Declining levels of serum chemokine (C-X-C motif) ligand 10 over time are associated with new onset of psoriatic arthritis in patients with psoriasis: a new biomarker?

BACKGROUND: We previously found that serum levels of chemokine (C-X-C motif) ligand 10 (CXCL10) decreased after the onset of psoriatic arthritis (PsA). OBJECTIVES: We measured CXCL10 levels over time in patients with psoriasis who developed PsA to determine whether the drop in CXCL10 was specific to these patients and further assess its association with PsA development. METHODS: Prospectively followed patients with psoriasis without arthritis [cutaneous psoriasis (PsC)] were assessed yearly by rheumatologists for the presence of PsA. Patients with PsC who developed PsA (converters) were matched to those that did not develop PsA (nonconverters) based on psoriasis duration and the interval between follow-up visits. The duration between baseline and the first visit postconversion in converters was used to assign a pseudoconversion date in nonconverters. Linear mixed-effects models were used to model the expression of CXCL10 over time. RESULTS: CXCL10 significantly declined over time in converters prior to PsA development with a significant difference in the trend over time between converters (n = 29) and nonconverters (n = 52; P < 0·001). CXCL10 continued to decline after PsA onset in a subset of converters. There was a significant difference in the trend of CXCL10 levels between converters (n = 24) and nonconverters (n = 16; P = 0·01) preconversion/pseudoconversion. This difference remained postconversion (P = 0·006) and was not different from the preconversion period (P = 0·75). CONCLUSIONS: A large difference in CXCL10 was identified in patients with PsC that are destined to develop PsA over time. This exploratory analysis supports the association of CXCL10 with PsA development in patients with PsC and warrants further study of the predictive ability of this chemokine. What is already known about this topic? Chemokine (C-X-C motif) ligand 10 (CXCL10) is elevated in psoriatic affected tissues and serum and/or plasma. Patients with psoriasis that develop psoriatic arthritis (PsA) have elevated CXCL10 levels at baseline and these levels drop after arthritis onset. What does this study add? By monitoring levels of CXCL10 in serum over multiple visits in patients with psoriasis that develop PsA as well as those that do not develop PsA, an association was identified between CXCL10 and PsA development. What is the translational message? CXCL10 is a strong candidate for use by physicians for the detection of patients with psoriasis that are at risk of developing PsA. Linked Comment: Kirby and Fitzgerald. Br J Dermatol 2020; 183:805-806.

The functional MICA-129 polymorphism is associated with skin but not joint manifestations of psoriatic disease independently of HLA-B and HLA-C.

A methionine/valine polymorphism at amino acid 129 of the major histocompatibility complex class I chain-related gene A (MICA-129) categorizes alleles into strong and weak binders of the natural killer (NK) and T-cell receptor NKG2D. We investigated whether MICA-129 is differentially associated with skin and joint manifestations of psoriatic disease (PsD) independently of human leukocyte antigen (HLA)-C and HLA-B in patients and controls from Toronto and St. John's. The MICA-129 methionine (Met) allele, particularly Met/Met homozygosity, was strongly associated with both cutaneous psoriasis (PsC) and psoriatic arthritis (PsA) independently of HLA-B and HLA-C in Toronto patients, and was also associated with PsA in St. John's patients, but with no additional effect of Met/Met homozygosity. No association remained after adjustment for HLA alleles in St. John's patients. MICA-129 was not associated with PsA when compared with PsC. We conclude that MICA-129 is a marker of skin manifestations of PsD that is independent of HLA class I in Toronto patients.

Anxiety sensitivity and auditory perception of heartbeat.

Anxiety sensitivity (AS) is the fear of sensations associated with autonomic arousal. AS has been associated with the development and maintenance of panic disorder. Given that panic patients often rate cardiac symptoms as the most fear-provoking feature of a panic attack, AS individuals may be especially responsive to cardiac stimuli. Consequently, we developed a signal-in-white-noise detection paradigm to examine the strategies that high and low AS individuals use to detect and discriminate normal and abnormal heartbeat sounds. Compared to low AS individuals, high AS individuals demonstrated a greater propensity to report the presence of normal, but not abnormal, heartbeat sounds. High and low AS individuals did not differ in their ability to perceive normal heartbeat sounds against a background of white noise; however, high AS individuals consistently demonstrated lower ability to discriminate abnormal heartbeats from background noise and between abnormal and normal heartbeats. AS was characterized by an elevated false alarm rate across all tasks. These results suggest that heartbeat sounds may be fear-relevant cues for AS individuals, and may affect their attention and perception in tasks involving threat signals.

Obsessive compulsive disorder in childhood.

