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.

The ornithine transcarbamylase leader peptide directs mitochondrial import through both its midportion structure and net positive charge.

The cytoplasmically synthesized precursor of the mitochondrial matrix enzyme, ornithine transcarbamylase (OTC), is targeted to mitochondria by its NH2-terminal leader peptide. We previously established through mutational analysis that the midportion of the OTC leader peptide is functionally required. In this article, we report that study of additional OTC precursors, altered in either a site-directed or random manner, reveals that (a) the midportion, but not the NH2-terminal half, is sufficient by itself to direct import, (b) the functional structure in the midportion is unlikely to be an amphiphilic alpha-helix, (c) the four arginines in the leader peptide contribute collectively to import function by conferring net positive charge, and (d) surprisingly, proteolytic processing of the leader peptide does not require the presence of a specific primary structure at the site of cleavage, in order to produce the mature OTC subunit.

GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle.

For survival, embryonic motoneurons in vertebrates depend on as yet undefined neurotrophic factors present in the limb bud. Members of the neurotrophin family are currently the best candidates for such neurotrophic factors, but inactivation of their receptor genes leads to only partial loss of motoneurons, which suggests that other factors are involved. Glial cell line-derived neurotrophic factor (GDNF), originally identified as a trophic factor specific for dopaminergic neurons, was found to be 75-fold more potent than the neurotrophins in supporting the survival of purified embryonic rat motoneurons in culture. GDNF messenger RNA was found in the immediate vicinity of motoneurons during the period of cell death in development. In vivo, GDNF rescues and prevents the atrophy of facial motoneurons that have been deprived of target-derived survival factors by axotomy. GDNF may therefore be a physiological trophic factor for spinal motoneurons. Its potency and specificity in vitro and in vivo also make it a good candidate for treatment of motoneuron disease.

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.

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.

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.

Identification of a putative structural gene for cathepsin D in Caenorhabditis elegans.

Mutants of Caenorhabditis elegans having about 10% of wild-type activity of the aspartyl protease cathepsin D have been isolated by screening. Mutant homozygotes have normal growth rates and no obvious morphological or developmental abnormalities. The mutant gene (cad-1) has been mapped to the right extremity of linkage group II. Heterozygous animals (cad-1/+) show intermediate enzyme levels and animals heterozygous for chromosomal deficiencies of the right extremity of linkage group II have 50% of wild-type activity. Cathepsin D purified from a mutant strain has a lower activity per unit mass of pure enzyme. These data suggest that cad-1 is a structural gene for cathepsin D.

Mitochondrial protein import.

A dynamic picture of the mitochondrial protein import pathway is emerging, with conformational alteration a critical feature both preceding and following membrane translocation. The mediators of these steps of conformational alteration, as well as steps of recognition, translocation, and proteolytic cleavage, appear to be proteins. Using powerful tools of genetics and biochemistry, in years to come it should be possible to determine the precise molecular function of these proteins in mediating these novel reactions.

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.

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.

The etiology of social phobia.

Human beings are by nature social animals, but for some, social scrutiny is a source of extreme anguish. Those with social phobia, for example, suffer excessive and often disabling concern about potential and real social-evaluative threat. As new and effective therapies for this condition are pursued, there is a simultaneous movement to extend the understanding of this disorder's etiology. In psychiatry, as in the rest of medicine, this development of new treatments often occurs in parallel with increasing sophistication about causes of illness. Advances in one area typically inform and predictably lead to advances in the other. Social phobia is recognized as a relatively common and significantly impairing anxiety disorder. As with other psychiatric disorders, emerging models of the etiology of social phobia are derived from converging evidence of interacting biological and environmental contributions. Current theories regarding the evolution of social phobia will be addressed, including biological preparedness to fear scrutiny by others, genetically transmitted predisposition to fear acquisition, nongenetic familial and environmental factors, as well as other possible causes and antecedents. Additionally, we describe recent work on behavioral inhibition in infancy as an identifiable early marker of proneness to the development of anxiety disorders, including social phobia.

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.

Malignant hyperthermia in the head and neck surgery patient: an update and review.

