Toward β-Secretase-1 Inhibitors with Improved Isoform Selectivity.

BACE1 is responsible for the first step in APP proteolysis, leading to toxic Aβ production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform-selective BACE1 inhibitors.

Wnt6 regulates epithelial cell differentiation and is dysregulated in renal fibrosis.

Diabetic nephropathy is the most common microvascular complication of diabetes mellitus, manifesting as mesangial expansion, glomerular basement membrane thickening, glomerular sclerosis, and progressive tubulointerstitial fibrosis leading to end-stage renal disease. Here we describe the functional characterization of Wnt6, whose expression is progressively lost in diabetic nephropathy and animal models of acute tubular injury and renal fibrosis. We have shown prominent Wnt6 and frizzled 7 (FzD7) expression in the mesonephros of the developing mouse kidney, suggesting a role for Wnt6 in epithelialization.

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H₁ antagonists. Part I.

The discovery of potent small molecule dual antagonists of the human CCR3 and H(1) receptors is described for the treatment of allergic diseases, for example, asthma and allergic rhinitis. Optimizing in vitro potency and metabolic stability, starting from a CCR1 lead compound, led to compound 20 with potent dual CCR3/H(1) activity and in vitro metabolic stability.

Discovery and evolution of phenoxypiperidine hydroxyamide dual CCR3/H₁ antagonists. Part II: optimising in vivo clearance.

The second part of this communication focuses on the resolution of issues surrounding the series of hydroxyamide phenoxypiperidine CCR3/H(1) dual antagonists described in Part I. This involved further structural exploration directed at reducing metabolism and leading to the identification of compound 60 with a greatly improved in vivo pharmacokinetic profile.

The discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS).

By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.

Gastric bypass in a factor V deficient patient.

Factor V deficiency is a rare bleeding disorder requiring special attention during the peri-operative period. Surgical intervention in these patients can be technically challenging. Because of the rarity of this condition, the optimal management is unknown.

2-aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution.

4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.

Safety of cystic duct clipping in healthy and cirrhotic livers: a cadaveric study.

Background And Objectives: Biliary leakage through the cystic duct stump due to clip dislodgement has been a concern since the advent of the laparoscopic cholecystectomy. The authors proposed a cadaveric model to test the safety of cystic duct clipping in a hypertensive biliary tract in healthy and cirrhotic livers.

Methods: Twenty fresh cadavers were studied (5 cirrhotic, 15 healthy).

1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo.

The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2-substituted 1,2-dihydro-4-quinazolinamines, and the related 4'-aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of both series exhibit nanomolar potency and high selectivity for the inducible isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro. Efficacy in acute and chronic animal models of inflammatory disease following oral administration has also been demonstrated using these compounds.

Two New York City hospitals' surgical response to the September 11, 2001, terrorist attack in New York City.

Background: We describe the surgical response of two affiliated hospitals during the day of, and week following, the September 11th, 2001 terrorist attack at the World Trade Center in New York City. The city of New York has 18 state designated regional trauma centers that receive major trauma victims. The southern half of Manhattan is served by a burn center, two regional trauma centers, and a community hospital that is an affiliate of one of the regional trauma centers.

Thienopyridines: nitric oxide synthase inhibitors with potent in vivo activity.

5-Substituted 7-amino-4,5-tetrahydrothieno[2,3-c]pyridines and 6-substituted 4-amino-6,7-dihydrothieno[3,2-c]pyridines were shown to be exceptionally potent inhibitors of inducible and neuronal nitric oxide synthase. Selectivity and potency could be modulated by variation of the 5- or 6-substituent. Compound 3e showed potent in vivo inhibition of iNOS.

3,4-Dihydro-1-isoquinolinamines: a novel class of nitric oxide synthase inhibitors with a range of isoform selectivity and potency.

3-Phenyl-3.4-dihydro-1-isoquinolinamine is a weak inhibitor of iNOS and nNOS. Structural variation of 5a results in inhibitors with a range of potency and selectivity for the NOS enzymes, including a potent and very selective iNOS inhibitor 5j.

Laparoscopic salvage of malfunctioning peritoneal catheters.

Background: Malfunction of peritoneal catheters due to mechanical outflow problems is an annoying complication in patients undergoing chronic peritoneal dialysis (PD). Correction often involves catheter replacement or revision via laparotomy.

Methods: Twenty-five patients undergoing PD who developed mechanical catheter flow restriction underwent 28 laparoscopic procedures.

Selective management of colonoscopic perforations.

Background: Colonoscopy is a safe procedure if performed properly. Perforations from such procedures are rare, but not entirely avoidable. Usually perforations from diagnostic colonoscopy result in large defects requiring surgical management.

Early endoscopic sphincterotomy for extraction of residual stones of the common bile duct.

Retained calculi of the common bile duct are a significant cause of morbidity after operations upon the biliary tract. When percutaneous extraction is not possible or delay undesirable, endoscopic sphincterotomy is a safe and effective technique even when used in the early postoperative period. Five such patients treated at Beth Israel Medical Center within the past year are presented and discussed.

Contribution of endoscopy to diagnosis and treatment of gastric cancer.

The contribution of fiberoptic endoscopy to the diagnosis and treatment of gastric cancer was evaluated in 174 patients. For the purpose of staging, they were compared with 99 patients admitted to the same institution in the pre-endoscopy era. The frequency of minimal gastric cancer (stages I and II) was 16.

Unsuspected hepatic abscess associated with biliary tract disease.

Experience at Beth Israel Medical Center with 10 patients who had unsuspected intrahepatic abscesses due to biliary tract disease led to a reevaluation of this entity. Ultrasonography, computerized tomography, and radionuclide imaging techniques have radically altered the approach to the evaluation and management of this disease in the last several years, and rapid diagnosis and treatment have led to a markedly improved prognosis, especially in those patients with calculous disease of the biliary tract.