Relapsing polychondritis: reversible airway obstruction is not always asthma

Relapsing polychondritis (RP) is a rare disease characterized by recurrent inflammation of cartilaginous and other proteoglycan-rich tissues. Respiratory tract involvement is a common cause of morbidity and mortality in RP. We describe a patient whose clinical features at onset of disease were typical of asthma. Later, the patient developed symptoms and signs characteristic of RP. Tracheobronchomalacia necessitated airway support by stenting. The possibility that airway obstruction in the initial stages of RP is due to airway inflammation and that early, aggressive immunosuppressive treatment of RP may delay or prevent irreversible cartilaginous destruction and airway collapse are discussed.     

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Childhood Bone Mineral Content Is Associated With Methylation Status of the RXRA Promoter at Birth

Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid‐X receptor‐alpha (RXRA) is an essential cofactor in the action of 1,25‐dihydroxyvitamin D (1,25[OH]₂‐vitamin D), and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual‐energy X‐ray absorptiometry, in a population‐based mother‐offspring cohort (Southampton Women's Survey). Relationships between maternal plasma 25‐hydroxyvitamin D (25[OH]‐vitamin D) concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, a higher percent methylation at four of six RXRA CpG sites measured was correlated with lower offspring bone mineral content (BMC) corrected for body size (β = ?2.1 to ?3.4 g/SD, p = 0.002 to 0.047). In a second independent cohort (n = 64), similar negative associations at two of these CpG sites, but positive associations at the two remaining sites, were observed; however, none of the relationships in this replication cohort achieved statistical significance. The maternal free 25(OH)‐vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β = ?3.3 SD/unit, p = 0.03). Thus, perinatal epigenetic marking at the RXRA promoter region in umbilical cord was inversely associated with offspring size–corrected BMC in childhood. The potential mechanistic and functional significance of this finding remains a subject for further investigation. © 2014 American Society for Bone and Mineral Research.     

Reduced Levels of Vasopressin and Reduced Behavioral Modulation of Oxytocin in Psychotic Disorders

Oxytocin (OT) and arginine vasopressin (AVP) exert robust influence on social affiliation and specific cognitive processes in healthy individuals. Abnormalities in these neuroendocrine systems have been observed in psychotic disorders, but their relation to impairments in behavioral domains that these endocrines modulate is not well understood. We compared abnormalities of OT and AVP serum concentrations in probands with schizophrenia (n = 57), schizoaffective disorder (n = 34), and psychotic bipolar disorder (n = 75); their first-degree relatives without a history of psychosis (n = 61, 43, 91, respectively); and healthy controls (n = 66) and examined their association with emotion processing and cognition. AVP levels were lower in schizophrenia (P = .002) and bipolar probands (P = .03) and in relatives of schizophrenia probands (P = .002) compared with controls. OT levels did not differ between groups. Familiality estimates were robust for OT (h ² = 0.79, P = 3.97e−15) and AVP (h ² = 0.78, P = 3.93e−11). Higher levels of OT were associated with better emotion recognition (β = 0.40, P < .001) and general neuropsychological function (β = 0.26, P = .04) in healthy controls as expected but not in any proband or relative group. In schizophrenia, higher OT levels were related to greater positive symptom severity. The dissociation of OT levels and behavioral function in all proband and relative groups suggests that risk and illness factors associated with psychotic disorders are not related to reduced OT levels but to a disruption in the ability of physiological levels of OT to modulate social cognition and neuropsychological function. Decreased AVP levels may be a marker of biological vulnerability in schizophrenia because alterations were seen in probands and relatives, and familiality was high.Key words: oxytocin, vasopressin, schizophrenia, bipolar disorder, emotion recognition     

Distinguishing Between Schizophrenia and Other Psychotic Disorders

The Diagnostic and Statistical Manual of Mental Disorders (DSM) has provided diagnostic reliability across observers while neglecting biological validity. The current theme issue explores the boundaries between schizophrenia and bipolar disorder, using neuro-cognition, systems neuroscience, and genetics as points of departure to begin consideration of a biologically based reclassification of these illnesses.Key words: schizophrenia, bipolar, validity, classification

