Left Adductor Muscle Research Articles

PSAT208 A Case of Hypercalcemia From PTHrP-Producing Fibromyxoid Sarcoma Responsive to Glucocorticoid Therapy

Abstract Background Parathyroid hormone-related protein (PTHrP) is a major cause of humoral hypercalcemia of malignancy. PTHrP-induced hypercalcemia can also occur in benign disorders including pneumonia, SLE, HIV, sarcoidosis, and mammary hyperplasia. Treatment for PTHrP-induced hypercalcemia includes treating the underlying disorder and general management of hypercalcemia. Clinical Case A 70-year-old male with a chronic left thigh mass following trauma 12 years prior diagnosed as myositis ossificans, presented with worsening pain and swelling over the mass. Evaluation revealed serum calcium 18.6 mg/dl, PTH 10 ng/L (18-90), 25(OH)D 7 ng/ml (20-50), 1,25(OH)2D 15 pg/ml (20-79), PTHrP 9.3 pmol/L (≤ 4.2), negative SPEP, UPEP, serum light chains and immunofixation, and no bony lesions. MRI showed a large heterogenous mass centered in the left adductor muscle compatible with chronic hematoma with myositis ossificans. FDG PET/CT scan showed FDG avidity and calcification of the left thigh without any other site of uptake. Combination of IV hydration, denosumab and zoledronic acid lowered his calcium to 9.5 mg/dl, but levels increased again within 10 days. Repeated treatments with zoledronic acid initially led to modest lowering of calcium to 10.5 mg/dl, but he became refractory to treatment after 6 weeks, with calcium increasing to 12.3 mg/dl.Two biopsies of the mass were performed, including an open biopsy. The pathology showed nonpolarizable crystalline material with foreign giant cell reaction, without evidence for malignancy. It was concluded therefore that the patient's PTHrP-induced hypercalcemia was secondary to an inflammatory granulomatous condition. Since it had been reported that PTHrP-induced hypercalcemia in SLE and sarcoidosis responded to glucocorticoids, we initiated treatment with methylprednisolone 24 mg daily. After 7 days, the calcium declined from 12.3 to 10.5 mg/dl and PTHrP declined to 2.5 pmol/L. When the methylprednisolone dose was reduced to 12 mg daily, calcium increased to 11.4 mg/dl and PTHrP to 5 pmol/L. Increasing the methylprednisolone briefly back to 24 mg daily, and then 20 mg daily, lowered calcium to 9.0 mg/dl, increased PTH to 74 ng/L, and normalized PTHrP to 1.3 pmol/L. As long-term management with high-dose steroids was not a tenable option, a decision was made to resect the mass. The pathological diagnosis of the surgical mass was low-grade fibromyxoid sarcoma (LGFMS). Immunohistochemical studies identified PTHrP in surrounding vasculature, suggesting possible tumor-vessel interaction. Conclusion PTHrP-mediated hypercalcemia is rarely seen in sarcomas and treatments include coadministration of bisphosphonates, chemotherapy and surgery. We report here the first case of PTHrP-induced hypercalcemia from LGFMS with sustained lowering of calcium and PTHrP levels with glucocorticoid treatment. Further studies are needed to elucidate the mechanism of glucocorticoids in the treatment of PTHrP-induced hypercalcemia and could include lowering levels of inflammatory cytokines that stimulate PTHrP production from tumor cells, or by directly suppressing PTHrP gene expression. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Abstract 133: Heterozygous Deletion of Transferrin Receptor 1 Suppresses Angiogenesis in a Mouse Model of Hind Limb Ischemia

