Downregulations of AKT/mTOR Signaling Pathway for Salmonella-Mediated Suppression of Matrix Metalloproteinases-9 Expression in Mouse Tumor Models.

The roles of Matrix MetalloProteinases (MMPs), such as MMP-9, in tumor metastasis are well studied, and this in turns stimulates the development of MMP inhibitors as antitumor agents. Previously, Salmonella accumulation was observed in the metastatic nodules of the lungs after systemic administration. Salmonella significantly enhanced the survival of the pulmonary metastatic tumor-bearing mice. Based on our previous observation, we hypothesized that Salmonella could affect metastasis-related protein expression. The treatment of Salmonella clearly reduced the expression of MMP-9. Meanwhile, the MMP-9 related signaling pathways, including Phosph-Protein Kinase B (P-AKT) and Phosph-mammalian Targets Of Rapamycin (P-mTOR) were decreased after a Salmonella treatment. The Salmonella inhibited tumor cell migration by wound-healing and Transwell assay. The anti-metastatic effects of Salmonella were evaluated in mice bearing experimental metastasis tumor models. Consequently, Salmonella inhibited the expression of MMP-9 by reducing the AKT/mTOR pathway and metastatic nodules in vivo.

The Extracts of Astragalus membranaceus Inhibit Melanogenesis through the ERK Signaling Pathway.

Melanin is a normal production protecting skin from environment-causing damage. Plants produce some agents in response to their environment. These agents could be applied in cosmetic production. Some Chinese herbals have immunomodulatory activities and modulate the symptoms of several diseases. Melanogenesis represents a complex group of conditions that are thought to be mediated through a complex network of regulatory processes. Previously, some studies found that the extracts of Astragalus membranaceus (PG2) regulated immunity and supported hematopoiesis. Herein, we want to determine the molecular mechanisms by which PG2 inhibits melanogenesis in B16F10 melanoma cells. The cellular melanin contents and expression of melanogenesis-related protein, including microphthalmia associated transcription factor (MITF) and tyrosinase were significantly reduced after PG2 treatment. Moreover, PG2 increased phosphorylation of ERK, without affecting phosphorylation of p38. These results suggested that PG2 as a new target in reducing hyperpigmentation through the ERK signal pathway. PG2 has potential for cosmetic usage in the future.

Osteocalcin Mediates Biomineralization during Osteogenic Maturation in Human Mesenchymal Stromal Cells.

There is a growing interest in cell therapies using mesenchymal stromal cells (MSCs) for repairing bone defects. MSCs have the ability to differentiate into osteoprogenitors and osteoblasts as well as to form calcified bone matrix. However, the molecular mechanisms governing mineralization during osteogenic differentiation remain unclear. Non-collagenous proteins in the extracellular matrix are believed to control different aspects of the mineralization. Since osteocalcin is the most abundant non-collagenous bone matrix protein, the purpose of this study is to investigate the roles of osteocalcin in mineral species production during osteogenesis of MSCs. Using Raman spectroscopy, we found that the maturation of mineral species was affected by osteocalcin expression level. After osteocalcin was knocked down, the mineral species maturation was delayed and total hydroxyapatite was lower than the control group. In addition, the expression of osteogenic marker genes, including RUNX2, alkaline phosphatase, type I collagen, and osteonectin, was downregulated during osteogenic differentiation compared to the control group; whereas gene expression of osterix was upregulated after the knockdown. Together, osteocalcin plays an essential role for the maturation of mineral species and modulates osteogenic differentiation of MSCs. The results offer new insights into the enhancement of new bone formation, such as for the treatments of osteoporosis and fracture healing.

Hinokitiol Inhibits Melanogenesis via AKT/mTOR Signaling in B16F10 Mouse Melanoma Cells.

H inokitiol purified from the heartwood of cupressaceous plants has had various biological functions of cell differentiation and growth. Hinokitiol has been demonstrated as having an important role in anti-inflammation and anti-bacteria effect, suggesting that it is potentially useful in therapies for hyperpigmentation. Previously, hinokitiol inhibited the production of melanin by inhibiting tyrosinase activity. The autophagic signaling pathway can induce hypopigmentation. This study is warranted to investigate the mechanism of hinokitiol-induced hypopigmentation through autophagy in B16F10 melanoma cells. The melanin contents and expression of microthphalmia associated transcription factor (MITF) and tyrosinase were inhibited by treatment with hinokitiol. Moreover, the phosphorylation of the protein express levels of phospho-protein kinase B (P-AKT) and phospho-mammalian targets of rapamycin (P-mTOR) were reduced after hinokitiol treatment. In addition, the microtubule associated protein 1 light chain 3 (LC3) -II and beclin 1 (autophagic markers) were increased after the B16F10 cell was treated with hinokitiol. Meanwhile, hinokitiol decreased cellular melanin contents in a dose-dependent manner. These findings establish that hinokitiol inhibited melanogenesis through the AKT/mTOR signaling pathway.

