Telomere length and cardiovascular aging: the means to the ends?

Epidemiologic and other evidence clearly indicates that peripheral blood leukocyte telomere length, a systemic marker for biological aging, can be useful as a cardiovascular aging biomarker. Although telomere biology might yield new insights into the underlying molecular biology of vascular aging and even radically improve current cardiovascular risk stratification, the specific nature of the association between telomere length and cardiovascular disease still remains to be elucidated. Here, we review several candidate hypotheses and critically review supporting and contesting scientific evidence for the underlying theories. For each hypothesis, we discuss the potential implications. We conclude that the most promising theory is based on an acceleration of the telomere attrition rate due to cardiovascular aging related factors, possibly complemented by telomere mediated hematopoietic senescence.     

Immune aging – A mechanism in autoimmune disease

Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.     

Does cellular aging relate to patterns of allostasis?: An e`xamination of basal and stress reactive HPA axis activity and telomere length

Long-term exposure to stress and its physiological mediators, in particular cortisol, may lead to impaired telomere maintenance. In this study, we examine if greater cortisol responses to an acute stressor and/or dysregulated patterns of daily cortisol secretion are associated with shorter telomere length. Twenty-three postmenopausal women comprising caregivers for dementia partners (n=14) and age- and BMI-matched non-caregivers provided home sampling of cortisol-saliva samples at waking, 30 min after waking, and bedtime, and a 12-hour overnight urine collection. They were also exposed to an acute laboratory stressor throughout which they provided saliva samples. Peripheral blood mononuclear cells were isolated from a fasting blood sample and assayed for telomere length. As hypothesized, greater cortisol responses to the acute stressor were associated with shorter telomeres, as were higher overnight urinary free cortisol levels and flatter daytime cortisol slopes. While robust physiological responses to acute stress serve important functions, the long-term consequences of frequent high stress reactivity may include accelerated telomere shortening.     

Trauma and PTSD – An overlooked pathogenic pathway for Premenstrual Dysphoric Disorder?

Summary ¶Background: A recent epidemiological analysis on premenstrual dysphoric disorder (PMDD) in the community revealed increased rates of DSM-IV posttraumatic stress disorder (PTSD) among women suffering from PMDD. Aims: To explore whether this association is artifactual or might have important pathogenic implications. Methods: Data come from a prospective, longitudinal community survey of an original sample of N=1488 women aged 14–24, who were followed-up over a period of 40 to 52 months. Diagnostic assessments are based on the Composite International Diagnostic Interview (CIDI) using the 12-month PMDD diagnostic module. Data were analyzed using logistic regressions (odds ratios) and a case-by-case review. Results: The age adjusted odds ratio between PTSD and threshold PMDD was 11.7 (3.0–46.2) at baseline. 10 women with full PTSD and at least subthreshold PMDD were identified at follow-up. Most reported an experience of abuse in childhood before the onset of PMDD. Some had experienced a life-threatening experience caused by physical attacks, or had witnessed traumatic events experienced by others. 3 women reported more than one traumatic event. Conclusions: A case-by-case review and logistic regression analyses suggest that women with traumatic events and PTSD have an increased risk for secondary PMDD. These observations call for more in-depth analyses in future research.Received March 3, 2003; accepted August 4, 2003 Published online October 22, 2003     

Chromogranin A – unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls

Chromogranin A, despite a number of limitations, is still the most valuable marker of neuroendocrine tumors (NETs). Granins belong to the family of acidic proteins that constitute a major component of secretory granules of various endocrine and neuroendocrine cells, which are components of both the classical endocrine glands and the diffuse neuroendocrine system. These cells are a potential source of transformation into neuroendocrine tumors. The awareness of potential causes influencing the false results of its concentrations simplifies diagnosis and treatment. One of the disadvantages of this marker is its non-specificity and the existence of a number of pathological processes leading to an increase in its concentration, which often results in confusion and diagnostic difficulties. The molecular structure is characterized by a number of sites susceptible to the proteolytic activity of enzymes, resulting in the formation of a number of biologically active peptides. Presumably they act as precursors of active proteins. Chromogranin expression correlates with the amount of secretory vesicles in neuroendocrine cells. The peptide chain during biochemical changes becomes a precursor of biologically active proteins with a wide range of activities. There are a number of commercially available kits for the determination of chromogranin A, which differ in methodology. We present the evaluation of chromogranin A as a marker of neuroendocrine tumors in clinical practice and the possible factors that may affect the outcome of its concentration.     

