint (r2 = 0.095). In addition, dietary disinhibition moderated the effect of RRVfood on energy intake. These results replicate the importance of RRVfood as a predictor of obesity, and show that psychological factors moderate the effect of food reinforcement on body weight and energy intake. This trial was registered at clinicaltrials.gov as NCT00962117.
reinforcement; obesity; disinhibition; restraint
The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a ‘Synthetic Lethal with Nutlin-3’ genome-wide shRNA screen, which revealed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors enable Nutlin-3 to kill tumor spheroids. These results identify novel pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies.
Metazoan histone mRNAs are unique: their pre-mRNAs contain no introns and the mRNAs are not polyadenylated ending instead in a conserved stem-loop structure. In Drosophila, canonical poly(A) signals are located downstream of the normal cleavage site of each histone gene, and are utilized when histone 3’end formation is inhibited. Here we define a sub-complex of poly(A) factors required for histone pre-mRNA processing. We demonstrate that Symplekin, CPSF73 and CPSF100 are present in a stable complex and interact with histone specific processing factors. We use chromatin immunoprecipitation to show that Symplekin and CPSF73, but not CstF50, cotranscriptionally associate with histone genes. Depletion of SLBP recruits CstF50 to histone genes. Knockdown of CPSF160 or CstF64 downregulates Symplekin but does not affect histone pre-mRNA processing or association of Symplekin with the histone locus. These results suggest that a common core cleavage factor is required for processing of histone and polyadenylated pre-mRNAs.
As a persistent pump, the mammalian heart demands a high-capacity mitochondrial system. Significant progress has been made in delineating the gene regulatory networks that control mitochondrial biogenesis and function in striated muscle. The PPARγ coactivator-1 (PGC-1) coactivators serve as inducible boosters of downstream transcription factors that control the expression of genes involved in mitochondrial energy transduction, ATP synthesis, and biogenesis. PGC-1 gain-of-function and loss-of-function studies targeting two PGC-1 family members, PGC-1α and PGC-1β, have provided solid evidence that these factors are both necessary and sufficient for perinatal mitochondrial biogenesis and maintenance of high-capacity mitochondrial function in postnatal heart. In humans, during the development of heart failure owing to hypertension or obesity-related diabetes, the activity of the PGC-1 coactivators, and several downstream target transcription factors, is altered. Gene targeting studies in mice have demonstrated that loss of PGC-1α and PGC-1β in heart leads to heart failure. Interestingly, the pattern of dysregulation within the PGC-1 transcriptional regulatory circuit distinguishes the heart disease caused by hypertension from that caused by diabetes. This transcriptional regulatory cascade and downstream metabolic pathways should be considered as targets for novel etiology-specific therapeutics aimed at the early stages of heart failure.