Ogilvie syndrome: a potentially life-threatening phenotype of immobilization hypercalcemia.

Ogilvie syndrome, also known as acute colonic pseudo-obstruction, is characterized by the clinical presentation and imaging evidence of acute colonic obstruction in the absence of a mechanical cause. Several comorbidities and serious associated medical or surgical conditions have been described to be relevant to this syndrome. In general, a preferred initial management with favorable treatment outcomes is virtually to correct underlying disorders. Although disrupted electrolyte homeostasis may induce impaired colonic motility, hypercalcemia secondary to immobilization as a major culprit in this syndrome has rarely been studied. In this report, we profiled radiographic features, therapeutic strategies, and pathogenetic hypothesis of this clinical entity and highlighted the need for clinicians to maintain awareness of this distinct manifestation.

Severe hypercalcemia in nonobstructive pyelonephritis with acute renal failure: hit or miss?

Severe hypercalcemia in the course of renal failure is quite unusual. If unrecognized, irreversible inexorable attrition of renal function takes place, carrying a substantial morbidity and mortality. In particular, acute nonobstructive pyelonephritis is barely considered in the primary differential diagnosis of renal failure. Without urinary obstruction, kidney hypoperfusion, or exposure to nephrotoxic agents, a significant decline in glomerular filtration rate generally does not occur. We report a case with severe hypercalcemia after acute renal failure caused by fulminating bacterial pyelonephritis. To obviate unnecessary intervention, preserve organ function, and achieve better outcomes, clinicians should not miss this entity.

Surviving a crisis of HIV-associated immune reconstitution syndrome.

The management of life-threatening complications in HIV-associated immune reconstitution syndrome is becoming a challenging scenario in emergency practice, especially in the era of highly active antiretroviral therapy paralleled by increased worldwide incidence of HIV infection. Here, we described a 37-year-old woman with acute hypoxic respiratory failure, acute renal failure, and hypercalcemic crisis as the presenting features of HIV-associated immune reconstitution syndrome. In this patient, the restored granulomatous host response toward isolated pulmonary Mycobacterium avium complex infection led to a near-fatal catastrophe. This report reinforces the importance of introducing a rapid, systematic approach of hypercalcemia at the emergency department and the need for clinicians to maintain awareness of this distinct manifestation.

Valsalva maneuver-induced priapism: a hidden culprit.

INTRODUCTION: Priapism is defined as an abnormal prolonged penile erection without sexual interest and failure to subside despite orgasm. The disorder is enigmatic yet devastating because of its elusive etiology, irreversible erectile tissue damage, and resultant erectile dysfunction. A wide variety of provocative factors have been implicated in different types of priapism; however, myelopathy-related ischemic priapism induced by the Valsalva maneuver in the context of spinal extradural arachnoid cyst has never been described. AIM: To report a case with spinal extradural arachnoid cyst heralded by Valsalva maneuver-induced priapism and review the mechanistic basis for acute myelopathy-related priapism. METHODS: The case report profiled a 42-year-old Chinese man presenting with ischemic priapism following in-flight Valsalva maneuver for unblocking the ears during descent. Magnetic resonance imaging unveiled the hidden culprit behind myelopathy-related priapism, as demonstrated by acute spinal cord compression from a giant extradural arachnoid cyst. RESULTS: The symptoms subsided rapidly after treatment with ice packing, analgesics, and corporal irrigation with diluted epinephrine. However, surgical removal of the extradural arachnoid cyst failed to achieve a complete recovery of neurological deficits. After 1 year of follow-ups, he still experienced a mild weakness and hypesthesia of the right leg but no further episodes of priapism or sexual dysfunction. CONCLUSIONS: Myelopathy-related priapism potentiated by the Valsalva maneuver can be easily overlooked without heightened vigilance, leading to poor therapeutic response and prognosis. The indolent nature of spinal extradural arachnoid cyst should be reinforced and better outcomes can only be achieved through expeditious diagnosis and management.