“Killing the Blues”: A role for cellular suicide (apoptosis) in depression and the antidepressant response?

Apoptosis or programmed cell death is a critical regulator of tissue homeostasis and emerging evidence is focused on the role of apoptosis mechanisms in the central nervous system. Generally, apoptosis is necessary to prevent cancerous growths. However, excessive apoptosis in post-mitotic cells such as neurons leads to neurodegeneration. Chronic stress, which can precipitate depression, has been shown to increase the susceptibility of certain populations of neurons to cell death while antidepressant treatment, in general, shows the ability to oppose these effects and promote neuroprotection. Here, we discuss the major players in cell death pathways, the physiological implications of chronic stress and depression, chronic stress models in animals which result in cell death and the different classes of antidepressants and mood stabilizers that have been shown to prevent cell death. We discuss the cellular effects of antidepressants and possible modes of action in preventing apoptosis. Investigations on the role of apoptosis in mediating the molecular, physiological and behavioural effects of antidepressants may help gain a better mechanistic insight into drug action and allow refinement of current therapeutics in order to target these pathways in a specific manner.     

FFPE tissue as a feasible source for gene expression analysis – A comparison of three reference genes and one tumor marker

Background

Formalin-fixation, paraffin-embedding is the standard processing technique for tumor tissue in modern pathology. New techniques such as cryo-conservation allow rapid fixation and long-time storage but come along with increased costs and enlarged storage complexity. However, formalin-fixed, paraffin-embedded (FFPE) tissue is available in a large quantity, making it the ideal material for retrospective studies.The following study was designed to investigate the influence of formalin-fixation on the quality of mRNA and applicability of FFPE-derived mRNA for gene expression analysis. Three potential reference genes for pulmonary tumors with neuroendocrine differentiation were included and tested for their robust expression.

Materials and methods

Eighty specimens collected from 2005 to 2012 at the Institute of Pathology and Neuropathology at the University Hospital Essen were analyzed for their gene expression by using TaqMan^® gene expression assays on demand (AoD). Three distinct potential reference genes (ACTB, GAPDH, HPRT1) were evaluated for their expression, and a proteasome subunit (PSMA1) was included in the analysis as tumor marker and functioned as an internal technical control.

Conclusion

For GAPDH and ACTB, a highly significant correlation and consistent expression between the investigated entities was found, making them reliable reference genes for further research. Additionally, the feasibility for a FFPE tissue-based gene expression analysis was verified by showing that the mRNA quality is sufficient. When standardized FFPE preparation is performed carefully, sufficient mRNA can be isolated for reliable and successful gene expression analysis. That provides the basis the door for large, retrospective studies that correlate molecular and clinical follow-up data.     

Back on track – On the role of the microtubule for kinesin motility and cellular function

The evolution of cytoskeletal filaments (actin- and intermediate-filaments, and the microtubules) and their associated motor- and non-motor-proteins has enabled the eukaryotic cell to achieve complex organizational and structural tasks. This ability to control cellular transport processes and structures allowed for the development of such complex cellular organelles like cilia or flagella in single-cell organisms and made possible the development and differentiation of multi-cellular organisms with highly specialized, polarized cells. Also, the faithful segregation of large amounts of genetic information during cell division relies crucially on the reorganization and control of the cytoskeleton, making the cytoskeleton a key prerequisite for the development of highly complex genomes. Therefore, it is not surprising that the eukaryotic cell continuously invests considerable resources in the establishment, maintenance, modification and rearrangement of the cytoskeletal filaments and the regulation of its interaction with accessory proteins. Here we review the literature on the interaction between microtubules and motor-proteins of the kinesin-family. Our particular interest is the role of the microtubule in the regulation of kinesin motility and cellular function. After an introduction of the kinesin–microtubule interaction we focus on two interrelated aspects: (1) the active allosteric participation of the microtubule during the interaction with kinesins in general and (2) the possible regulatory role of post-translational modifications of the microtubule in the kinesin–microtubule interaction.     

