Anti-salivary gland protein 1 antibodies in two patients with Sjogren’s syndrome: two case reports

INTRODUCTION: Current diagnostic criteria for Sjogren’s syndrome developed by the American College of Rheumatology include the presence of antinuclear antibodies, rheumatoid factor, anti-Ro or anti-La autoantibodies. The purpose of this report is to describe two patients with biopsy-proven Sjogren’s syndrome lacking these autoantibodies but identified by antibodies to salivary gland protein 1. Diagnosis was delayed until salivary gland tumors developed in these patients because of the lack of the classic autoantibodies. This report emphasizes the existence of patients with primary Sjogren’s syndrome who lack autoantibodies anti-Ro or anti-La and may therefore be misdiagnosed. Antibodies to salivary gland protein 1 identify some of these patients. CASE PRESENTATION: Two patients are described and were seen in the autoimmune disease clinics of the State University of New York (SUNY) at the Buffalo School of Medicine. In both patients, chronic dry mouth and dry eye had been dismissed as idiopathic because test results for autoantibodies anti-Ro and anti-La were negative. Both patients had swelling of major salivary glands that prompted biopsies. Biopsies of major salivary glands from both cases demonstrated salivary gland tumors and existence of inflammation consistent with Sjogren’s syndrome. Serologic testing revealed antibodies to salivary gland protein 1. CONCLUSIONS: Patients presenting with classic clinical symptoms of dry mouth and eyes do not always show the current serologic markers of Sjogren’s syndrome, anti-Ro and anti-La. In these cases, investigation for antibodies to salivary gland protein 1 is of importance to make the diagnosis of Sjogren’s syndrome. Early diagnosis of Sjogren’s syndrome is necessary for improved management as well as for vigilance regarding potential complications, such as salivary gland tumors as were seen in the described cases

BIPHASIC PATTERN OF THYMUS REGENERATION AFTER WHOLE-BODY IRRADIATION

Whole-body irradiation of mice with 300 or 400 R causes a precipitous fall in thymus weight, followed by an increase in the mitotic index and an almost complete restoration of thymus mass. This phase is followed by a secondary fall in thymus weight and gradual recovery. This secondary fall can be prevented by intravenous injection of bone marrow or shielding of the hind limbs during irradiation. The hypothesis is proposed that the thymus depends on the migration of cells from the bone marrow to the thymus for the maintenance of its cell population. Bone marrow cells with chromosome markers injected intravenously into normal or lightly irradiated (150 R) animals do not populate the host bone marrow to any significant degree. After whole-body irradiation with heavy doses (400 R), donor cells dominate the marrow. There may be a competition between dividing cells in the bone marrow which regulates proliferation of hemic cells. Bone marrow cells with marker chromosomes do not repopulate the thymus in irradiated animals until long after repopulating the bone marrow. It is possible that these cells have to pass through the marrow or the blood-marrow barrier to acquire characteristics needed for entering the thymus. After whole-body irradiation with 500 R or more, the first phase of regeneration of the thymus, represented by an increase in the mitotic index, does not occur to a significant degree. Apparently cells in the thymus capable of proliferation have been largely eliminated, and restoration of organ mass depends chiefly on seeding from other sources, probably the bone marrow. After whole-body irradiation with 200 R, only the first phase of thymus weight loss and regeneration takes place. Probably bone marrow injury is too small to interfere with the supply of cells repopulating the thymus

Decrease in alpha-1 antiproteinase antitrypsin is observed in primary Sjogren's syndrome condition

