Systemic Lupus Erythematosus Presenting With Thrombotic Thrombocytopenic Purpura at Onset: A Case Report.

Background: Thrombotic microangiopathy (TMA) is a syndrome associated with hemolytic anemia, thrombocytopenia, and various organ disorders. Thrombotic thrombocytopenic purpura (TTP) is a disease that develops when a disintegrin-like and metalloproteinase with thrombospondin type l motif 13 (ADAMTS13) activity decreases to < 10% of that in normal plasma, causing platelet thrombosis in microvessels throughout the body. Currently, ADAMTS13-deficient TMA is diagnosed as TTP. Systemic lupus erythematosus (SLE)-related TMA includes both acquired TTP, in which ADAMTS13 activity is significantly reduced, and secondary TMA, in which ADAMTS13 activity is not reduced. Both diseases have different prognoses. Case Presentation: An 11-year-old girl was admitted to our hospital on suspicion of TMA with thrombocytopenia and hemolytic anemia. Because the patient had hypocomplementemia, SLE-related TMA or complement-related TMA was considered. Therefore, we initiated plasma exchange (PE) for the patient. Subsequently, she fulfilled the pediatric SLE diagnostic criteria, and ADAMTS13 activity was shown to be decreased and the anti-ADAMTS13 antibody titer increased. She was thus diagnosed with acquired TTP caused by SLE. Treatment response was good as a platelet count and ADAMTS13 activity improved with three times of PE, followed by methylprednisolone pulse therapy and administration of mycophenolate mofetil. Renal pathology showed thrombus formation in glomerular arterioles and lupus nephritis categorized as Class III (A) of the International Society of Nephrology and the Renal Pathology Society classification. Because the patient was thought to be in the high-risk group of SLE, three courses of intravenous cyclophosphamide pulse therapy were administered as an additional induction therapy. No recurrence of TTP was observed. Conclusion: In SLE-related TMA, measurement of ADAMTS13 activity and the anti-ADAMTS13 antibody titer are necessary for diagnosis, and for predicting prognosis and recurrence of the disease; however, in the acute phase of immune-mediated TMA, it is important to initiate proper treatments even before knowing the results to improve prognosis.

Any modality of renal replacement therapy can be a treatment option for Joubert syndrome.

Joubert syndrome (JS) is an inherited ciliopathy characterized by a distinctive cerebellar and brain stem malformation which is known as the "molar tooth sign" on axial brain images, hypotonia, and developmental delay. Approximately 25-30% of patients with JS have kidney disease and many of them progress to end-stage kidney disease (ESKD). However, there are few reports on the outcomes of renal replacement therapy (RRT) in patients with JS and ESKD. In this study, we clarified the clinical features, treatment, and outcomes of patients with JS who underwent RRT. We retrospectively analyzed the medical records and clinical characteristics of 11 patients with JS who underwent RRT between June 1994 and July 2019. Data are shown as the median (range). Gene analysis was performed in 8 of the 11 cases, and CEP290 mutations were found in four patients, two had TMEM67 mutations, one had a RPGRIP1L mutation, and one patient showed no mutation with the panel exome analysis. Complications in other organs included hydrocephalus in two cases, retinal degeneration in eight cases, coloboma in one case, liver diseases in four cases, and polydactyly in one case. Peritoneal dialysis (PD) was introduced in seven cases, with a median treatment duration of 5.4 (3.4-10.7) years. Hemodialysis was performed using arteriovenous fistula in two cases, and kidney transplantation was performed 9 times in eight cases. Only one of the grafts failed during the observation period of 25.6 (8.2-134.2) months. The glomerular filtration rate at the final observation was 78.1 (41.4-107.7) mL/min/1.73 m2. The median age at the final observation was 13.4 (5.6-25.1) years, and all patients were alive except one who died of hepatic failure while on PD. Any type of RRT modality can be a treatment option for patients with JS and ESKD.

Brainstem infarction associated with HHV-6 infection in an infant.

INTRODUCTION: The relevant literature includes several case reports on cerebral infarction in children with HHV-6 infection; however, there is no report of brain stem infarction. CASE: An 11-month-old girl was hospitalized because of fever. She was unable to stand up and meet her mother's gaze. Magnetic resonance imaging (MRI) indicated a right pons and mid-brain lesion; a diagnosis of brainstem infarction was made. After her fever subsided, a rash developed on her trunk and limbs; blood examination results indicated a primary HHV-6 infection. She was treated with aspirin, edaravone, and mannitol to prevent further complications. At the age of 18months, the auditory brainstem response (ABR) was unremarkable and she is developing well. DISCUSSION AND CONCLUSION: A limited number of studies have reported HHV-6 infection-associated infarction, and no cases of brainstem infarction have been reported. One possible cause of cerebral infarction is antiphospholipid antibody syndrome (APS) triggered by the infection. HHV-6 may also directly infect vascular endothelial cells and cause angiopathy. However, the real mechanism of infarction remains unclear. Our patient had a favorable prognosis despite brainstem infarction.

Vasopressin phosphorylates HSP27 in aortic smooth muscle cells.