An unusual cause of thyrotoxic periodic paralysis: triiodothyronine-containing weight reducing agents.

Thyrotoxic periodic paralysis resulting from exogenous thyroid hormone administration (thyrotoxicosis factitia) has been rarely reported. We describe a 23-year-old man who presented with limbs paralysis upon awakening in the morning. Pertinent history revealed that he took drugs containing triiodothyronine (64 mug) and propranolol (40 mg) twice daily for weight reduction in the past month and discontinued these drugs 3 days before admission. Physical examination showed systolic hypertension (160/76 mm Hg), relative tachycardia (98 bpm), and symmetrical flaccid paralysis of all extremities. The most striking laboratory finding was severe hypokalemia (1.6 mmol/L) with low urinary potassium excretion and normal blood acid-base status, suggesting acute potassium shifting into cells. Approximately, 174 mmol of potassium chloride was administrated to restore his muscle strength within 12 hours, but rebound hyperkalemia (6.1 mmol/L) developed upon recovery. Despite normal serum free triiodothyronine and thyroxine levels, the suppressed concentration of thyroid stimulating hormone indicated hyperthyroidism. The low radioiodine uptake (4%) and serum thyroglobulin level (2 ng/mL) were consistent with thyrotoxicosis factitia. This is the first reported case of exogenous triiodothyronine-induced thyrotoxic periodic paralysis, which may have been precipitated by the withdrawal of propranolol.

Unveiling tuberculous pyomyositis: an emerging role of immune reconstitution inflammatory syndrome.

Immune reconstitution inflammatory syndrome is recognized as a paradoxical worsening of preexisting or smoldering opportunistic infections in patients with human immunodeficiency virus on highly active antiretroviral therapy because of the recuperating of immune system. We report a 42-year-old man on antiretroviral therapy with silent mycobacterium tuberculosis pyomyositis presenting with characteristic clinical and imaging features of immune reconstitution inflammatory syndrome. Because tuberculosis pyomyositis is less recognized and may be easily overlooked in terms of protean manifestations in extrapulmonary tuberculosis spreading, such mycobacterial infection can bring about substantial morbidity and even mortality during the immune recovery phase. The worldwide incidence of human immunodeficiency virus combined with tuberculosis infection is skyrocketing; therefore, emergency physicians must keep a heightened awareness and proficiency of this emerging culprit to obviate unnecessary intervention, preserve organ function, and achieve better outcomes.

Sentinel central retinal artery occlusion: a forme fruste of idiopathic renal infarction.

Central retinal artery occlusion is one of the most challenging practices and is not an infrequent presentation at the emergency department. We describe a 46-year-old man presenting with abrupt onset of amaurosis fugax secondary to sentinel central retinal artery occlusion followed by acute idiopathic renal infarction. This patient highlights that the preceding visual events could portend a devastating thromboembolic insult in the clinical setting. Early recognition with prompt treatment may preserve organ function, avoid unnecessary management, and prevent debilitating complication.

Immune reconstitution associated hypercalcemia.

The emergence of highly active antiretroviral therapy using combinations of reverse transcriptase and protease inhibitors ushered the dawn of a new era in management of human immunodeficiency virus infection. Immune reconstitution inflammatory syndrome is an adverse consequence of the restoration of pathogen-specific immune responses during the early phase of antiretroviral therapy. Pre-existing subclinical or opportunistic infections become apparent or even "worse" as host immunological inflammatory responses are "switched on". Major reductions in plasma viral load were associated with substantial increases in circulating CD4 T-cell lymphocyte counts and restoration of immune function. The rapid reversal in immune function gives rise to paradoxical therapeutic reaction by rebuilding host immune responses. Herein, a hidden culprit responsible for tuberculosis-associated immune reconstitution characterized by severe hypercalcemia and acute renal failure is reported, illustrating the compounded therapeutic strategy in AIDS patients.

Association of plasma adiponectin and cardiovascular risk profiles in nondiabetic uremic patients on peritoneal dialysis.