Objective: Angiogenesis can be triggered under conditions of ischemia and plays a protective role in peripheral artery disease. Iron is an essential trace mineral in the living body whose intracellular metabolism is regulated by transferrin receptor 1 (TfR1). Excess iron causes tissue damage and has been reported in patients with peripheral artery disease. Therefore, we hypothesized that TfR1 contributes to the pathophysiology of hind limb ischemia through iron overload. The aim of this study is to examine whether TfR1 deletion effects angiogenesis in hind limb ischemia. Methods and Results: Since homozygous TfR1 deletion is embryonically lethal, mice with heterozygous TfR1 deletion and their wild type littermates were used in this study. To induce hind limb ischemia, the left femoral artery in 8 - 9 week-old male mice was ligated and stripped. The non-ligated right hind limb was used as a control. Blood flow was measured by laser Doppler blood flowmetry at both a baseline of 1 hour and 28 days after the surgery. In wild type, the ratio of ischemc/non-ischemic hind limb blood flow was significantly decreased to 12% at baseline, and recovered to 62% at day 28. On the other hand, TfR1 deleted mice also showed similar reduction of blood flow at baseline, whereas blood flow recovery at day 28 was attenuated to 42%. Subsequently, both right and left adductor muscles were harvested for Western blot and immunohistochemistry. TfR1 expression in the adductor muscle was decreased in TfR1 deleted mice compared to wild type, regardless of the ligation. Ferritin, a marker for iron storage, was 10 times higher in ischemic muscles than in wild type non-ischemic muscles. In contrast, ferritin levels in TfR1 deleted mice were not altered by the surgery. Finally, immunohistochemistry for CD31 was performed to evaluate angiogenesis. The ischemic adductor muscle of TfR1 deleted mice had few CD31 positive vascular structures. Conclusions: Heterozygous deletion of TfR1 attenuated iron overload and angiogenesis in a mouse model of hind limb ischemia. TfR1 may be a novel therapeutic target for the treatment of peripheral artery disease.

Asymmetric larval head and mandibles of Hydrophilus acuminatus (Insecta: Coleoptera, Hydrophilidae): Fine structure and embryonic development

The larvae of a water scavenger beetle, Hydrophilus acuminatus, have strongly asymmetric mandibles; the right one is long and slender, whereas the left one is short and stout. The fine structure and embryonic development of the head capsule and mandibles of this species were examined using light and scanning electron microscopy, and asymmetries in shape were detected in these structures applying an elliptic Fourier analysis. The larval mandibles are asymmetric in the following aspects: whole length, the number, structure and arrangement of retinacula (inner teeth), and size and shape of both the molar and incisor regions. The larval head is also asymmetric; the left half of the head capsule is larger than the right, and the left adductor muscle of the mandible is much thicker than the right. The origin and developmental process of asymmetric mandibles were traced in developing embryos whose developmental period is about 270 h and divided into 10 stages. Mandibular asymmetries are produced by the cumulative effects of six stepwise modifications that occur from about 36% of the total developmental time onward. The significance of these modifications was discussed with respect to the functional advantages of asymmetries and the phylogeny of members of the Hydrophilidae.

Sciatica due to pelvic hematoma: case report

Abstract Sciatica is defined as pain in the sciatic nerve distribution. The most common reason of sciatica is radiculopathy due to lumbar disc hernia. Other causes can be congenital, acquired, infectious, neoplastic, or inflammatory. The piriformis syndrome is another cause. The pain starts in an insidious manner when the cause of sciatica is an extraspinal tumor. It is intermittent at first but a constant and progressive pain that does not decrease with position or rest gradually develops in all patients. The possibility of an intraabdominal or pelvic mass should always be considered and the relevant tests requested when the cause of the sciatica cannot be explained. We present an 83-year-old male who presented with non-traumatic and non-vascular lumbosacral plexopathy due to a large hematoma in the left adductor muscle following the use of warfarin sodium.

Adequate Selection of a Therapeutic Site Enables Efficient Development of Collateral Vessels in Angiogenic Treatment With Bone Marrow Mononuclear Cells.

