Down-regulation of mannosyl receptor-mediated endocytosis and antigen F4/80 in bacillus calmette-guerin-activated mouse macrophages. Role of T lymphocytes and lymphokines

Bacillus Calmette-Guerin (BCG) infection alters the surface and endocytic properties of mouse peritoneal macrophages (PM) compared with thioglycollate- elicited (TPM) or resident PM (RPM). Expression of Ia antigen (Ag) is enhanced up to fourfold, but plasma membrane receptors that mediate binding and uptake of mannosyl/fucosyl-terminated glycoconjugates (MFR), Fc receptors, and the macrophage (m)-specific Ag F4/80 are reduced by 50-80 percent. Levels of Mac-1 remain relatively stable. These changes are accompanied by enhanced secretion of O(2)(-), after further stimulation with phorbyl myristate acetate, and of plasminogen activator. Both these products are released by TPM, but not RPM. The characteristic surface phenotype of BCG-PM can also be induced by injection of C. parvum, another m- activating agent, but not by thioglycollate broth, lipopolysaccharide, or proteose peptone. Purified protein derivative (PPD) and N-acetylmuramyl-L- alanyl-D-isoglutamine. 2H(2)0 are soluble agents with partial activity. Alteration of m markers by BCG infection depends on T lymphocyte function, although studies with nude mice indicate that other pathways may also serve to modify the surface of the m. M from uninfected animals displayed all markers of activation after adoptive transfer of specifically-sensitised lymphocytes with PPD, intraperitoneally, or after co- cultivation. Treatment of primed lymphocytes with anti-Thy-1 antibody and complement ablated this effect. Lymphokines obtaned by Ag or mitogen stimulation induced similar changes in TPM and RPM. Mannose-specific endocytosis decayed rapidly, time 1/2 approximately equal to 16 h and stabilized at approximately 25 percent of control values. Single-cell analysis showed that residual MFR activity was uniform in the target population. Loss of Ag F4/80 after activation by lymphocyte and PPD was less marked than after infection (35 percent vs 80 percent), unlike MFR activity, which declined to a similar extent. Induction of m Ia by lymphokine reached a peak after 2-3 d and was lost within 2 d of its removal. Recovery of MFR and F4/80 was incomplete under these conditions. These studies establish that activated m known to display enhanced antimicrobial/anticellular activity express markedly different surface properties distinct from elicited or resident cells. The role of antigen- stimulated T cell products in regulating m function is confirmed, and down-regulation of mannosyl-receptor-mediated endocytosis provides a sensitive, quantitative, and cell-specific new marker to study their properties and mechanism of action. Extensive, but selective remodeling of m plasma membrane structure could play an important role in controlling recognition and effector mechanisms of the activated m.     

Treatment of myofascial trigger points in patients with chronic shoulder pain: a randomized,controlled trial

Background  

Shoulder pain is a common musculoskeletal problem that is often chronic or recurrent. Myofascial trigger points (MTrPs) cause shoulder pain and are prevalent in patients with shoulder pain. However, few studies have focused on MTrP therapy. The aim of this study was to assess the effectiveness of multimodal treatment of MTrPs in patients with chronic shoulder pain.     

Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling

Achromatopsia is an autosomal recessive disease of the retina, characterized clinically by an inability to distinguish colors, impaired visual acuity, nystagmus and photophobia. A genome-wide search for linkage was performed using an inbred Jewish kindred from Iran. To facilitate the genome-wide search, we utilized a DNA pooling strategy which takes advantage of the likelihood that the disease in this inbred kindred is inherited by all affected individuals from a common founder. Equal molar amounts of DNA from all affected individuals were pooled and used as the PCR template for short tandem repeat polymorphic markers (STRPs). Pooled DNA from unaffected members of the kindred was used as a control. A reduction in the number of alleles in the affected versus control pool was observed at several loci. Upon genotyping of individual family members, significant linkage was established between the disease phenotype and markers localized on chromosome 2. The highest LOD score observed was 5.4 (theta = 0). When four additional small unrelated families were genotyped, the combined peak LOD score was 8.2. Analysis of recombinant chromosomes revealed that the disease gene lies within a 30 cM interval which spans the centromere. Additional fine-mapping studies identified a region of homozygosity in all affected individuals, narrowing the region to 14 cM. A candidate gene for achromatopsia was excluded from this disease interval by radiation hybrid mapping. Linkage of achromatopsia to chromosome 2 is an essential first step in the identification of the disease-causing gene.      