Obsessive compulsive disorder (OCD) involves obsessions and compulsions that cause impairment and distress, and which interfere with children's developmental adaptation and daily functioning. Furthermore, OCD often disrupts peer and family relationships and school performance and may compromise physical health. Once considered rare, recent epidemiologic studies report prevalence rates ranging from 1% in prepubertal children to 4% in adolescents. In addition, children with OCD are at high risk for comorbid psychopathology. Recent theoretic formulations for OCD encourage the integration of both psychological and biological perspectives. To fully understand the cause and course of OCD, integrated assessment of psychological and biological vulnerability as well as prospective longitudinal studies are needed.

The familial and developmental context of obsessive-compulsive disorder.

This article discusses developmental and familial factors in childhood obsessive-compulsive disorder (OCD) highlighting the spectrum of normative to pathologic obsessions and rituals. In addition, it explores the possible role of family functioning in the emergence and maintenance of OCD in childhood and adolescence. Finally, it posits a developmental model that integrates genetic and neurobiologic vulnerability, cognitive models of information processing, behavioral coping strategies, and familial and peer relationships.

Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation.

PURPOSE: Radiotherapy for soft tissue sarcoma is typically preoperative or postoperative, with advocates of each. In this study, the relationship of the sequencing of radiotherapy and surgery to local control was examined. METHODS AND MATERIALS: The cohort consisted of 453 patients with Grade 2-3 malignant fibrous histiocytoma, synovial sarcoma, or liposarcoma treated from 1965-1992. Retroperitoneal sarcomas were excluded. Median follow-up was 97 months. There were 3 groups of patients that were classified by the treatment administered at our institution: preoperative radiotherapy to a median dose of 50 Gy given before excision at MDACC (Preop; n = 128); postoperative radiotherapy to a median dose of 64 Gy given after excision at MDACC (Postop; n = 165); and radiotherapy to a median dose of 65 Gy without excision at MDACC (RT Alone; n = 160). Those in the RT Alone Group had gross total excision at an outside center prior to referral. RESULTS: Histological classification, whether locally recurrent at referral, and final MDACC margins were independent determinants of local control in Cox proportional hazards multivariate analysis using the entire cohort. The type of treatment was not significant; however, tumor status at presentation (gross disease vs. excised) affected these findings greatly. Gross disease treated with Preop was controlled locally in 88% at 10 years, as compared to 67% with Postop (p = 0.01). This association was independently significant for patients treated primarily (not for recurrence). In contrast, for those presenting after excision elsewhere, 10-year local control was better with Postop (88% vs. 73%,p = 0.07), particularly for patients treated primarily (91% vs. 72%, p = 0.02 in univariate analysis; p = 0.06 in multivariate analysis). Re-excision at MDACC (Postop) resulted in enhanced 10-year local control over that with RT Alone (88% vs. 75%, p = 0.06), and was confirmed to be an independent predictor in multivariate analysis (p = 0.02). CONCLUSION: Local control was highest with Preop in patients presenting primarily with gross disease, and with Postop in patients presenting primarily following gross total excision. The data suggest that 50 Gy is inadequate after gross total excision, possibly due to hypoxia in the surgical bed.

Traumatic aneurysms of the face and temple: a patient report and literature review, 1644 to 1998.

The branches of the external carotid artery are protected from injury in most locations by an adequate buffer of soft tissue. On occasion, the vessels approach the surface to cross bone structures, and in these key areas they become vulnerable to blunt trauma. The facial, superficial temporal, and terminal branches of the internal maxillary arteries are the branches most often affected via this mechanism of injury. In addition, damage to deeper branches of the internal maxillary artery and to the subparotid portion of the superficial temporal artery has been reported secondary to maxillary fractures and craniofacial surgery. A brief patient report illustrates the highlights of clinical examination, diagnostic study, and surgical management of an aneurysm of the facial artery. A review of the world literature since 1644 has revealed 386 patients with traumatic aneurysms of the face and temple.

Synergistic effects of schwann- and muscle-derived factors on motoneuron survival involve GDNF and cardiotrophin-1 (CT-1).

The survival of central neurons depends on multiple neurotrophic factors produced by different cell types. We demonstrate that media conditioned by muscle and Schwann cell lines show strong synergistic effects on survival of purified embryonic day 14.5 rat motoneurons in culture. Different lines of evidence implicate glial cell line-derived neurotrophic factor (GDNF) and cardiotrophin-1 (CT-1) in this synergy. Their expression in the environment of the motoneuron is compartmentalized: gdnf transcripts are expressed principally in Schwann cell lines, whereas ct-1 mRNA is present in myotubes. Blocking antibodies to GDNF inhibit the trophic activity of Schwann cell line-conditioned media by 75%, whereas CT-1 antibodies diminish the myotube-derived activity by 46%. CT-1 and GDNF act synergistically to enhance motoneuron survival in vitro. In vivo, individual motoneurons coexpress both GDNF and CT-1 receptor components. GDNF and CT-1, therefore, are major components of the trophic support provided by the Schwann and muscle cells, respectively. The possibility that they act together on individual motoneurons suggests that the motoneuron must integrate distinct signals from different cellular partners when deciding whether to die or to survive.