Microarrays of over 2000 hydrogels – Identification of substrates for cellular trapping and thermally triggered release

In this paper we describe an approach whereby over 2000 individual polymers were synthesized, in situ, on a microscope slide using inkjet printing. Subsequent biological analysis of the entire library allowed the rapid identification of specific polymers with the desired properties. Herein we demonstrate how this array of new materials could be used for the identification of polymers that allow cellular adherence, proliferation and then mild thermal release, for multiple cell lines, including mouse embryonic stem (mES) cells. The optimal, identified hydrogels were successfully scaled-up and demonstrated excellent cell viability after thermal detachment for all cell lines tested. We believe that this approach offers an avenue to the discovery of a specific thermal release polymer for every cell line.     

Subthreshold depression in children and adolescents – a systematic review

Background

Depressive disorders are disabling conditions striking at all ages. In adults, subthreshold depression (SD) is viewed as being on a continuum with major depressive disorder (MDD). Whether this holds for children and adolescents, is still unclear. We performed the first systematic review of SD in subjects below 18 years, in order to explore if childhood SD and MDD share causal pathways, phenomenology and outcomes, supporting a dimensional view.

Methods

A critical systematic review in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. A review protocol was developed a priori, and all reports were assessed by two reviewers.

Results

The literature search generated 941 eligible references and 24 studies were included. Although diagnostic criteria for SD showed great variability, similarities for SD and MDD were striking. Both were common conditions with similar risk factor patterns. Clinical characteristics in both groups were depressed mood, suicidal ideation and high comorbidity. Outcomes were almost equally poor, with increased psychiatric morbidity and health service use. SD intervention studies showed promising results.

Limitations

Reports with data on SD not reported in keywords or abstract may have been missed by the search strategy.

Conclusion

A dimensional view of depressive disorders is also supported in children and adolescents, suggesting SD to be a precursor to MDD. Although SD is a somewhat milder condition than MDD, it has severe outcomes with psychopathology and impairment. There is a need of identifying cost-efficient and longlasting interventions in order to prevent development of early SD into MDD     

Antineutrophil cytoplasmic antibody—A useful serological marker for vasculitis

Systemic necrotizing vasculitides, including polyarteritis nodosa, Churg-Strauss syndrome, overlap systemic vasculitis, Wegener's granulomatosis, and idiopathic crescentic glomerulonephritis, are frequent clinical diagnostic problems. These diseases have diverse presentations and are often rapidly progressive, causing irreversible injury to the vessels of the kidneys and lungs before effective immunosuppressive therapy is instituted. Even in their less fulminant forms, they are a cause of significant morbidity and mortality. Antineutrophil cytoplasmic antibody, a recently identified autoantibody, has a high sensitivity and specificity for this spectrum of diseases. The clinical and pathological similarities, the high frequency of antineutrophil cytoplasmic antibody expression, and the similar good response to immunosuppressive therapy suggest that these diseases may be linked by a common pathophysiological mechanism. Evidence is growing that antineutrophil cytoplasmic antibody plays a central role in this mechanism. A revision in the classification scheme of vasculitides to recognize that the polyarteritis group (polyarteritis nodosa, Churg-Strauss syndrome, and overlap systemic vasculitis), Wegener's granulomatosis, and idiopathic crescentic glomerulonephritis are closely related diseases may be warranted. The clinical and pathological features of systemic necrotizing vasculitides and the current knowledge concerning antineutrophil cytoplasmic antibodies are reviewed.     

Torque teno virus load as marker of rejection and infection in solid organ transplantation – A systematic review and meta-analysis

