A case of acute renal and liver dysfunction with light chain deposition disease

A 62 year old woman was referred to our hospital because of acute renal and liver dysfunction. Prior to admission, she had already been started on hemodyalysis filtration(HDF). She showed facial edema and lumbar pain caused by an Ll compressive fracture. Laboratory examinations revealed hypercalcemia (13.2 mg/dL), hyperammonemia (297 microg/dL) and her serum creatinine, blood urea nitrogen and total bilirubin levels were 3.9 mg/dL, 37.4 mg/dL and 3.2 mg/dL, respectively. Among the components of immunoglobulin, IgA was increased, while IgG and IgM were decreased. Serum immunoelectrophoresis revealed the presence of the IgA kappa type of M component. Punched out lesions were noted on her head radiography. Severe plasmacytosis (60-70 % of total cells) were observed by a bone marrow aspiration test, indicating the diagnosis of multiple myeloma. Steroid pulse therapy was started with dexamethasone (40 mg/day, 3 days), and plasma exchange was performed 8 times with continuous HDF. These treatments failed to control hemodynamics and she died of disseminated intravascular coagulation (DIC). Autopsy demonstrated amyloid-like depositions in perisinusoidal space in the liver. In the kidney, there were nodular lesions in the glomeruli, and depositions in the basement membrane of the uriniferous tubuli. Congo red staining of these organs for amyloid yielded negative results. Immunohistochemical staining gave positive results for IgA and kappa. Electron microscopy revealed granular electron deposits in the glomeruli and tubular basement membrane as well. Taken altogether, the diagnosis of the patient could be light chain deposition disease (LCDD).     

Assessment of the anatomical relationship between the arcuate eminence and superior semicircular canal by computed tomography

The anatomical relationship between the arcuate eminence (AE) and the superior semicircular canal (SSC) was examined by computed tomography (CT) in 52 petrous bones of 26 patients. After acquiring volume data by multidetector CT, 1-mm thick oblique bone window images perpendicular to the SSC were obtained from the axial images. The distances between the AE and the SSC, and the SSC and the superior surface of the petrous bone were measured. The AE corresponded exactly with the SSC in only 2/52 petrous bones, and corresponded well in 7/52. The AE was lateral to the SSC in 25/52 cases, medial to the SSC in 6/52 cases, intersected in 3/52 cases, and was indiscernible in 9/52 cases. The distance between the SSC and the petrous surface was 0 mm in 45/52 petrous bones, 1 mm in 5/52, 2 mm in 1/52, and 3 mm in 1/52. The SSC typically does not correspond exactly with the AE, and is generally located just under the surface of the petrous bone. Planning of the middle cranial fossa approach requires location of the SSC by CT.     

Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water

The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and 4-N-(Nomega-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), led to the discovery of a conserved structural water molecule that was hydrogen bonded between the two heme propionates and the inhibitors (Figure 2). On the basis of this observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of 2 or to the secondary amine nitrogen of 1, the inhibitor molecules could displace the structural water molecule and obtain a direct interaction with the heme cofactor. To test this hypothesis, peptidomimetic analogues 3-5, which have either an N-hydroxyl (3 and 5) or N-amino (4) donor group, were designed and synthesized. X-ray crystal structures of nNOS with inhibitors 3 and 5 bound verified that the N-hydroxyl group had, indeed, displaced the structural water molecule and provided a direct interaction with the heme propionate moiety (Figures 5 and 6). Surprisingly, in vitro activity assay results indicated that the addition of a hydroxyl group (3) only increased the potency slightly against the neuronal isoform over the parent compound (1). Rationalizations for the small increase in potency are consistent with other changes in the crystal structures.     

Vitamin D3 derivatives with adamantane or lactone ring side chains are cell type-selective vitamin D receptor modulators

The vitamin D receptor (VDR) mediates the biological actions of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, which regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. We investigated the effects of three 1,25(OH)(2)D(3) derivatives on VDR function. AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position. These vitamin D derivatives bind to VDR but do not stabilize an active cofactor conformation. In a VDR transfection assay, AD47 and LAC67b act as partial agonists and all three compounds inhibit VDR activation by 1,25(OH)(2)D(3). The derivatives enhanced the heterodimerization of VDR with the retinoid X receptor, an effect unrelated to agonist/antagonist activity. AD47 and LAC67b weakly induced recruitment of the SRC-1 cofactor to VDR, and all three derivatives inhibited the recruitment of p160 family cofactors to VDR induced by 1,25(OH)(2)D(3). It is noteworthy that AD47 induced DRIP205 recruitment as effectively as 1,25(OH)(2)D(3), whereas LAC67a and LAC67b were not effective. We examined the expression of endogenous VDR target genes and the nuclear protein levels of VDR and cofactors in several cell lines, including cells derived from intestine, bone, and monocytes, and found that the vitamin D(3) derivatives act as cell type-selective VDR modulators. The data indicate that side chain modification is useful in the development of VDR antagonists and tissue-selective modulators. Further elucidation of the molecular mechanisms of action of selective VDR modulators will be essential for their clinical application.     

Exploring Ligand-Directed N-Acyl-N-alkylsulfonamide-Based Acylation Chemistry for Potential Targeted Degrader Development

Ligand-directed bioconjugation strategies have been used for selective protein labeling in live cells or tissue samples in applications such as live-cell imaging. Here we hypothesized that a similar strategy could be used for targeted protein degradation. To test this possibility, we developed a series of CDK2-targeting N-acyl-N-alkylsulfonamide (NASA)-containing acylation probes. The probes featured three components: a CDK2 homing ligand, a CRL4^CRBN E3 ligase recruiting ligand, and a NASA functionality. We determined that upon target binding, NASA-mediated reaction resulted in selective functionalization of Lys89 on purified or native CDK2. However, we were unable to observe CDK2 degradation, which is in contrast to the efficient degradation achieved by the use of a structurally similar reversible bivalent degrader. Our analysis suggests that the lack of degradation is due to the failure to form a productive CDK2:CRBN complex. Therefore, although this work demonstrates that NASA chemistry can be used for protein labeling, whether this strategy could enable efficient protein degradation remains an open question.     

Retreatment using a dual mode of low-fluence Q-switched and long-pulse Nd:YAG laser in patients with melasma aggravation after previous therapy

Background: Aggravated melasma after treatment is vulnerable to stimulation, can easily deteriorate, and may be distressing without proper management. Objective: To retrospectively assess the effectiveness and safety of combination therapy using low-fluence Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser (QSNY) and long-pulse Nd:YAG laser (LPNY) (dual toning) in patients with rebound melasma. Materials and methods: A total of 30 patients with aggravated melasma after previous therapy who were treated with dual toning were enrolled. A total of 10 sessions were conducted at 1-week intervals, followed by maintenance treatment. The results were evaluated using the modified Melasma Area and Severity Index (mMASI) and the physician's global assessment (PGA) before and 2 months after completing the 10 treatment sessions. Results: The baseline mMASI was 10.48 ± 3.64, which significantly decreased to 3.22 ± 1.45 2 months after completing the 10 treatment sessions (p < 0.001). Twenty-four patients (80%) had PGA grade 4 (76–100% improvement) and 6 patients (20%) had PGA grade 3 (51–75% improvement). Conclusion: Dual toning may be a safe and effective salvage treatment for patients with aggravated melasma after previous treatment. LPNY may stabilize melasma activity to prevent rebound hyperpigmentation via dermal remodeling.