BACKGROUND: Adiponectin, a novel adipocytokine with antiinflammatory and antiatherosclerosis properties, has been found to be an inverse predictor of cardiovascular outcomes among uremic patients on hemodialysis. However, its role in uremic patients on continuous ambulatory peritoneal dialysis (CAPD) remains unclear. The aim of the study was to evaluate the association of adiponectin and cardiovascular risk factors in nondiabetic CAPD patients. METHODS: Sixty nondiabetic uremic patients on CAPD for more than 6 months were enrolled. Plasma adiponectin levels were measured along with cardiovascular risk profiles, including body mass index (BMI), waist to hip ratio (WHR), insulin resistance, lipid profiles, ankle-brachial pressure index (ABPI), brachial-ankle pulse wave velocity (BaPWV), inflammatory markers and peritoneal membrane characteristics. Dialysis adequacy, protein intake, residual renal function and serum biochemistries were also studied. RESULTS: Plasma adiponectin levels were significantly higher in CAPD patients than healthy subjects (16.0 +/- 11.8 vs. 6.4 +/- 1.8 microg/mL, p<0.001); inversely related to BMI, WHR, triglyceride levels, atherogenic index, insulin levels, homeostasis model assessment of insulin resistance and C-reactive protein (CRP), and directly related to high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). There was also a positive trend between plasma adiponectin levels and the ratios of dialysate to plasma creatinine concentration (D/P Cr). On multivariate regression analysis, BMI and HDL-C were the strongest variables associated with plasma adiponectin levels. CONCLUSIONS: Hyperadiponectinemia in nondiabetic uremic patients on CAPD is in part associated with cardiovascular risk factors. Whether elevated adiponectin concentrations exert cardioprotective and antiinflammation effects in uremic patients on CAPD warrants further prospective investigation.

A life-threatening double gap metabolic acidosis.

Double gap metabolic acidosis represents the high anion gap metabolic acidosis combined with raised serum osmolal gap due to retention of unmeasured osmole with accompanied metabolite. We describe a 62-year-old man diagnosed with community-acquired pneumonia undergoing continuous sedation in the context of asynchronous mechanical ventilation. High anion gap metabolic acidosis coupled with high plasma osmolal gap was noted with resultant severe bradyarrhythmia. D-Lactic acidosis and high serum concentration of propylene glycol (PG) eventually established the diagnosis of lorazepam-induced PG intoxication. Discontinuation of lorazepam followed by emergent long-extended hemodialysis effectively resolved the metabolic derangement without further recurrence. Serum osmolal gap is a sensitive and convenient surrogate for both early bedside detection and monitoring the therapeutic efficacy. Therefore, PG intoxication must be considered in the differential diagnosis of double gap metabolic acidosis. Early recognition with prompt hemodialysis intervention can avoid a life-threatening catastrophe.

Acute myeloid leukemia presenting as one-and-a-half syndrome.

One-and-a-half syndrome is a clinical disorder featuring extraocular movements characterized by horizontal conjugate gaze palsy with internuclear ophthalmoplegia. It usually results from a unilateral lesion of the midbrain, and the most common cause of this syndrome in young women is multiple sclerosis. We report the case of a 38-year-old woman diagnosed as having acute myeloblastic leukemia presenting with characteristic neurologic and imaging features of one-and-a-half syndrome. Hyperleukocytosis, cancer procoagulants, tissue factor expression, and the increased proteolysis of coagulation factors by leukemic cells may all contribute to the propensity for thrombotic vascular occlusion. The optimal treatment of acute brain infarction in acute leukemia patients with hyperleukocytosis remains unclear. However, this patient illustrates that leukapheresis alone can provide rapid and effective relief of visual symptoms without neurologic sequela. To achieve better outcomes and survival, clinicians must maintain a heightened awareness of this distinctly unusual manifestation.

Pelvic ectopic kidney with acute pyelonephritis: wolf in sheep's clothing.

The differential diagnosis of right lower quadrate pain at the emergency department is quite perplexing. We describe a 38-year-old woman presenting with characteristic clinical and laboratory features of ruptured appendicitis with severe sepsis. However, contrast-enhanced computed tomography scan of the abdomen established the diagnosis of pelvic ectopic kidney with acute pyelonephritis. Antibiotic treatment eventually achieved satisfactory resolution without compromise of renal function. It is should be addressed that, even with the advent of modern imaging modalities, there can be a diagnostic pitfall in general practice when managing right lower quadrate pain in patients with typical presentations of acute appendicitis without sonographic evidence, as illustrated in this case. In conclusion, early recognition using exquisite imaging studies with raised awareness in the clinical setting and prompt antibiotic treatment can avoid unnecessary intervention, preserve renal function, and prevent a life-threatening catastrophe.