Balancing immunosuppression to prevent rejection in solid organ transplant (SOT) recipients remains challenging. Torque teno virus (TTV), a commensal non-pathogenic virus, has been proposed as marker of functional immunity: higher loads correspond to over-immunosuppression, and lower loads to under-immunosuppression. This review offers an overview of the current evidence of the association between TTV-load and infection and rejection after SOT. A systematic literature search strategy, deposited in the PROSPERO registry, resulted in 548 records. After screening, 23 original and peer-reviewed articles were assessed investigating the association between TTV-load, infection and/or rejection in SOT. The Quality in Prognostic Studies (QUIPS)-tool was used to assess the risk of bias. Meta-analysis with random-effects was performed on results with similar outcomes and exposure measures. Most of the included studies involved retrospective cohorts in which the TTV-load was measured longitudinally, within the first 2 years post-transplantation. Infection outcomes differed between studies and included viral, bacterial, parasitic and fungal infections. Rejection was defined by biopsy confirmation or initiation of rejection treatment. Twelve out of 16 studies reported an association between high TTV-load and infections, whereas 13 out of 15 reported an association between low TTV-load and rejection. Meta-analysis showed an increased risk of infection (OR: 1.16, 95% CI: 1.03–1.32; HR: 1.05, 95% CI: 0.97–1.14) and a decreased risk of rejection (OR: 0.90, 95% CI: 0.87–0.94; HR: 0.74, 95% CI: 0.71–0.76) per 1 log TTV-load increase. The qualitative assessment showed varying risks of bias in the included studies. This systematic review and meta-analysis indicates that blood TTV-load measured within the first 2 years after SOT is associated with the risk of infection or allograft rejection, although substantial risk of bias in the studies included warrant cautious interpretation. The results in this review provide a rationale for larger, prospective, studies into TTV as marker of infection and rejection after SOT.     

Challenges and opportunities in developing a psychological intervention for perinatal depression in rural Pakistan – a multi-method study

Summary Perinatal depression, due to its high prevalence and associations with disability, poor infant development and family disruption, is a major public health problem in developing countries. In non-literate and poor communities where depression is not recognised and where there are no specialists, developing a culturally acceptable, deliverable psychological intervention that community members find useful, presents special challenges but also opportunities. We describe lessons learned from a multi-method formative study to develop and deliver a psychological intervention to depressed mothers and their infants through non-specialist village based health workers.     

A review of technology-assisted self-help and minimal contact therapies for anxiety and depression: is human contact necessary for therapeutic efficacy?

Technology-based self-help and minimal contact therapies have been proposed as effective and low-cost interventions for anxiety and mood disorders. The present article reviews the literature published before 2010 on these treatments for anxiety and depression using self-help and decreased therapist-contact interventions. Treatment studies are examined by disorder as well as amount of therapist contact, ranging from self-administered therapy and predominantly self-help interventions to minimal contact therapy where the therapist is actively involved in treatment but to a lesser degree than traditional therapy and predominantly therapist-administered treatments involving regular contact with a therapist for a typical number of sessions. In the treatment of anxiety disorders, it is concluded that self-administered and predominantly self-help interventions are most effective for motivated clients. Conversely, minimal-contact therapies have demonstrated efficacy for the greatest variety of anxiety diagnoses when accounting for both attrition and compliance. Additionally, predominantly self-help computer-based cognitive and behavioral interventions are efficacious in the treatment of subthreshold mood disorders. However, therapist-assisted treatments remain optimal in the treatment of clinical levels of depression. Although the most efficacious amount of therapist contact varies by disorder, computerized treatments have been shown to be a less-intensive, cost-effective way to deliver empirically validated treatments for a variety of psychological problems.     

Distal femoral replacement – Does length matter? Mid-term results for distal femoral replacements

BackgroundReview of mid-term results (five years) for tumour and revision arthroplasty surgery using the Stanmore METS® distal femoral replacement.MethodsData were collected retrospectively for 90 patients for procedures performed between 2002 and 2019. Kaplan-Meier survivorship for implant was estimated at five years post-op. Endpoints for survivorship analysis included revision for any cause and as per Henderson classification. Log rank test was used to compare implant survival for different categorical variables. Musculo-Skeletal Tumour Society (MSTS) score was used to estimate function.ResultsOverall implant survival at five years was 76% (95% CI 66–86). Implants with a short body (<= 45 mm) had significantly better implant survival [87% (95% CI 78–99)] compared to those with larger bodies [63% (95% CI 48–82)] (logrank test, p = 0.031). There was no significant difference in implant survival for tumour and revision arthroplasty patients (logrank test, p = 0.61). Mean MSTS scores (median follow-up = 3.5 years) for tumour and revision arthroplasty patient were 71% and 63% respectively (Wilcoxon rank test, p < 0.05). Higher total number of surgeries was a significant predictor of patient mortality [HR = 0.7 (95% CI 0.49–0.99)]. Longer bodies were a significant predictor of implant failure [HR = 3.2 (95% CI 1.05–10.53), p < 0.05].ConclusionOverall outcome of Stanmore METS® distal femoral replacement at five years following tumour and revision arthroplasty reconstruction is comparable to the other implants.