Juvenile myasthenia gravis

Juvenile myasthenia gravis shares a similar pathophysiologic origin with adult myasthenia gravis, but there are important differences, mostly relating to epidemiology, presentation, and therapeutic decision making. Gender ratios and the proportion of seropositive patients differ in the pre‐ and postpubertal age groups. The diagnostic evaluation is similar to that in adults, although special techniques are sometimes necessary to perform single‐fiber electromyography in younger patients. Therapeutic decisions in affected children and adolescents are complicated by the greater long‐term consequences of using steroids, and thus other interventions, such as intravenous immunoglobulin (IVIg) and plasmapheresis, may play a greater therapeutic role in this population than in adults. Steroid‐sparing agents may contribute to the management of refractory cases, but they should be used with caution due to the risk of malignancy. Muscle Nerve, 2008     

A pilot methodology study for the photographic assessment of post‐inflammatory hyperpigmentation in patients treated with tretinoin

Background Post‐inflammatory hyperpigmentation (PIH) is a common occurrence in patients with acne vulgaris, particularly in those with skin of colour. Aims A previous study has demonstrated the benefit of tretinoin (retinoic acid) in the treatment of PIH; however, there is currently no standard protocol to evaluate change in PIH following treatment. Based on these findings, we performed a pilot, exploratory, blinded, intraindividual‐controlled methodology study that consisted of a photographic assessment protocol with facial mapping. Materials and methods The study was based on a secondary analysis of a phase 4, community‐based trial of 544 acne patients who were treated with tretinoin gel microsphere 0.04% or 0.1%. Only patients with Fitzpatrick types III–V (skin of colour) were included in the study; subjects with Fitzpatrick skin type VI were excluded because the photographic assessment did not allow for proper evaluation. Results Despite the small number of subjects evaluated (n = 25), the results revealed consistent assessment of improvement in PIH between two independent graders (weighted κ = 0.84). Conclusion Further study with a larger population is recommended to validate the accuracy of this method.     

Adipokine Chemerin Bridges Metabolic Dyslipidemia and Alveolar Bone Loss in Mice

Chemerin is an adipokine that regulates adipogenesis and metabolic functions of mature adipocytes mainly through the activation of chemokine‐like receptor 1 (CMKLR1). Elevated levels of chemerin have been found in individuals with obesity, type 2 diabetes, and osteoporosis. This adipokine was identified as an inflammatory and metabolic syndrome marker. Considering that the association between metabolic syndrome and bone health remains unclear, the present study aimed to clarify the role of chemerin in the pathophysiology of bone loss induced by dyslipidemia, particularly modulating osteoclastogenesis. In vitro analyses showed a downregulation of CMKLR1 at the early stage of differentiation and a gradual increase at late stages. Strikingly, chemerin did not modify osteoclast differentiation markers or osteoclast formation; however, it increased the actin‐ring formation and bone resorption activity in mature osteoclasts. The increased bone resorption activity induced by chemerin was effectively inhibited by CMKLR1 antagonist (CCX832). Chemerin boosting mature osteoclast activity involves ERK5 phosphorylation. Moreover, two models of dyslipidemia (high‐fat diet [HFD]‐treated C57/BL6 and db/db mice) exhibited significantly increased level of chemerin in the serum and gingival tissue. Morphometric analysis showed that HFD‐treated and db/db mice exhibited increased alveolar bone loss compared to respective control mice, which was associated with an up‐regulation of chemerin, CMKLR1 and cathepsin K mRNA expression in the gingival tissue. The treatment of db/db mice with CCX832 effectively inhibited bone loss. Antagonism of chemerin receptor also inhibited the expression of cathepsin K in the gingival tissue. Our results show that chemerin not only increases osteoclasts activity in vitro, but also that increased level of chemerin in dyslipidemic mice plays a critical role in bone homeostasis. © 2016 American Society for Bone and Mineral Research.     

Renal and hematologic side effects of long‐term intravenous immunoglobulin therapy in patients with neurologic disorders

Introduction: For patients receiving intravenous immunoglobulin (IVIg), renal and hemolytic side effects are well recognized. However, there are very few data on the effects of chronic IVIg therapy. Methods: We retrospectively analyzed laboratory data on 166 patients who received IVIg for 12 months with a dose range of 0.441–2.58 g/kg/month, measuring changes in hematocrit and glomerular filtration (GFR) rates at 6 and 12 months. Results: Of the 2,232 infusions, there were no incidents of clinical hemolysis. However, after 12 months of treatment, 21% of patients had a ≥3‐g/dl decline in hematocrit and 10% had a ≥20% decline in GFR. Discussion: No clinically significant hemolysis was observed in patients receiving chronic IVIg therapy. However, a significant number of patients had a decline in hematocrit and/or GFR while on therapy. This emphasizes the need for observation of hematologic and renal function in patients treated with chronic IVIg. Muscle Nerve 56 : 1173–1176, 2017