Hepatocyte growth factor (HGF/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons.

Muscle-derived factors are known to be important for the survival of developing spinal motoneurons, but the molecules involved have not been characterized. Hepatocyte growth factor/scatter factor (HGF/SF) plays an important role in muscle development and motoneuron axon outgrowth. We show that HGF/SF has potent neurotrophic activity (EC50=2 pM) for a subpopulation (40%) of purified embryonic rat motoneurons. Moreover, HGF/SF is an essential component of muscle-derived support for motoneurons, since blocking antibodies to HGF/SF specifically inhibited 65% of the trophic activity of media conditioned by C2/C7 skeletal myotubes, but did not inhibit the trophic activity secreted by Schwann cell lines. High levels of expression of the HGF/SF receptor c-Met in the spinal cord are restricted to subsets of motoneurons, mainly in limb-innervating segments. Consistent with this distribution, cultured motoneurons from limb-innervating brachial and lumbar segments showed a more potent response to HGF/SF than did thoracic motoneurons. By the end of the period of motoneuron cell death, levels of c-Met mRNA in motoneurons were markedly reduced, suggesting that the effects of HGF/SF may be limited to the period of motoneuron cell death. HGF/SF may play an important role during motoneuron development as a muscle-derived survival factor for a subpopulation of limb-innervating motoneurons.

Cross-sectional area of the mandible.

PURPOSE: The anatomy of the mandible was examined by measuring the cross-sectional area (CSA) of multiple regions of 10 fully dentulous hemimandibles to provide a better understanding of regional structural differences that may have implications regarding biomechanical strength, surgical reconstruction, and fracture site frequency. MATERIALS AND METHODS: Fifteen cuts from the condyle to the symphysis were made of each hemimandible (n = 150 cuts). A Zeiss Videoplan digitizer was used to determine the CSA. RESULTS: The total CSA through the condyle was greater than the CSA through the condylar neck. The CSA through the ramus exceeded that of the condylar neck. The total CSA of the midramus was significantly greater than that of the upper ramus. The total CSA at the body, parasymphysis, and symphysis was significantly greater than at the mid-angle. The total CSA of the cortex increased anteriorly; these differences become significant between the condylar neck and the body, parasymphysis, and symphysis. The total CSA, and the CSA of the cortex and spongiosa, remained relatively constant from the inferior angle anteriorly. CONCLUSIONS: Significant differences exist in the CSA at different points, with an increase in the total, cortical, and spongiosal CSA anteriorly from the condylar neck to the angle. The total CSA and the CSA of the cortex and spongiosa remain relatively constant anterior to the inferior angle. These data suggest that bony CSA alone is not the sole factor in determining fracture site frequency.

Functional specificity of Hoxa-4 in vertebral patterning lies outside of the homeodomain.

The Hox family of proteins plays a central role in establishing the body plan of a wide range of metazoan organisms. Each member of this family of transcriptional regulators has a distinct functional specificity, yet they bind to similar DNA target sequences through their conserved homeodomain. The mechanisms whereby Hox proteins achieve their diverse specificities in vivo remain undefined. Using the opposing effects of Hoxa-4 and Hoxc-8 in vertebral patterning, we demonstrate by replacing the homeodomain of Hoxa-4 with that of Hoxc-8 that the functional specificity of Hoxa-4 does not track with the homeodomain. These observations provide evidence that other regions of Hox proteins play an important role in mediating functional specificity during mammalian embryogenesis.

Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons.

The muscle-derived factors required for survival of embryonic motoneurons are not clearly identified. Cardiotrophin-1 (CT-1), a cytokine related to ciliary neurotrophic factor (CNTF), is expressed at high levels in embryonic limb bud and is secreted by differentiated myotubes. In vitro, CT-1 kept 43% of purified E14 rat motoneurons alive for 2 weeks (EC50 = 20 pM). In vivo, CT-1 protected neonatal sciatic motoneurons against the effects of axotomy. CT-1 action on motoneurons was inhibited by phosphatidylinositol-specific phospholipase C (PIPLC), suggesting that CT-1 may act through a GPI-linked component. Since no binding of CT-1 to CNTFR alpha was detected, CT-1 may use a novel cytokine receptor alpha subunit. CT-1 may be important in normal motoneuron development and as a potential tool for slowing motoneuron degeneration in human diseases.