“Ce n’est qu’un début, continuons le débat.” (“This is just the beginning, let’s continue the debate.”)French students (May 1968)

In the ongoing debate over where to draw the boundary (if any) between schizophrenia and bipolar disorder, the arguments are familiar, the battle lines clearly drawn, but the scientific observations continue to be updated in important ways that make a reassessment timely. The current issue of the Bulletin features comprehensive overviews from the vantage points of genetics and systems neuroscience that continue to reshape the nature of the debate.Arguments over the discrete vs continuous nature of schizophrenia and bipolar disorder are important because they promise to translate into improved, more patient-specific prognoses and therapies.Disease classifications proceed from some logical beginning: In the absence of both informative biological data and clinical physical signs, clinical phenomenology, family history, and disease course constitute the mandatory starting points on the road to meaningful diagnostic categories. Hence, Kraepelin began in 1893 by defining these 2 entities based on longitudinal course and outcome. He had already begun to backtrack from this dichotomy by 1920 in the final edition of his Lehrbuch.¹ Before that, the follow-up studies from his pupil Zendig² demonstrated favorable outcome in a third of Kraepelin’s own large schizophrenia case series. The boundaries between clinical entities defined by phenomenology appear to be distributed on a continuum and to lack sharp demarcations. Thus, one-third of patients with schizophrenia simultaneously meet criteria for major depression,³ one-third of patients with bipolar illness manifest psychotic symptoms, which in some cases persist between overt episodes of mood disturbance.⁴ Recently, Keshavan⁵ showed no point of symptomatic rarity between schizophrenia, psychotic bipolar disorder, and schizoaffective disorder in the large Bipolar Schizophrenia Network on Intermediate Phenotypes sample. Similarly, the Suffolk County mental health project showed a lack of boundary, defined in terms of functioning, between schizoaffective disorder and schizophrenia,⁶ although there are occasional reports of biological distinctions between them, for example.⁷ Response to medications has not been especially helpful as a guide. The early Northwick Park studies offered some suggestion that patients with psychosis responded to antipsychotics, patients with mood disorders responded to lithium, and patients with features of both syndromes responded to both medicines.⁸ However, antipsychotic medications are now prescribed routinely for schizophrenia, bipolar disorder, and antidepressant treatment–resistant major depression, presumably, in part because they are effective in these conditions. Real-world experience with these patients shows that many are being prescribed polypharmaceutical cocktails of antipsychotic, antidepressant, and mood stabilizer medications. As is frequently pointed out, the one exception to this cross-diagnostic promiscuity seems to be lithium, to which about one-third of nonpsychotic bipolar patients and a much smaller proportion of classic schizophrenia patients respond with symptom remission.⁹ Although both schizophrenia and bipolar disorder are clearly heritable, as Cardno and Owen¹⁰ illustrate in this issue, segregation within families is less clear-cut than believed previously, and these conditions do not decisively “breed true,”¹¹ although psychotic bipolar illness may aggregate familially.⁴ Genome wide–association studies tend to uncover candidate single-nucleotide polymorphisms that confer risk for both disorders, and genes such as DISC-1 are also associated with increased risk for schizophrenia, bipolar illness, major depression, and other conditions.As pointed out by Frangou¹² in this issue, emergent properties such as cognition are an excellent starting point for examining differences between syndromes because they are reliably assessed across centers with standardized tests. Because they demonstrate both heritability and frequent abnormality in unaffected first-degree relatives, they constitute phenotypes, conceptually.¹¹ In this issue, Reilly and Sweeney¹³ point out, “Considerable evidence supports the notion that broadly impaired cognitive functioning is central to the pathophysiology of psychosis, and … [its] magnitude, rather than [its] presence differentiates syndromes within the psychosis spectrum.” They further suggest, “The detection of specific effects … is challenging yet critical if the field is to further advance development of pharmacological treatments targeting cognitive deficits … .” In our search for specificity, we ask if there is any point in the illness course where differences emerge? Frangou¹² notes that important differences are detectable in that premorbid cognitive and social abnormalities appear to be less marked in bipolar illness, although these differences diminish after illness onset. Similarly, copy number variants occurring in central nervous system–relevant genes are