BackgroundInduction of angiogenic mechanisms to promote development of collateral vessels is considered promising for the treatment of peripheral arterial diseases. Collateral vessels generally develop from preexisting arteriolar connections, bypassing the diseased artery. We speculated that induction of angiogenic mechanisms should be directed to such arteriolar connections to achieve efficient collateral development. The aim of this study was to verify this hypothesis using autologous transplantation of bone marrow mononuclear cells in the rabbit model of chronic limb ischemia.Methods and ResultsThe left femoral artery was excised to induce limb ischemia in male rabbits. In this model, arteriolar connections in the left coccygeofemoral muscle tend to develop into collateral vessels, although this transformation is insufficient to alleviate the limb ischemia. In contrast, arteriolar connections in the closely located adductor muscle do not readily develop into collateral vessels. At 21 days after ischemia initiation, a sufficient number of automononuclear cells were selectively injected in the left coccygeofemoral muscle (coccygeo group) or left adductor muscle (adductor group). Evaluation of calf blood pressure ratios, blood flow in the left internal iliac artery, and angiographic scores at day 28 after injection revealed that collateral development and improvement of limb ischemia were significantly more efficient in the coccygeo group than in the adductor group. Morphometric analysis of the coccygeofemoral muscle at day 14 showed similar results.ConclusionsSpecific delivery of mononuclear cells to the coccygeofemoral but not the adductor muscle effectively improves collateral circulation in the rabbit model of limb ischemia and suggests that adequate site selection can facilitate therapeutic angiogenesis.

Neuron-derived Neurotrophic Factor Functions as a Novel Modulator That Enhances Endothelial Cell Function and Revascularization Processes

Strategies to stimulate revascularization are valuable for cardiovascular diseases. Here we identify neuron-derived neurotrophic factor (NDNF)/epidermacan as a secreted molecule that is up-regulated in endothelial cells in ischemic limbs of mice. NDNF was secreted from cultured human endothelial cells, and its secretion was stimulated by hypoxia. NDNF promoted endothelial cell network formation and survival in vitro through activation of Akt/endothelial NOS (eNOS) signaling involving integrin αvβ3. Conversely, siRNA-mediated knockdown of NDNF in endothelial cells led to reduction of cellular responses and basal Akt signaling. Intramuscular overexpression of NDNF led to enhanced blood flow recovery and capillary density in ischemic limbs of mice, which was accompanied by enhanced phosphorylation of Akt and eNOS. The stimulatory actions of NDNF on perfusion recovery in ischemic muscles of mice were abolished by eNOS deficiency or NOS inhibition. Furthermore, siRNA-mediated reduction of NDNF in muscles of mice resulted in reduction of perfusion recovery and phosphorylation of Akt and eNOS in response to ischemia. Our data indicate that NDNF acts as an endogenous modulator that promotes endothelial cell function and ischemia-induced revascularization through eNOS-dependent mechanisms. Thus, NDNF can represent a therapeutic target for the manipulation of ischemic vascular disorders.

Therapeutic site selection is important for the successful development of collateral vessels

Induction of collateral development to improve tissue perfusion is a promising approach for the treatment of arterial occlusive diseases. Several growth factors and cells have been reported to increase collateral circulation; however, the appropriate site for the delivery of these factors and cells is unclear. In this study, we identified the delivery site for growth factor in a rabbit model of limb ischemia and evaluated whether specific delivery of basic fibroblast growth factor (bFGF) to this site enhanced collateral augmentation. The left femoral artery of Japanese white rabbits was excised to induce limb ischemia. Twenty-eight days thereafter, angiograms were obtained to identify the typical pattern of collateral development in this model. Subsequently, bFGF (100 μg) was selectively injected into the left coccygeofemoral muscle (coccygeo group) or adductor muscle (adductor group), major thigh muscles in proximity. Collateral development was evaluated at 28 days after injection, and its mechanism was assessed by immunologic and morphometric analyses of muscle samples. Angiographic evaluation of this model revealed that after femoral artery excision, collateral vessels generally developed in the left coccygeofemoral muscle, whereas few collateral vessels were detected in the left adductor muscle. At 28 days after injection, calf blood pressure ratio, defined as left pressure to right pressure, was significantly higher in the coccygeo group than in the adductor group (0.85 ± 0.05 vs 0.69 ± 0.05, respectively; P < .01). Similar results were observed in blood flow through the internal iliac artery (resting: 24.6 ± 6.1 vs 17.4 ± 8.0 mL/min, P < .01; maximum: 47.4 ± 12.3 vs 33.2 ± 10.7 mL/min, P < .01) and in the angiographic score (0.67 ± 0.13 vs 0.39 ± 0.11; P < .01). Immunologic analyses of the coccygeofemoral muscle at day 3 showed marked expressions of Ki-67, monocyte chemotactic protein 1, and FGF receptor 1 in the coccygeo group compared with the adductor group. Morphometric analyses of the same muscle at day 14 also revealed that collateral vessel density and wall thickness were significantly increased in the coccygeal group compared with the adductor group. These findings demonstrated that selective bFGF delivery to the coccygeofemoral muscle markedly improved collateral development and limb perfusion compared with delivery to the adductor muscle, suggesting that site selection is important in increasing therapeutic efficacy.

