Piperidine-derived gamma-secretase modulators.

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

Incidence of Acute Post-Streptococcal Glomerulonephritis in Hawai'i and Factors Affecting Length of Hospitalization.

Acute post-streptococcal glomerulonephritis (APSGN) is a disorder of inflammation in the glomeruli and vasculature of the kidneys that is caused by immune-complex formation after Streptococcus pyogenes infection. Most patients with APSGN present with macroscopic hematuria, edema, and hypertension, however presentation can vary from no symptoms to severe proteinuria, or even acute renal failure. This study sought to estimate the incidence of APSGN among children in Hawai'i, to identify populations at increased risk for APSGN, and to recognize risk factors correlated with the length of hospitalization by subtype of APSGN (eg, pyoderma-associated, pharyngitis-associated). This retrospective review of 106 patients found that the incidence of APSGN in Hawai'i is greater than 4 per 100,000 children, which is significantly higher than the incidence of APSGN in high-income countries at 0.3 per 100,000 children. This increased incidence may be due to Hawai'i's unique racial group composition and therefore the unique immunologic response of the children of Hawai'i (particularly Pacific Islanders, who represent 62% of patients with APSGN in this study, but only represent 10% of Hawai'i's general population). In addition, there may be increased prevalence of nephritogenic strains of Streptococcus pyogenes in Hawai'i. The length of hospitalization was significantly increased in children with elevated serum creatinine levels (P <.0001) and lower bicarbonate levels (P =.0003).

Hemodialysis in the Compact Nations of the US Affiliated Pacific: History and Health Care Implications.

Background: The epidemic of non-communicable disease in the Compact nations of the US Affiliated Pacific Islands and the associated renal complications drive the demand for hemodialysis. Limited healthcare budgets and a lack of trained human health resources in these areas make hemodialysis a challenging undertaking that may require significant sacrifices in competing health care priorities. Methods: Two nephrologists who developed hemodialysis in the US Affiliated Pacific Islands provide its history. Cost estimates of hemodialysis for the Compact nations are collected from a 2014 hemodialysis feasibility report. The experiences and outcomes of current hemodialysis centers in the United States and other island nations provide a framework by which to assess the potential benefit and impact of hemodialysis in the Compact nations. Discussion: A consideration of how and why different stakeholders value hemodialysis will be crucial because they will drive the public's response to the institutionalization of any new intervention or the cessation of any existing intervention like hemodialysis. Conclusion: Updated cost estimates for dialysis clinics and data on renal disease rates in the Compact nations will be necessary to make informed decisions about hemodialysis in the current health systems. In the meantime, it is essential to enhance current medical interventions and public health strategies to prevent kidney disease and decrease the risks for kidney failure. Such preventive interventions must be culturally appropriate, effective, cost-efficient, and sustainable in the unique context of the Pacific.

1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3.

A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10- and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38alpha and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent.

Immune globulin-responsive thrombocytopenia in acute post-streptococcal glomerulonephritis: report of a case in Hawai'i.

A 9-year-old boy in Hawai'i presented with bleeding and thrombocytopenia and was subsequently found to have post-streptococcal glomerulonephritis. He recovered completely with intravenous immune globulin, antibiotics, short-term antihypertensive therapy, and supportive management. This case was similar to the 5 cases previously reported in the literature, with the exception that steroids were not used as the primary immune-modulating therapy.

A Case of Escherichia coli Hemolytic Uremic Syndrome in a 10-Year-Old Male With Severe Neurologic Involvement Successfully Treated With Eculizumab.

Hemolytic uremic syndrome (HUS) can be classified as typical and atypical, and the treatment recommendations currently differ between the 2 types. Eculizumab is recommended as first-line treatment for atypical HUS; however, its use in typical HUS has been controversial. We report a case of a 10-year-old male with severe neurologic impairment who was successfully treated with eculizumab, which was started 4 days after onset of neurologic symptoms. Our case supports the use of eculizumab in typical HUS with neurologic involvement, even when given later in the course, as the pathophysiology of typical HUS has been shown to involve activation of the complement pathway, similar to atypical HUS. Further studies are required to establish the efficacy and duration of eculizumab use in this patient population.

N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3.

The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.