Influence of anxiety on the course of heart disease after acute myocardial infarction - risk factor or protective function?

BACKGROUND: There is a lack of clarity concerning the effect of anxiety on the course of cardiac events following myocardial infarction. Some studies have identified anxiety as a risk factor for further cardiac events. However, it is also considered to be a protective factor, as a higher level of anxiety may improve patient compliance and regular medical checkups. METHODS: A group of 76 patients with myocardial infarction underwent physical examination and had their anxiety levels assessed within the first week, and 31 months after myocardial infarction. Cardiac events were documented during the follow-up period. We investigated the predictive value for the occurrence of cardiac events of sociodemographic, psychological and physical parameters when evaluated within the first week after myocardial infarction. Compliancy and regularity of medical checkups were registered. RESULTS: Cardiac events occurred in 24 patients during a mean follow-up period of 31 months. The group of anxious patients not only suffered more often from cardiac events, these events also occurred earlier than in nonanxious patients. Age, gender, partner status, level of anxiety and comorbid diabetes at the time of first assessment proved to be discriminatory variables between patients suffering further cardiac incidents and those free of further events. Anxious patients were more likely to continue smoking, whereas less anxious patients were more likely to give up smoking.     

What causes the build-up of ubiquitin-containing inclusions in Parkinson's disease?

Parkinson's disease (PD) is characterized by the presence of neuronal inclusions in the midbrain known as Lewy bodies. These proteinaceous intracellular deposits may contribute to subsequent dopaminergic neurodegeneration in this brain region. While it is assumed by many investigators that immunopositive ubiquitin staining in Parkinson's-associated Lewy bodies represents the presence of elevated levels of intracellular ubiquitin-protein conjugates, this has yet to be definitively proven. Increases in oxidative stress along with decreased levels of the thiol regulatory molecule glutathione in the midbrain in PD may cause S-thiolation of important components of the ubiquitination system drastically reducing their activities and in fact impairing the cell's ability to ubiquitinate proteins at all. Here, we review evidence for free versus protein-bound ubiquitin in Parkinsonian-associated Lewy bodies and discuss future directions towards resolving this important question as well as its implication for future treatment therapies.     

Is Parkinson's disease an autoimmune disorder of endogenous vasoactive neuropeptides?

Parkinson's disease (PD) is a motor disease including disorders of mobility, fine tremor, rigidity and posture caused by a relentless deterioration of dopaminergic cells in the substantia nigra (SN). Disorders of affect and a range of other symptoms including fatigue, cognitive dysfunction and mental confusion, sleep disorder and addictions are also seen as other CNS sites are also affected. Idiopathic and genetic causes together with inflammatory and degenerative disorders of ageing have been postulated as contributing to PD. Autoimmunity affecting certain vasoactive neuropeptides (VNs) has been postulated as contributing to certain fatigue-related conditions in humans and may be consistent with compromise of receptors associated with VNs and including receptors for vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Pro-inflammatory responses are seen in PD patients consistent with apoptotic neurodegeneration. Involvement of the Th1 directed cytokine interferon-gamma has been demonstrated and Th2 directed cytokines such as IL-10 protect against inflammation-mediated degeneration of dopaminergic neurons in the SN. Nitric-oxide dysregulation is also postulated in PD by fostering dopamine depletion via nitric-oxide synthase (iNOS). Both PACAP and VIP have neuroprotective effects in PD models by inhibiting the production of inflammatory mediators. PACAP specifically protects against the neurotoxicity induced by rotenone as well as protecting against oxidative stress-induced apoptosis. These findings suggest that a defect in VN function may act adversely on SN cells and hence contribute to a clinical presentation consistent with PD. The conclusion drawn from these findings is that PD may be an autoimmune disorder of VNs, specifically PACAP and VIP. Possibly unusual or anatomically specific receptors for these VNs may be involved. If proven, this hypothesis would have significant implications for immunological and pharmacological treatment and prevention of PD.     

Are dopamine derivatives implicated in the pathogenesis of Parkinson's disease?

Parkinson's disease (PD) is the most common motor system disorder affecting 1–2% of people over the age of sixty-five. Although PD is generally a sporadic neurological disorder, the discovery of monogenic, hereditable forms of the disease, representing 5–10% of all cases, has been very important in helping to partially delineate the molecular pathways that lead to this pathology. These mechanisms include impairment of the intracellular protein-degradation pathways, protein aggregation, mitochondria dysfunction, oxidative stress and neuroinflammation. Some of these features are also supported by post-mortem analyses. One of the main pathological hallmarks of PD is the preferential degeneration of dopaminergic neurons, which supports a direct role of dopamine itself in promoting the disorder. This review presents a comprehensive overview of the existing literature that links the aforementioned pathways to the oxidative chemistry of dopamine, ultimately leading to the formation of free radicals and reactive quinone species. We emphasize, in particular, how the reaction of dopamine-derived quinones with several cellular targets could foster the processes involved in the pathogenesis of PD and contribute to the progression of the disorder.     

