Methotrexate myelopathy with extensive transverse necrosis: Report of an autopsy case

The patient was a 70‐year‐old woman with lymphoplasmacytic lymphoma which showed a predominantly diffuse involvement of the bone marrow and kidney. Because atypical lymphocytes appeared in the cerebrospinal fluid, the intrathecal administration of methotrexate (MTX) and cytosine arabinoside (Ara‐C) was repeated several times. The patient developed flaccid paraplegia 8 months after the beginning of intrathecal administration, and died 4 months later. Autopsy demonstrated extensive transverse necrosis involving the lower thoracic cord and marked vacuolar degeneration of the white matter of the cervical, upper thoracic and lumbo‐sacral cord. Focal vacuolar degeneration of the white matter was also noted in the left parietal lobe. Although vacuolar degeneration of the white matter is a common feature in MTX myelopathy, extensive transverse necrosis is rare. In the present case, an overlapping of two mechanisms, that is, injury of vascular endothelial cells and the direct toxic effect of MTX and Ara‐C on the white matter, probably played a crucial role in the pathogenesis of severe myelopathy. Because severe myelopathy occurs infrequently, considering the large number of patients receiving the intrathecal administration of MTX, it is possible that a constitutional predisposition or abnormal sensitivity to MTX was involved in the pathogenesis in the present patient.     

Significance of combined cyclosporine−prednisolone therapy and cyclosporine blood concentration monitoring for idiopathic membranous nephropathy with steroid-resistant nephrotic syndrome: a randomized controlled multicenter trial

Background

Combined treatment with cyclosporine microemulsion preconcentrate (CyA MEPC) and steroids has been widely used for idiopathic membranous nephropathy (IMN) associated with steroid-resistant nephrotic syndrome (SRNS). Recent studies have shown that once-a-day and preprandial administration of CyA MEPC is more advantageous than the conventional twice-a-day administration in achieving the target blood CyA concentration at 2 h post dose (C2). We designed a randomized trial to compare these administrations.

Methods

IMN patients with SRNS (age 16–75 years) were divided prospectively and randomly into 2 groups. In group 1 (n = 23), 2–3 mg/kg body weight (BW) CyA MEPC was given orally once a day before breakfast. In group 2 (n = 25), 1.5 mg/kg BW CyA MEPC was given twice a day before meals. CyA + prednisolone was continued for 48 weeks.

Results

Group 1 showed a significantly higher cumulative complete remission (CR) rate (p = 0.0282), but not when incomplete remission 1 (ICR1; urine protein 0.3–1.0 g/day) was added (p = 0.314). Because a C2 of 600 ng/mL was determined as the best cut-off point, groups 1 and 2 were further divided into subgroups A (C2 ≥600 ng/mL) and B (C2 <600 ng/mL). Groups 1A and 2A revealed significantly higher cumulative remission (CR + ICR1) (p = 0.0069) and CR-alone (p = 0.0028) rates. On the other hand, 3 patients with high CyA levels (C2 >900 ng/mL) in Group 1A were withdrawn from the study because of complications.

Conclusion

CyA + prednisolone treatment is effective for IMN with associated SRNS at a C2 of ≥600 ng/mL. To achieve remission, preprandial once-a-day administration of CyA at 2–3 mg/kg BW may be the most appropriate option. However, we should adjust the dosage of CyA by therapeutic drug monitoring to avoid complications.     

Adverse Effects of High Temperature On Mammary Alveolar Development In Vitro

Journal of Mammary Gland Biology and Neoplasia - In the mammary glands during pregnancy, the alveolar buds are first branched from the mammary ducts after which they form the alveolar luminal...     

Spondylocostal dysostosis with tetralogy of Fallot and herniation of the spleen through the diaphragm

Spondylocostal dysostosis (SCD) is a very rare syndrome characterized by vertebral malformation and rib deformity. Some of the patients with SCD have other birth defects in the central nervous system, the genitourinary tract, diaphragm or heart and so forth. There have been reported SCD with complex congenital heart disease, such as pulmonary atresia, double outlet right ventricle, and d‐transposition of great arteries. However, there have been no reported SCD patients with confirmed tetralogy of Fallot (TOF). Here, a patient with SCD having a very rare combination of rib defects on the right side and left‐sided scoliosis, tetralogy of Fallot, and diaphragmatic spleen herniation, which had not been reported before, was described.     