Letter to the Editor Complex-I defect with minimal manifestations

Letter to the Editor Complex-I defect with minimal manifestations

COMPROMISO MUSCULAR POR LINFOMA NO HODGKIN: CASO CLÍNICO Y REVISIÓN DEL TEMA

A case report of a patient with treated Non-Hodgkin Lymphoma is presented. In his usual tomographic control patient was requested a PET-CT scan to supplement prior study that showed a metabo- lically active focus on the left adductor muscle without evident tomographic correlation. Lesion underwent both a soft tissue ultrasound study and a directed biopsy, the latter being positive for secondary infiltra - tion by lymphoma. This case has demonstrated the usefulness of applying complementary techniques in the management of these lesions, mainly of PET-CT scans in the study of unusual sites of spread. This combined medical imaging technique allows accurate lesion localization, which in turn permits performance of a subsequent directed study.

Effect of Electrical Stimulation on Arteriogenesis and Angiogenesis after Bilateral Femoral Artery Excision in the Rabbit Hind-Limb Ischemia Model

The effects of electrical stimulation (ES) on arteriogenesis (the opening of preexisting collaterals) and angiogenesis (formation of new capillaries) were studied after acute bilateral hind limb ischemia was induced via bilateral femoral artery excision in a rabbit model. The study evaluated the rabbit hind limbs' normal response to acute ischemia and to application of ES by calculating changes in arterial and capillary densities. Comparisons were made with our prior study, in which the femoral artery was unilaterally excised, as we attempted to expand on the topics of arteriogenesis and angiogenesis. Twelve adult New Zealand white rabbits were randomly assigned to 1 of 2 series. In Series 1, the control group, both femoral arteries were excised and no ES was applied. In Series 2, both femoral arteries were excised and ES was applied to the left limb. One lead was implanted into the left adductor muscle near the site of the excised left femoral artery (Series 2), and a stimulator (Thera, Medtronic, Inc, Minneapolis, MN) was implanted in a separate pocket. ES was applied at a rate of 3 V, 30 contractions per minute, beginning immediately after surgery and continuously for 1 month. Angiography was performed in all 12 rabbits 1 month after surgery to establish the anatomy of the collateral vessels and to demonstrate that the femoral artery stump continued to be an end artery. Contrast-opacified arteries (COAs) that crossed the grid's midline, and the total number of grid lines intersected by COAs, were tallied according to an established method. Capillary density was calculated as the number of capillaries per square millimeter of muscle. In Series 1, after 1 month, the number of COAs crossing the grid's midline was 4.5 +/-1.5 on the left and 4.8 +/-1.2 on the right side. In Series 2, the number of COAs crossing the grid's midline was 7.9 +/-1.8 on the left side (p<0.05 vs Series 1) and 5.9 +/-1.6 on the right side of the same rabbit (p=NS vs Series 1). In Series 1, 36.7 +/-5.4 and 30.5 +/-7.7 total intersections were crossed by COAs on the left and right sides, respectively. In Series 2, total grid intersections crossed by COAs were 48.4 +/-8.5 and 47.5 +/-9.1 in the left and right sides, respectively (p<0.001 vs series 1). Baseline capillary density before femoral artery excision was 180.2 +/-21.3/mm(2). The capillary densities on the left sides were 94.2 +/-19.1 and 264.5 +/-7.6 in Series 1 and 2, respectively (p<0.001). The right sides showed a similar pattern with capillary densities of 88.5 +/-37.2 and 135.8 +/-6.8 (p<0.05) in Series 1 and 2, respectively. When capillary density was compared on the left and right sides of the same rabbit in Series 2, a statistically significant increase was also found; 264.5 +/-7.6 vs 135.8 +/-6.8 (p<0.001) in the left and right sides, respectively. Comparisons of the effect of electrical stimulation and the body's normal physiologic response to acute ischemia revealed a significant increase in the opening of preexisting collaterals (arteriogenesis) and the promotion of capillary density (angiogenesis) with the use of electrical stimulation.

Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice.

Diabetes macro- and microvascular disease causes tissue hypoperfusion. This deficit, together with a failure to mount an adequate angiogenic response, might explain why vascular occlusion evolves more severely among diabetic patients. The present study investigated whether prophylactic gene therapy with human tissue kallikrein (hTK) may protect diabetic limbs from the consequences of supervening ischemia. Vehicle (saline) or an adenovirus carrying the gene for either hTK (Ad.hTK) or luciferase (Ad.Luc) was injected into left adductor muscles of streptozotocin-induced type 1 diabetic mice 2 weeks before operative occlusion of the ipsilateral femoral artery. Saline-injected nondiabetic mice served as controls. Hindlimb blood flow recovery was analyzed sequentially over the 2 weeks after ischemia induction. At necroscopy, microvessel density and endothelial cell proliferation and apoptosis were quantified in skeletal muscles. We found that limb perfusion recovery of saline-injected type 1 diabetic mice is delayed because of insufficient reparative neovascularization and excessive activation of endothelial cell apoptosis. By contrast, prophylactic Ad.hTK renewed the ability to mount an appropriate neovascularization response to ischemia, suppressed apoptosis, and upregulated endothelial nitric oxide synthase expression. Ultimately, correction of diabetic endotheliopathy by Ad.hTK allowed proper perfusion recovery as seen in nondiabetic mice. These discoveries disclose new therapeutic options for the treatment of diabetic complications.

Examination of the laryngeal musculature and recurrent laryngeal nerves of zebra (Equus burchelli) for evidence of idiopathic laryngeal hemiplegia

Aims: This study was undertaken in order to determine whether wild Burchell's Zebra (Equus burchelli) are affected by Idiopathic Laryngeal Hemiplegia (ILH). ILH has a high prevalence in the domestic horse and a negative control population has not been identified. dMethods:The work was conducted in two phases on two large farms in central Kenya during routine culls.The larynges of 42 zebra were removed and the left and right intrinsic laryngeal adductor and abductor muscles and recurrent laryngeal nerves were isolated. The muscles were weighed and biopsy samples of left and right recurrent laryngeal nerve and cricoarytenoideus lateralis muscles from 16 animals were taken for histological examination. dResults: Left adductor muscles were observed to be significantly lighter than right adductor muscles (p = 0.001). There was no significant difference between the weights of left and right laryngeal abductors (p = 0.260). There was no light microscopic evidence of pathological changes consistent with ILH in any of the muscle or nerve samples. dConclusions: Zebra do not appear to suffer from ILH and equids unaffected by ILH can have significantly lighter muscles on the left of the larynx. dClinical relevance: Mild asymmetries of the larynx on palpation may not be a reliable indicator of ILH. Zebra may be a potentially useful negative control animal for observational ILH studies.