What contributes to depression in Parkinson's disease?

BACKGROUND: Depression is a common problem in patients with Parkinson's disease, but its mechanism is poorly understood. It is thought that neurochemical changes contribute to its occurrence, but it is unclear why some patients develop depression and others do not. Using a community-based sample of patients with Parkinson's disease, we investigated the contributions of impairment, disability and handicap to depression in Parkinson's disease. METHODS: Ninety-seven patients seen in a population-based study on the prevalence of Parkinson's disease completed the Beck Depression Inventory (BDI). Clinical and historical information on symptoms and complications of Parkinson's disease were obtained from the patients by a neurologist. In addition, clinician and patient ratings of disability on the Schwab and England scale were obtained and a quality of life questionnaire was completed. RESULTS: Moderate to severe depression (BDI > or = 18) was reported by 19.6% of the patients. Higher depression scores were associated with advancing disease severity, recent self-reported deterioration, higher akinesia scores, a mini-mental score of < 25 and occurrence of falls. Disability as rated by the neurologist accounted for 34% of the variance of depression scores. Self-reported impairment of cognitive function and the feeling of stigmatization accounted for > 50% of the variance of depression scores. CONCLUSIONS: Depression in patients with Parkinson's disease is associated with advancing disease severity, recent disease deterioration and occurrence of falls. Regression analysis suggests that depression in Parkinson's disease is more strongly influenced by the patients' perceptions of handicap than by actual disability. The treatment of depression should therefore be targeted independently of treatment of the motor symptoms of Parkinson's disease, and consider the patients' own perception of their disease.     

Are somatic symptoms of depression better predictors of cardiac events than cognitive symptoms in coronary heart disease?

Several recent studies have found that somatic symptoms of depression predict cardiac events in patients with established coronary heart disease but cognitive symptoms of depression do not. However, other studies have not supported this finding, and the research in this area is complicated by methodological differences and inconsistencies in the classification of "cognitive" and "somatic" symptoms. In addition, somatic symptoms are more common than cognitive symptoms in cardiac patients and are often associated with more severe depression. These factors may confound the relationship between somatic symptoms and cardiac outcomes. Some reasons why somatic symptoms may be more common than cognitive symptoms in cardiac patients are considered, as well as whether somatic symptoms are likely to be symptoms of depression or of medical illness. Finally, some directions for future research are proposed.     

Which early ‘red flag’ symptoms identify children with meningococcal disease in primary care?

Background

Symptoms are part of the initial evaluation of children with acute illness, and are often used to help identify those who may have serious infections. Meningococcal disease is a rapidly progressive infection that needs to be recognised early among children presenting to primary care.

Aim

To determine the diagnostic value of presenting symptoms in primary care for meningococcal disease.

Design of study

Data on a series of presenting symptoms were collected using a parental symptoms checklist at point of care for children presenting to a GP with acute infection. Symptom frequencies were compared with existing data on the pre-hospital features of 345 children with meningococcal disease.

Setting

UK primary care.

Method

The study recruited a total of 1212 children aged under 16 years presenting to their GP with an acute illness, of whom 924 had an acute self-limiting infection, including 407 who were reported by parents to be febrile. Symptom frequencies were compared with those reported by parents of 345 children with meningococcal disease. Main outcome measures were diagnostic characteristics of individual symptoms for meningococcal disease.

Results

Five symptoms have clinically useful positive likelihood ratios (LR+) for meningococcal disease: confusion (LR+ = 24.2, 95% confidence interval [CI] = 11.5 to 51.3), leg pain (LR+ = 7.6, 95% CI = 4.9 to 11.9), photophobia (LR+ = 6.5, 95% CI = 3.8 to 11.0), rash (LR+ = 5.5, 95% CI = 4.3 to 7.1), and neck pain/stiffness (LR+ = 5.3, 95% CI = 3.5 to 8.3). Cold hands and feet had limited diagnostic value (LR+ = 2.3, 95% CI = 1.9 to 3.0), while headache (LR+ = 1.0, 95% CI = 0.8 to 1.3), and pale colour (LR+ = 0.3, 95% CI = 0.2 to 0.5) did not discriminate meningococcal disease in children.

Conclusion

This study confirms the diagnostic value of classic ‘red flag’ symptoms of neck stiffness, rash, and photophobia, but also suggests that the presence of confusion or leg pain in a child with an unexplained acute febrile illness should also usually prompt a face-to-face assessment to exclude meningococcal disease. Telephone triage systems and primary care clinicians should consider these as ‘red flags’ for serious infection.     

Which measures of obesity are related to depressive symptoms and in whom?

The authors asked which obesity measurements were associated with depressive symptoms, whether this relationship differed by gender, and whether controlling for fatigue and response bias affected the relationship. A sample of 129 subjects (66 men, 63 women), with a mean age of 36.9 years and a mean Body Mass Index (BMI) of 26.4 participated in the study. Depressive symptoms, levels of fatigue, response bias, and anthropometrics were assessed. In women, but not men, BMI and percent of ideal body weight were related to depression. However, percent of body fat did not show a relationship with depression after controlling for fatigue and response bias. These findings suggest that women's depressive symptoms are more influenced by body size than body fat composition, whereas men's depressive symptoms seem to be unrelated to obesity.     

Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?

Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed.     

Is Parkinson's disease the heterozygote form of Wilson's disease: PD = 1/2 WD?

Wilson's disease (WD) patients often present with Parkinson's disease (PD). Furthermore, most patients with PD have reduced ceruloplasmin, a characteristic of Wilson's disease. WD is an autosomal recessive disease (requires two faulty copies of a gene to produce a homozygote individual) that afflicts 1 in 1000 people. However, the number of people with one faulty copy (heterozygotes) is much larger, probably about 2% of the population. I hypothesize that the large number of heterozygotes for WD are at greatly increased risk for idiopathic PD, because these people accumulate free copper in the basal ganglia at a slower rate than homozygotes, which accounts for the fact that PD usually develops after 40 years of age. In WD, a ceruloplasmin deficiency results in accumulation of free Cu in the liver, brain, kidneys, etc. The excess Cu results in impaired Zn absorption, which would account for the low levels of Zn in the brains of PD patients. Moreover, the high levels of Fe found in the substantia nigra of PD patients may perhaps be explained by free Cu binding to iron binding protein-1 (IBP-1), causing it to malfunction and preventing it from detaching itself from the transferrin receptor (TfR) inhibition gene, resulting in expression of TfR even when the cell has plenty of Fe. The gradual accumulation of Fe and Cu would explain the damage inflicted on the substantia nigra by free radicals catalyzed by these two metals and which is exacerbated by the low levels of CuZnSOD, due to the Zn deficiency mentioned above. Moreover, if this hypothesis is correct, then PD could be used to help discover the gene (or genes) responsible for WD and vice versa. Furthermore, idiopathic PD could be prevented by identifying the heterozygote individuals and providing them with Zn supplementation, Cu chelation therapy and phlebotomy to eliminate Fe.     

Which presenteeism measures are more sensitive to depression and anxiety?

BACKGROUND: Lost productivity from attending work when unwell, or "presenteeism", is a largely hidden cost of mental disorders in the workplace. Sensitive measures are needed for clinical and policy applications, however there is no consensus on the optimal self-report measure to use. This paper examines the sensitivity of four alternative measures of presenteeism to depression and anxiety in an Australian employed cohort. METHODS: A prospective single-group study in ten call centres examined the association of presenteeism (presenteeism days, inefficiency days, Work Limitations Questionnaire, Stanford Presenteeism Scale) with Patient Health Questionnaire depression and anxiety syndromes. RESULTS: At baseline, all presenteeism measures were sensitive to differences between those with (N=69) and without (N=363) depression/anxiety. Only the Work Limitations Questionnaire consistently showed worse productivity as depression severity increased, and sensitivity to remission and onset of depression/anxiety over the 6-month follow-up (N=231). There was some evidence of individual depressive symptoms having a differential association with different types of job demands. LIMITATIONS: The study findings may not generalise to other occupational settings with different job demands. We were unable to compare responders with non-responders at baseline due to anonymity. CONCLUSIONS: In this community sample the Work Limitations Questionnaire offered additional sensitivity to depression severity, change over time, and individual symptoms. The comprehensive assessment of work performance offers significant advantages in demonstrating both the individual and economic burden of common mental disorders, and the potential gains from early intervention and treatment.     

Depressive symptoms in inflammatory bowel disease: an extraintestinal manifestation of inflammation?

Depressive symptoms are reported by more than 20% of people with inflammatory bowel disease (IBD), while sleep difficulties and fatigue are even more common. Co-morbid depressive symptoms predict a poor IBD course, including increased risk of relapse and surgery, which is inconsistently improved by psychological treatments. Rather than being distinct systems, there is compelling evidence for bidirectional communication between gut and brain, driven by neural, metabolic, endocrine and inflammatory mediators. An emerging concept is that depressive symptoms may be mechanistically linked to excess inflammation and dysregulation of the gut–brain axis. Given the close link between the intestinal microbiota and host immune responses, patients prone to shifts in their intestinal microbiome, including smokers, those with poor diet and early life stress, may be exposed to exaggerated immune responses. Excess inflammation is associated with brain changes (depressive symptoms, fatigue, sleep difficulties) and worsening gastrointestinal symptoms, which are exacerbated by psychological distress. Equally, treatments both for depressive symptoms and IBD provide opportunities to break this cycle by reducing the causes and effects of inflammation. As well as addressing potential risk factors such as smoking and diet, treatments to alter the microbiome may reduce depressive symptoms. Observational evidence suggests that anti-inflammatory treatments for IBD may improve co-morbid depressive symptoms correlating with reduction in inflammation. With a growing range of treatments targeting inflammation centrally, peripherally and in the gut, IBD provides a unique model to understand the interplay between brain and gut in the pathogenesis of depressive symptoms, both in IBD and in the whole population.