Malignant hyperthermia, a disorder often initiated by exposure to a variety of anesthetic agents, continues to be of major importance to the head and neck surgeon because: 1. approximately 40% of all reported reactions have occurred during anesthesia for head and neck surgery; 2. the possibility of mortality still exists despite the use of new pharmacologic agents, such as dantrolene; and, 3. subtle variations in the intraoperative and postoperative presentation of malignant hyperthermia are being increasingly recognized and treated. The authors briefly tabulate the 280 cases--which have occurred worldwide during otolaryngologic, dental, facial plastic, ophthalmologic and neurosurgical procedures--that are registered with the Department of Anaesthesia, University of Toronto, Canada. A case report depicting a less-than-typical reaction is presented. The authors emphasize that early recognition of the clinical features of an ongoing reaction, whether mild or severe, is by far the most important factor in reducing morbidity and mortality of patients who suffer hyperthermic crises while undergoing head and neck surgery.

Nasal trauma. Pathomechanics and surgical management of acute injuries.

This article delineates the structural features of the nose and discusses the major patterns of nasal injury as seen in the cadaveric laboratory and in the setting of two large metropolitan surgical centers. Diagnostic methods are reviewed, including a test of structural integrity by digital compression. Methods of reduction, internal fixation, and techniques of grafting that include the use of overlay and underlay cantilevers complete the author's approach to nasal injury.

Inferior turbinate surgery: an adjunct to successful treatment of nasal obstruction in 408 patients.

Septal deviation is often associated with hypertrophy of the contralateral inferior turbinate. Failure to reduce the size of the turbinate at the time of septal reconstruction may result in persistent nasal obstruction. The authors present their experience with 408 patients who underwent one of four turbinate procedures over a 6-year period. Most patients underwent unilateral turbinate surgery, although bilateral procedures were undertaken in 7 percent of patients. A graduated surgical approach was taken that varied according to the amount of turbinate enlargement and the degree to which mucosa and bone were involved. Full-thickness excision of the anterior third to half of the inferior turbinate (turbinectomy) became a favored procedure. Relief of nasal obstruction was obtained in greater than 90 percent of patients. Healing was satisfactory regardless of the method, and complications, including hemorrhage and infection, were few. Long-term follow-up revealed no untoward sequelae, and no patient developed atrophic rhinitis. The authors conclude that turbinate surgery, particularly when unilateral, in the carefully selected patient with nasal obstruction is a useful adjunct to septal surgery.

The gluteus maximus musculocutaneous island flap: refinements in design and application.

The gluteus maximus island musculocutaneous flap has been described using a variety of designs. We employ an island whose long axis is directed toward the pressure sore, minimizing tension in wound closure. Skin overlying the greater trochanter is avoided. Previously undermined skin can be included in the flap. Fifty patients with ischial or sacral pressure sores have been managed by this technique. Superficial dehiscence occurred in 13 percent of patients, and deep dehiscence occurred in 10 percent. The dehiscence closed spontaneously in all but one patient. Forty-nine of the 50 patients experienced complete wound healing at the pressure sore site. The patients have been observed for an average of 20 months (range 3 to 38 months), with one recurrent pressure sore seen at 28 months postoperatively. The gluteus maximus musculocutaneous island flap has proven to be both reliable in healing and durable over the observed interval.

More experience with the "reverse" latissimus dorsi musculocutaneous flap: precise location of blood supply.

Our work demonstrates that the "reverse" latissimus dorsi musculocutaneous flap has a predictable and consistent blood supply. A major portion of the muscle can be nourished by the dorsal perforating branches of the ninth, tenth, and eleventh intercostal vessels. The skin island based on the "reverse" latissimus dorsi muscle can be as large as 8 X 20 cm. This is confirmed by anatomic dissections and clinical cases. Knowledge of the blood supply facilitates elevation of the flap and extends its utility.

Esophageal and hypopharyngeal injuries in patients with cervical spine trauma.

The authors review their recent experience with four patients referred to the Shepherd Spinal Center, Atlanta, with cervical spine fracture dislocation and quadriplegia. The patients were subsequently found to have tears of the hypopharynx or the esophagus as a complication of their injury. Unexplained fever, swelling of the neck, dysphagia or leukocytosis in the patient with acute cervical spine injury suggest, the authors urge, the possibility of esophageal or hypopharyngeal perforation. The authors review the kinematics and pathophysiology of cervical fractures and provide clues to early detection and management of perforation of the hypopharynx or esophagus, including the use of radiographic study and endoscopy.