Characterization of a multicomponent receptor for GDNF.

Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for central and peripheral neurons, and is essential for the development of kidneys and the enteric nervous system. Despite the potential clinical and physiological importance of GDNF, its mechanism of action is unknown. Here we show that physiological responses to GDNF require the presence of a novel glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) that is expressed on GDNF-responsive cells and binds GDNF with a high affinity. We further demonstrate that GDNF promotes the formation of a physical complex between GDNFR-alpha and the orphan tyrosin kinase receptor Ret, thereby inducing its tyrosine phosphorylation. These findings support the hypothesis that GDNF uses a multi-subunit receptor system in which GDNFR-alpha and Ret function as the ligand-binding and signalling components, respectively.

H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells.

H19 is a developmentally regulated gene with putative tumor suppressor activity, and loss of H19 expression may be involved in Wilms' tumorigenesis. In this report, we have performed in situ hybridization analysis of H19 expression during normal rabbit development and in human atherosclerotic plaques. We have also used cultured smooth muscle cells to identify H19 regulatory factors. Our data indicate that H19 expression in the developing skeletal and smooth muscles correlated with specific differentiation events in these tissues. Expression of H19 in the skeletal muscle correlated with nonproliferative, actin-positive muscle cells. In the prenatal blood vessel, H19 expression was both temporally and spatially regulated with initial loss of expression in the inner smooth muscle layers adjacent to the lumen. We also identified H19-positive cells within the adult atherosclerotic lesion and we suggest that these cells may recapitulate earlier developmental events. These results, along with the identification of the insulin family of growth factors as potent regulatory molecules for H19 expression, provide additional clues toward understanding the physiological regulation and function of H19.

The pharmacotherapy of panic disorder.

The biological model for panic disorder posits a specific, genetically inherent neurochemical dysfunction; pharmacological treatment attempts to reregulate the dysregulated physiological system, thereby achieving remission (or, ideally, recovery) or amelioration of the symptoms sufficient for nonpharmacological therapies to be viable. This article will review the evidence of the efficacy of single classes of pharmacological agents (antidepressants, including TCAs, MAOIs, and SSRIs; benzodiazepines; and other agents) and integrated treatments, involving coadministration of medications within or across classes or a combination of pharmacological and nonpharmacological therapies, such as cognitive-behavioral therapy. Research pertaining to the relative efficacy of administering combination treatments concurrently or sequentially is examined. Individualized treatment plans for patients maximize the benefits of integrated treatments.

Clinical issues in the long-term treatment of panic disorder.

Longitudinal studies in naturalistic settings have shed new light on the course and value of therapeutic interventions in panic disorder and agoraphobia. Patients, their families, and clinicians need additional information about the natural course of the disorders and the factors that predispose patients to sustained illness, recovery, and relapse during treatment and upon treatment discontinuation. Clinical experience and controlled studies confirm the efficacy of pharmacologic and cognitive-behavioral therapy (CBT). Newer antidepressants, especially the serotonin selective reuptake inhibitors, represent a significant advance in effective pharmacologic intervention. However, despite the availability of effective treatment options, panic disorder often remains a chronic condition characterized by intermittent remissions and relapses over many years. Depression and comorbid anxiety disorders are associated with increased disease severity, treatment refractoriness, and relapse. The role of CBT as both a primary intervention and as an aid in the discontinuation of pharmacotherapy is reviewed.

Anxiety disorders of childhood, Implications for adult psychopathology.

Although the exact path of acquisition remains incompletely understood, research supports the association between anxiety disorders in children and psychopathologic conditions in adults. This article addresses this relationship; reviews findings on the temperamental profile and behavioral inhibition, which may be an early identifiable childhood predictor of later anxiety disorders; and discusses the importance of early intervention.

Gain of function mutations for paralogous Hox genes: implications for the evolution of Hox gene function.

To investigate the functions of paralogous Hox genes, we compared the phenotypic consequences of altering the embryonic patterns of expression of Hoxb-8 and Hoxc-8 in transgenic mice. A comparison of the phenotypic consequences of altered expression of the two paralogs in the axial skeletons of newborns revealed an array of common transformations as well as morphological changes unique to each gene. Divergence of function of the two paralogs was clearly evident in costal derivatives, where increased expression of the two genes affected opposite ends of the ribs. Many of the morphological consequences of expanding the mesodermal domain and magnitude of expression of either gene were atavistic, inducing the transformation of axial skeletal structures from a modern to an earlier evolutionary form. We propose that regional specialization of the vertebral column has been driven by regionalization of Hox gene function and that a major aspect of this evolutionary progression may have been restriction of Hox gene expression.