A case report of adenomyosis-induced spontaneous rupture in an unscarred and unpregnant uterus.

Rationale: Spontaneous uterine rupture, although rare, is a life-threatening obstetric emergency with a high maternal and fetal mortality rate. It can occur without warning, leading to severe complications, including hemorrhage, shock, and fetal demise. The risk factors contributing to uterine rupture are diverse and include a history of uterine surgery (such as cesarean section), trauma to the uterus, abnormal uterine contractions during labor, and underlying conditions like adenomyosis.

Study on Cynodon dactylon root system affecting dry-wet cracking behavior and shear strength characteristics of expansive soil.

Expansive soil exhibits remarkable characteristics of water absorption expansion and water loss shrinkage, rendering it susceptible to cracking under the alternating dry-wet environments of nature. The generation and development of cracks in expansive soil can result in catastrophic engineering accidents such as landslides. Vegetation protection is an important approach to stabilizing expansive soil slopes and fulfilling ecological protection requirements.

Selective thyroid hormone receptor β agonists with oxadiazolone acid isosteres.

Use of the oxadiazolone acid isostere in triiodothyronine analogs yielded potent and selective agonists for the thyroid hormone receptor β. Selected examples showed good in-vivo efficacy in a rat hypercholesterolemic model. One compound was further profiled in a diet-induced mouse model of nonalcoholic steatohepatitis (NASH) and showed robust target engagement and significant histological improvements in both liver steatosis and fibrosis.

The Race to Bash NASH: Emerging Targets and Drug Development in a Complex Liver Disease.

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) characterized by liver steatosis, inflammation, and hepatocellular damage. NASH is a serious condition that can progress to cirrhosis, liver failure, and hepatocellular carcinoma. The association of NASH with obesity, type 2 diabetes mellitus, and dyslipidemia has led to an emerging picture of NASH as the liver manifestation of metabolic syndrome.

Impact of Job Demands and Resources on Nurses' Burnout and Occupational Turnover Intention Towards an Age-Moderated Mediation Model for the Nursing Profession.

This longitudinal study among Registered Nurses has four purposes: (1) to investigate whether emotional, quantitative and physical demands, and family-work conflict have a negative impact on nurses' perceived effort; (2) to investigate whether quality of leadership, developmental opportunities, and social support from supervisors and colleagues have a positive impact on meaning of work; (3) to investigate whether burnout from the combined impact of perceived effort and meaning of work mediates the relationship with occupational turnover intention; and (4) whether the relationships in our overall hypothesized framework are moderated by age (nurses categorized under 40 years versus ≥ 40 years old). In line with our expectations, emotional, quantitative, and physical demands, plus family-work conflict appeared to increase levels of perceived effort. Quality of leadership, developmental opportunities, and social support from supervisors and colleagues increased the meaning of work levels.

A computational and functional study elicits the ameliorating effect of the Chinese herbal formula Huo Luo Xiao Ling Dan on experimental ischemia-induced myocardial injury in rats via inhibition of apoptosis.

Ischemic heart disease (IHD) is the leading cause of death worldwide and remains a major life-threatening factor in humans. Apoptosis has been implicated in the pathogenesis of IHD. The Chinese herbal formula Huo Luo Xiao Ling Dan (HLXLD), one of the commonly used Chinese herbal formulas, consists of Salviae miltiorrhizae, Angelica sinensis, Gummi olibanum, and Commiphora myrrha, with a wide spectrum of pharmacological activity.

Jaypatient-induced service sabotage behavior: the issue of self-esteem of hospital nurses.

Worrying incidents exist where disgruntled nurses destroy good service quality through sabotage behavior. Previous studies report the organizational and environmental factors that might lead to service sabotage behaviors; here individual differences in proclivity to service sabotage within any given environment of managerial context are reported. The study first uses interviews to establish typologies of difficult patients.

Thermodynamic and kinetic characterization of hydroxyethylamine β-secretase-1 inhibitors.

Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. β-Secretase-1 (BACE-1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Aβ, is a well validated target for AD. Herein, the authors characterize 10 randomly selected hydroxyethylamine (HEA) BACE-1 inhibitors in terms of their association and dissociation rate constants and thermodynamics of binding using surface plasmon resonance (SPR).

Orally available and efficacious α4β1/α4β7 integrin inhibitors.

A series of potent α4β1/α4β7 integrin inhibitors is reported, including an inhibitor 12d with remarkable oral exposure and efficacy in rat models of rheumatoid arthritis and Crohn's disease.

PEG conjugates of potent α4 integrin inhibitors, maintaining sustained levels and bioactivity in vivo, following subcutaneous administration.

Mitsunobu reactions were employed to link t-butyl esters of α4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent α4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats.

Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch.

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials.

Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.

Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed.

Arylsulfonamide pyrimidines as VLA-4 antagonists.

A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.

Development of a novel β-secretase binding assay using the AlphaScreen platform.

Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. β-secretase-1 (BACE1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Aβ is a validated target for AD. Herein, the authors develop and validate a novel binding assay for BACE1 using the AlphaScreen platform that is amenable for high-throughput screening (HTS).

Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates.

The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond.

Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors.

Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described.

Small-molecule BACE1 inhibitors: a patent literature review (2006 - 2011).

Introduction: Alzheimer's disease is a devastating neurodegenerative disorder for which no disease-modifying therapy exists. The amyloid hypothesis, which implicates Aβ as the toxin initiating a biological cascade leading to neurodegeneration, is the most prominent theory concerning the underlying cause of the disease. BACE1 is one of two aspartyl proteinases that generate Aβ, thus inhibition of BACE1 has the potential to ameliorate the progression of Alzheimer's disease by abating the production of Aβ.

A label-free approach to identify inhibitors of alpha4beta7-mediated cell adhesion to MadCAM.

Traditionally, cell adhesion assays are performed in a manual workstation format using fluorescence-based readouts. Herein, the authors describe a label-free homogeneous assay to identify inhibitors of α4β7 integrin-mediated cell adhesion to its ligand, the mucosal addressin cell adhesion molecule (MadCAM), using the SRU BIND platform. The biosensor is optically based and comprises a subwavelength polymer grating.

Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model.

A series of N-(pyrimidin-4-yl)-phenylalanine VLA-4 antagonists is described. Optimization of substituents at the 2 and 5 positions of the pyrimidine ring gave 14, a very potent VLA-4 inhibitor which is orally active in a sheep asthma model.

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.

Introduction: Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.

Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: structure-activity relationship of the aryl region.

The structure-activity relationship of the prime region of hydroxyethylamine BACE inhibitors is described. Variation in the aryl linker region with 5- and 6-membered heterocycles provided compounds such as 33 with improved permeability and reduced P-gp liability compared to benzyl amine analog 1.

Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious gamma-secretase inhibitors.

Discovery of a series of pyrazolopiperidine sulfonamide based gamma-secretase inhibitors and its SAR evolution is described. Significant increases in APP potency on the pyrazolopiperidine scaffold over the original N-bicyclic sulfonamide scaffold were achieved and this potency increase translated in an improved in vivo efficacy.