Primary Sjogren’s syndrome (pSS) is a systemic autoimmune disease that is characterized by the infiltration of immune cells. Although the loss of salivary gland function is a major manifestation observed in pSS, the factors that could promote these changes in salivary gland tissue in pSS is not yet determined. Herein, we provide evidence that loss of alpha-1 antiproteinase antitrypsin could contribute to the induction of pSS. Alpha-1 antiproteinase antitrypsin belongs to the family of serpin proteins that function as protease inhibitors and protect secretory cells against proteases, especially to elastases that is secreted from lymphocytes. Importantly, expression of alpha-1 antiproteinase antitrypsin was decreased (more than 3-fold), along with an increase in elastase expression, in pSS samples when compared with age-matched non-SS-SICCA patients. Consistent with the human data, loss of alpha-1 antiproteinase antitrypsin, as well as an increase in immune infiltration, was observed in IL14α transgenic mice that exhibit SS like symptoms. Moreover, an age-dependent increase in elastase expression was observed in IL14α transgenic mice along with a decrease in total saliva secretion. Importantly, a 4-fold increase in microRNA132 expression, but not in other microRNAs, and increased DNA methylation in the promoter/noncoding region of serpina gene was observed in pSS, which could be responsible for the inhibition of alpha-1 antiproteinase antitrypsin expression in salivary gland cells of pSS patients. Together, these findings demonstrate that epigenetic regulations that include DNA methylation and microRNAs that could modulate the expression of alpha-1 antiproteinase antitrypsin in salivary glands and could be involved in the onset of pSS

Mitochondrial myopathy presenting as fibromyalgia: a case report

<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, we describe for the first time the case of a woman who met the diagnostic criteria for fibromyalgia, did not respond to therapy for that disorder, and was subsequently diagnosed by biochemical and genetic studies with a mitochondrial myopathy. Treatment of the mitochondrial myopathy resulted in resolution of symptoms. This case demonstrates that mitochondrial myopathy may present in an adult with a symptom complex consistent with fibromyalgia.</p> <p>Case presentation</p> <p>Our patient was a 41-year-old Caucasian woman with symptoms of fatigue, exercise intolerance, headache, and multiple trigger points. Treatment for fibromyalgia with a wide spectrum of medications including non-steroidal anti-inflammatory drugs, antidepressants, gabapentin and pregabalin had no impact on her symptoms. A six-minute walk study demonstrated an elevated lactic acid level (5 mmol/L; normal < 2 mmol/L). Biochemical and genetic studies from a muscle biopsy revealed a mitochondrial myopathy. Our patient was started on a compound of coenzyme Q10 (ubiquinone) 200 mg, creatine 1000 mg, carnitine 200 mg and folic acid 1 mg to be taken four times a day. She gradually showed significant improvement in her symptoms over a course of several months.</p> <p>Conclusions</p> <p>This case demonstrates that adults diagnosed with fibromyalgia may have their symptom complex related to an adult onset mitochondrial myopathy. This is an important finding since treatment of mitochondrial myopathy resulted in resolution of symptoms.</p

Metabolic myopathy presenting with polyarteritis nodosa: a case report

<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, we describe for the first time a patient in whom an unusual metabolic myopathy was identified after failure to respond to curative therapy for a systemic vasculitis, polyarteritis nodosa. We hope this report will heighten awareness of common metabolic myopathies that may present later in life. It also speculates on the potential relationship between metabolic myopathy and systemic vasculitis.</p> <p>Case presentation</p> <p>A 78-year-old African-American woman with a two-year history of progressive fatigue and exercise intolerance presented to our facility with new skin lesions and profound muscle weakness. Skin and muscle biopsies demonstrated a medium-sized artery vasculitis consistent with polyarteritis nodosa. Biochemical studies of the muscle revealed diminished cytochrome C oxidase activity (0.78 μmol/minute/g tissue; normal range 1.03 to 3.83 μmol/minute/g tissue), elevated acid maltase activity (23.39 μmol/minute/g tissue; normal range 1.74 to 9.98 μmol/minute/g tissue) and elevated neutral maltase activity (35.89 μmol/minute/g tissue; normal range 4.35 to 16.03 μmol/minute/g tissue). Treatment for polyarteritis nodosa with prednisone and cyclophosphamide resulted in minimal symptomatic improvement. Additional management with a diet low in complex carbohydrates and ubiquinone, creatine, carnitine, folic acid, α-lipoic acid and ribose resulted in dramatic clinical improvement.</p> <p>Conclusions</p> <p>Our patient's initial symptoms of fatigue, exercise intolerance and progressive weakness were likely related to her complex metabolic myopathy involving both the mitochondrial respiratory chain and glycogen storage pathways. Management of our patient required treatment of both the polyarteritis nodosa as well as metabolic myopathy. Metabolic myopathies are common and should be considered in any patient with exercise intolerance. Metabolic myopathies may complicate the management of various disease states.</p

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Purpose We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis

A Temporal Comparative RNA Transcriptome Profile of the Annexin Gene Family in the Salivary versus Lacrimal Glands of the Sjögren’s Syndrome-Susceptible C57BL/6.NOD-<i>Aec1Aec2</i> Mouse

A generally accepted hypothesis for the initial activation of an immune or autoimmune response argues that alarmins are released from injured, dying and/or activated immune cells, and these products complex with receptors that activate signal transduction pathways and recruit immune cells to the site of injury where the recruited cells are stimulated to initiate immune and/or cellular repair responses. While there are multiple diverse families of alarmins such as interleukins (IL), heat-shock proteins (HSP), Toll-like receptors (TLR), plus individual molecular entities such as Galectin-3, Calreticulin, Thymosin, alpha-Defensin-1, RAGE, and Interferon-1, one phylogenetically conserved family are the Annexin proteins known to promote an extensive range of biomolecular and cellular products that can directly and indirectly regulate inflammation and immune activities. For the present report, we examined the temporal expression profiles of the 12 mammalian annexin genes (Anxa1-11 and Anxa13), applying our temporal genome-wide transcriptome analyses of ex vivo salivary and lacrimal glands from our C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren’s Syndrome (SS), a human autoimmune disease characterized primarily by severe dry mouth and dry eye symptoms. Results indicate that annexin genes Anax1-7 and -11 exhibited upregulated expressions and the initial timing for these upregulations occurred as early as 8 weeks of age and prior to any covert signs of a SS-like disease. While the profiles of the two glands were similar, they were not identical, suggesting the possibility that the SS-like disease may not be uniform in the two glands. Nevertheless, this early pre-clinical and concomitant upregulated expression of this specific set of alarmins within the immune-targeted organs represents a potential target for identifying the pre-clinical stage in human SS as well, a fact that would clearly impact future interventions and therapeutic strategies

STUDY ON THE EFFECT OF STREPTOKINASE-ACTIVATED PLASMIN (FIBRINOLYSIN) ON CLOTS IN VARIOUS STAGES OF ORGANIZATION 1.2

In previous studies (1, 4), a method was developed for the quantitative recording of the lysis of thrombi and emboli produced with I&apos;31-labeled fibrinogen. Using this method, the in vivo fibrinolytic activity of human and bovine plasmin was demonstrated (2). Other proteolytic enzymes (crude pancreatic protease, trypsin, carboxypeptidase, papain and ficin) were ineffective in maximal tolerated doses (1, 3, 4). Literature on the therapeutic use of proteolytic enzymes has been reviewed (1, 2). In all previous experiments, treatment was started one-half hour after forming labeled clots in the experimental animals. The question arose whether plasmin treatment would be effective in dissolving organized clots and whether there is a correlation between degree of organization and plasmin-induced lysis. The preparations referred to as &quot;plasmin &quot; in this study actually contain a variety of enzymatic activities; they are fibrinolytic, proteolytic and are able to activate the fibrinolysin system. Presumably they represent a mixture of plasmin, plasmin-activator and free streptokinase. It is difficult to ascribe therapeutic activity to any one of these components. The purpose of these experiments is to study therapeutic indications and conditions for the preparations currently undergoing clinical trial. Labeled clots were produced in several veins of dogs at various time intervals. At the time of treatment, these clots were of various ages. Differences in lysis were established by recordin