The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells. Dependence on the availability of downstream targets.

Activation of the classical mitogen-activated protein kinase (MAPK) pathway leads to proliferation of many cell types. Accordingly, an inhibitor of MAPK kinase, PD 098059, inhibits PDGF-induced proliferation of human arterial smooth muscle cells (SMCs) that do not secrete growth-inhibitory PGs such as PGE2. In striking contrast, in SMCs that express the inducible form of cyclooxygenase (COX-2), activation of MAPK serves as a negative regulator of proliferation. In these cells, PDGF-induced MAPK activation leads to cytosolic phospholipase A2 activation, PGE2 release, and subsequent activation of the cAMP-dependent protein kinase (PKA), which acts as a strong inhibitor of SMC proliferation. Inhibition of either MAPK kinase signaling or of COX-2 in these cells releases them from the influence of the growth-inhibitory PGs and results in the subsequent cell cycle traverse and proliferation. Thus, the MAPK pathway mediates either proliferation or growth inhibition in human arterial SMCs depending on the availability of specific downstream enzyme targets.     

Osteopontin deficiency suppresses high phosphate load-induced bone loss via specific modulation of osteoclasts

Phosphate (Pi) plays a critical role in the maintenance of mineralized tissues and signaling in the intracellular environment. Although extracellular phosphate concentration is maintained at fixed levels, physiological machineries involved in phosphate homeostasis in bone, which is the largest phosphate storage site, have not yet been fully elucidated. Here we examined the role of osteopontin (OPN) in a high-Pi diet load-induced bone loss. A high-Pi diet significantly reduced bone mineral density as well as bone mass in wild type. In contrast, OPN deficiency totally prevented reduction in bone mineral density and bone mass. Analyses of bone turnover-related components revealed that bone formation parameters (bone formation rate and mineral apposition rate) were enhanced by high-Pi diet load similarly in wild-type and OPN-deficient mice. In sharp contrast, bone resorption parameters (osteoclast number and osteoclast surface) were enhanced by high-Pi diet load in wild type but not at all in OPN-deficient mice. Bone marrow cell cultures revealed no major effects of OPN deficiency on high-Pi diet modulation of mineralized nodule formation in culture. On the other hand, tartrate-resistant acid phosphatase-positive multinucleated cell development in cultures were enhanced by high-Pi diet load in wild-type cells, but such effects of high Pi-diet were totally abolished in the absence of OPN. These data indicated that OPN is needed for osteoclastic activity to resorb bone on high phosphate loading.     

The activation of supraspinal GPR40/FFA1 receptor signalling regulates the descending pain control system

Background and Purpose

The ω-3 polyunsaturated fatty acids exert antinociceptive effects in inflammatory and neuropathic pain; however, the underlying mechanisms remain unclear. Docosahexaenoic acid-induced antinociception may be mediated by the orphan GPR40, now identified as the free fatty acid receptor 1 (FFA1 receptor). Here, we examined the involvement of supraspinal FFA1 receptor signalling in the regulation of inhibitory pain control systems consisting of serotonergic and noradrenergic neurons.

Experimental Approach

Formalin-induced pain behaviours were measured in mice. Antinociception induced by FFA1 receptor agonists was examined by intrathecal injections of a catecholaminergic toxin, 5-HT lowering drug or these antagonists. The expression of FFA1 receptor protein and c-Fos was estimated by immunohistochemistry, and the levels of noradrenaline and 5-HT in the spinal cord were measured by LC-MS/MS.

Key Results

FFA1 receptors colocalized with NeuN (a neuron marker) in the medulla oblongata and with tryptophan hydroxylase (TPH; a serotonergic neuron marker) and dopamine β-hydroxylase (DBH; a noradrenergic neuron marker). A single i.c.v. injection of GW9508, a FFA1 receptor agonist, increased the number of c-Fos-positive cells and the number of neurons double-labelled for c-Fos and TPH and/or DBH. It decreased formalin-induced pain behaviour. This effect was inhibited by pretreatment with 6-hydroxydopamine, DL-p-chlorophenylalanine, yohimbine or WAY100635. Furthermore, GW9508 facilitated the release of noradrenaline and 5-HT in the spinal cord. In addition, GW1100, a FFA1 receptor antagonist, significantly increased formalin-induced pain-related behaviour.

Conclusion and Implications

Activation of the FFA1 receptor signalling pathway may play an important role in the regulation of the descending pain control system.