significantly commoner in schizophrenia than bipolar disorder, although, as mentioned earlier, genetic differences are not schizophrenia-specific, being found in association with other serious neurodevelopmental disorders, including epilepsy, learning disabilities, and autism spectrum disorders.Where do we go from here? This debate will continue until distinct etiopathologies for schizophrenia and bipolar disorder emerge—parallel events that ultimately ended this type of debate in clinical medicine. Ultimately, though, we are likely to define the new “illnesses” based on regularly co-occurring biological (including genetic) characteristics. One possibility in the short term is that we remain diagnostically uncommitted and code psychosis and mood disorder separately, as suggested by Kotov.¹⁴ Some researchers have argued strongly against this stance.¹⁵ Different associations with indices of neurodevelopmental impairment may be one point of departure as suggested in this issue by Cardno and Owen¹⁰ and Frangou.¹² Frangou suggests that “abnormalities in multiple large-scale neural networks and alterations in local micro-scale circuitry within associative and sensory cortices” caused by environmental insults and genetic variation, “disrupt processes responsible for orderly neuronal configuration” (eg, synaptic integrity, neurotransmission). Identifying such abnormalities then proceeds logically toward a redefinition of major mental illnesses based on systems neuroscience and the defining of “more homogeneous groups of patients.”¹² This strategy may reveal similarities across all putatively developmentally based psychiatric illnesses, including autism and learning disabilities, extending beyond schizophrenia and bipolar disorder. Cardno and Owen¹⁰ suggest we move away from lifetime diagnostic categories toward a system that relies more on “categorical or dimensional syndromes, networks of correlated symptoms, and/or endophenotypes … according to particular research or clinical requirements.”Regarding the genetic underpinnings of these disorders, we ask, “Precisely what is being inherited?” One possibility is that a small number of genes are being passed on that are responsible for multiple clinical manifestations, from mood instability to psychoticism (ie, an instance of pleiotropy). Another possibility is that risk is being inherited for more than one behavioral trait, which happens to commonly co-occur, for a variety of reasons including assortative mating. For example, “psychoticism,” whose pure form is expressed as Kraepelinian schizophrenia, and “mood instability,” whose pure form is expressed as nonpsychotic bipolar illness, may both be passed on, with the possibility of them being mixed together in various combinations to produce, eg, schizoaffective or psychotic bipolar disorder.What might the new disease landscape look like, whether based on neuronal circuit-based endophenotypes or commonalities in risk genes and their associated molecular biological processes? One possibility is that several clinical groupings will emerge that are phenomenologically heterogeneous, containing examples of what we now define clinically as schizophrenia and bipolar disorder, but consistent in their underlying biological markers. This would be analogous to the fate of “dropsy” in medicine. A less satisfactory outcome would be that more knowledge of etiopathology would result in the fissuring of familiar clinical syndromes into unique biological clusters, representing agglomerations defined by differing pathologic processes leading to disruption in final common biological pathways, more along the lines of the manner in which Alzheimer’s disease is now considered. The ultimate hope is to aggregate disorders according to biological mechanisms that underlie clinical phenomena and that point us toward evidence-based treatment targets and interventions. This is consistent with the National Institute of Mental Health’s Research Domain Criteria¹⁶ and the earlier cognitive neuropsychiatric approach.^17–19 This debate began with Kraepelin, is moving forward, but continues.     

Mechanisms of exercise-induced asthma

In a previous review in this journal McFadden eloquently presented the findings which led him and his colleagues to propose that respiratory heat loss and the subsequent cooling of the airways are the initial reaction sequence leading to airway obstruction in hyperventilation and exercise-induced asthma [62]. He further concluded that: “Exercise per se is not essential and serves only as means to increase ventilation”. Our interpretation of currently available data has led us to conclude that while respiratory heat loss may play an important permissive role in initiating the bronchoconstriction which follows exercise, the weight of evidence indicates that exercise per se serves as the trigger mechanism and is not just a tool to increase ventilation. Moreover, we believe that the role of exercise in releasing chemical mediators has been established, although pathways by which the airway smooth muscle is affected are still uncertain.