Administration of arginine vasopressin (AVP) time-dependently induced the phosphorylation of heat shock protein 27 (HSP27) at Ser-15 and Ser-85 in smooth muscle of aorta in vivo. The AVP-induced phosphorylation of HSP27 at Ser-15 and Ser-85 was inhibited by a V1a receptor antagonist but not by a V2 receptor antagonist. In cultured aortic smooth muscle A10 cells, AVP markedly stimulated the phosphorylation of HSP27 at Ser-15 and Ser-85. The AVP-induced phosphorylation of HSP27 was attenuated by SB203580 and PD169316, inhibitors of p38 mitogen-activated protein (MAP) kinase, but not by PD98059, a MEK inhibitor. These results strongly suggest that AVP phosphorylates HSP27 via p38 MAP kinase in aortic smooth muscle cells.

Simvastatin enhances the regeneration of endothelial cells via VEGF secretion in injured arteries.

The search for a novel therapy for endothelial regenerating is an area of intensive investigation. Recent experimental and clinical evidence strongly suggests that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) have several physiological effects independent of low-density lipoprotein cholesterol reduction. We here report that the carotid arterial blood flow after endothelial injury in hamsters treated with simvastatin was restored, in contrast to the situation in nontreated hamsters. Histologic observations showed a prompt recovery of endothelial cells with a much higher DNA synthesis index in repaired endothelium of hamsters treated with simvastatin. The amount of secreted vascular endothelial cell growth factor (VEGF) by cultured vascular smooth muscle cells from hamsters treated with simvastatin was significantly increased. Mevalonate reduced the amount of VEGF secretion by simvastatin in vitro. Finally, an injection of either an anti-VEGF antibody or an anti-VEGF receptor-1 (Flt-1) antibody, but not anti-VEGF receptor-2 (Flk-1), reduced the prompt endothelial healing. Simvastatin regulates endothelial regenerating by an over-release of VEGF and by this may result in prompt endothelial healing after vascular injury. Our results provide new insights into the role of statin and VEGF in the pathogenesis of vascular diseases.

Platelet-derived growth factor-BB phosphorylates heat shock protein 27 in cardiac myocytes.

It is recognized that heat shock protein 27 (HSP27) is highly expressed in heart. In the present study, we investigated whether platelet-derived growth factor (PDGF) phosphorylates HSP27 in mouse myocytes, and the mechanism underlying the HSP27 phosphorylation. Administration of PDGF-BB induced the phosphorylation of HSP27 at Ser-15 and -85 in mouse cardiac muscle in vivo. In primary cultured myocytes, PDGF-BB time dependently phosphorylated HSP27 at Ser-15 and -85. PDGF-BB stimulated the phosphorylation of p44/p42 mitogen-activated protein (MAP) kinase, p38 MAP kinase, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) among the MAP kinase superfamily. SB203580, a specific inhibitor of p38 MAP kinase, reduced the PDGF-BB-stimulated phosphorylation of HSP27 at both Ser-15 and -85, and phosphorylation of p38 MAP kinase. However, PD98059, a specific inhibitor of MEK, or SP600125, a specific inhibitor of SAPK/JNK, failed to affect the HSP27 phosphorylation. These results strongly suggest that PDGF-BB phosphorylates HSP27 at Ser-15 and -85 via p38 MAP kinase in cardiac myocytes.

Lack of alpha 2-antiplasmin enhances ADP induced platelet micro-aggregation through the presence of excess active plasmin in mice.

BACKGROUND: The role of alpha2-antiplasmin (alpha2-AP) on platelet aggregation was investigated using mice deficient in alpha2-AP (alpha2-AP(-/-)) or using wild type mice (alpha2-AP(+/+)). METHODS: Blood samples were taken from each mouse under anesthesia with ether and platelet rich plasma (PRP) was prepared. Platelet aggregation induced by various doses of ADP (0.3-30 microM) was detected using a laser-light scattering (LS) system. Aggregated forms were observed using a scanning electron microscopy (SEM). RESULTS: Dose-dependent platelet aggregation was not different in both types of mice. However, platelet micro-aggregate formation in alpha2-AP(-/-) mice induced by low dose of ADP (1.0 microM) markedly increased compared to the situation in wild type mice. Aggregated form detected by SEM showed supported data from LS analysis. When washed platelets of alpha2-AP(+/+) mice were resuspended in plasma of alpha2-AP(-/-) mice, platelet micro-aggregation was also increased. On the contrary, when washed platelets of alpha2-AP(-/-) mice were suspended in plasma of alpha2-AP(+/+) mice, platelet micro-aggregation did not change. In separate experiments, tPA (1.0 microg/ml) was added to PRP before the stimulation of ADP. tPA had no effect on platelet aggregation in alpha2-AP(+/+) mice, however platelet micro-aggregation in alpha2-AP(-/-) mice was markedly increased by the treatment with tPA. Moreover, the amount of released ATP from stimulated platelets was increased in alpha2-AP(-/-) mice treated with tPA. CONCLUSION: Lack of alpha2-AP increased platelet micro-aggregation, and plasmin plays an important role in the formation of platelet aggregation when alpha2-AP knockout mice are used. Consequently, the reduction of alpha2-AP could be a risk factor for the activation of platelets resulting in thrombus formation.