Chronic pelvic pain due to pelvic lymphangioleiomyomatosis: A case report

AbstractLymphangioleiomyomatosis (LAM), a rare multisystem disease affecting mainly young women, is characterized by an abnormal proliferation of smooth muscle-like cells in the lungs. We report a case of endometriosis with chronic pelvic pain due to pelvic LAM. A 41-year-old gravida 1, para 1 woman had been experiencing intermittent left pelvic pain for several years. She also complained of dyspnea on effort 2 years previously, and was diagnosed with pulmonary LAM. Abdominal magnetic resonance imaging showed a right ovarian endometriotic cyst and a left pelvic mass. She was referred to our hospital for the treatment of pelvic pain; she underwent laparoscopic cystectomy of the right ovarian endometriotic cyst. Her left pelvic cyst was found in the retroperitoneal space, and biopsy confirmed the diagnosis of LAM. Therefore, we suggest that LAM localized in the pelvis should be considered when a patient with pulmonary LAM presents with pelvic pain or abdominal distention

Nuclear protein LEDGF/p75 recognizes supercoiled DNA by a novel DNA-binding domain

Lens epithelium-derived growth factor (LEDGF) or p75 is a co-activator of general transcription and also involved in insertion of human immunodeficiency virus type I (HIV-1) cDNA into host cell genome, which occurs preferentially to active transcription units. These phenomena may share an underlying molecular mechanism in common. We report here that LEDGF/p75 binds negatively supercoiled DNA selectively over unconstrained DNA. We identified a novel DNA-binding domain in the protein and termed it ‘supercoiled DNA-recognition domain’ (SRD). Recombinant protein fragments containing SRD showed a preferential binding to supercoiled DNA in vitro. SRD harbors a characteristic cluster of lysine and glutamic/aspartic acid residues. A polypeptide mimicking the cluster (K9E9K9) also showed this specificity, suggesting that the cluster is an essential element for the supercoil recognition. eGFP-tagged LEDGF/p75 expressed in the nucleus distributed partially in transcriptionally active regions that were identified by immunostaining of methylated histone H3 (H3K4me3) or incorporation of Br-UTP. This pattern of localization was observed with SRD alone but abolished if the protein lacked SRD. Thus, these results imply that LEDGF/p75 guides its binding partners, including HIV-1 integrase, to the active transcription site through recognition of negative supercoils generated around it

<Regular article>Opioid Receptor Affinities of Tyrosine ω-Phenylalkyl Esters, Simple Enkephalin Pharmacophore-mimics.

In order to substantiate the hypothesis that the μ-, δ-, or κ-opioid receptor Affinity of opioid peptides can be elicited by an amino-terminus tyrosine residue and the 4th phenylalanine aromatic ring lying in the proper spatial disposition, a series of simple peptide-mimic tyrosine esters, in which tyrosine is linked to aromatic ring separated by a variety of methylene spacers, were prepared and evaluated by in vitro radioligand receptor assay. Compounds having the 6 or 7 methylene spacers were more potent in opioid receptor affinity than those having fewer or more methylene spacers. The N-monomethyl- and N, N-dimethyltyrosine congeners were more potent than the corresponding tyrosine esters. The order of the receptor type selectivity of these compounds was μ>>δ>κ

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie