Evaluation of Coumarin and Neoflavone Derivatives as HCV NS5B Polymerase Inhibitors

Coumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS5B polymerase and predicted their binding in thumb pocket‐1 (TP‐1) of NS5B. As the coumarins are structurally related to coumestans by virtue of their common A‐ and B‐rings, we postulated them to also exhibit similar binding interaction with NS5B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS5B inhibitors and identified 14 compounds inhibiting NS5B polymerase activity with IC₅₀ values between 17 and 63 μm . Of these, the newly synthesized 6,8‐diallyl‐5,7‐dihydroxycoumarin ( 8a ) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB‐ 34 . The binding site of 8a was mapped to TP‐1 of NS5B by counter screening against P495L NS5B mutant, employed as a screen for TP‐1 site binders. NS5B‐TP‐1‐ 8a interaction map provided insight into 8a binding and offered clues for future SAR optimization.     

Diagnosing vestibular hypofunction: an update

Journal of Neurology - Unilateral or bilateral vestibular hypofunction presents most commonly with symptoms of dizziness or postural imbalance and affects a large population. However, it is often...     

Selective Retreatment and Sinus Lift: An Alternative Approach to Surgically Manage the Palatal Roots of Maxillary Molars

Endodontic microsurgery on the palatal root of maxillary molars presents a clinical challenge because of the root position and approximation from the maxillary sinus floor. Attempting a buccal or a palatal approach to address the root is associated with limited accessibility and visibility as well as the risk of injury to the maxillary sinus membrane and/or the greater palatine nerves and vessels. If all the maxillary molar roots require surgical intervention, two flaps may even be needed, which can make the procedure technically more difficult and lengthier. This case report presents 2 clinical cases in which apicoectomy was needed on the palatal roots of maxillary molars. The treatment includes selective nonsurgical retreatment of the palatal root and obturation using a root repair material followed by a surgical intervention from a buccal approach to treat the buccal roots, sinus lift using piezosurgery, and root resection of the palatal root. The approach was successful in both cases without any untoward events. We monitored the radiographic changes using cone-beam computed tomographic imaging immediately after the surgery and at multiple follow-up appointments. The cone-beam computed tomographic images revealed healing of the periapical disease around all the roots up to 14 and 24 months and apical repositioning of the maxillary sinus floor.     

Urothelial Cancer in Patients with Endemic Balkan Nephropathy (EN) after Renal Transplantation

Goal. Analysis of the incidence of urothelial cancer and outcome of treatment in patients with Endemic Balkan Nephropathy (EN) after renal transplantation. Methods. From January 1985 until October 2006, 550 kidney transplantations (389 cadaveric) and 5 combined kidney and pancreas transplantations were performed in University Hospital Center Rijeka. In only 6 (1.1%) of 555 transplant recipients, EN was diagnosed as the original kidney disease, based on medical history, clinical findings, and laboratory results, but without pathohistologic verification. All patients with EN received the first renal transplant from a cadaver. Patients' mean age at transplantation was 50.3 ±15.9 yrs, five patients (83.3%) were male. The incidence of malignant tumors in all 555 transplant recipients was analyzed, with an emphasis on the incidence of urothelial cancer and outcome of treatment in the group of patients with EN. Results. During posttransplant follow-up period, malignancy was diagnosed in 27 (4.9%) out of 555 transplant recipients. Skin cancer was diagnosed in 7 patients (1.3%), followed by cancer of the urinary tract in 6 patients (1.1%) and breast cancer in 3 patients (0.5%). In 3 of 6 patients with EN, urothelial cancer was diagnosed, resulting in the death in two patients. In the third patient, urothelial cancer showed a high affinity for recurrence, and besides the strong reduction of immunosuppressive therapy, repeated surgical treatment was needed. Conclusions. Patients with EN show a high incidence of urothelial cancer after renal transplantation. A thorough nephro-urological evaluation is needed before transplantation, and a careful follow-up is required afterward to ensure an early diagnosis of malignancy. Preventive nephroureterectomy is recommended.     

Who Is Responsible? A Man With Dementia Wanders From Home,Is Hit by a Train,and Dies

The impact of dementia and Alzheimer's disease extends far beyond the healthcare needs of the person with dementia. As the disease progresses, individuals with dementia often require ongoing formal or informal care for their basic daily routine because of behavior changes and continuing loss of cognitive function. Most of the care for people with dementia takes place at home, and the unpaid, informal caregivers are often spouses or other relatives. Providing long-term informal care at home for someone with dementia is psychologically, physically, and financially draining. The tragedy described in this case elucidates the far-reaching societal impact of dementia care and the implicit health policy considerations.In 2007, a 91-year-old Japanese man with dementia was in the care of his wife when he wandered from home, was hit by a train, and died, immediately affecting the Central Japan Railway Company operations and, subsequently, legal practice as well as Japanese elder care policy. The railway sued the man's wife and son for negligence and lost revenue, winning both trials at the local and district courts. This ruling shocked families and caregivers in Japan, where care for elderly parents traditionally falls on the oldest son, and brought attention to the complex issues related to dementia care. A decade later, we revisit this case to provoke a renewed dialogue about the matrix of responsibilities and liabilities associated with caregiving; to illuminate the unmet needs of the person with dementia, as well as his or her informal caregivers; and the financial implications related to long-term care policy. We close with 2 practical suggestions which preserve the dignity of the individual and provide reassurance for caregivers.     

Study of the Hydrolytic Stability of Fine-Grained Ceramics Based on Y2.5Nd0.5Al5O12 Oxide with a Garnet Structure under Hydrothermal Conditions

The hydrolytic stability of ceramics based on Y_2.5Nd_0.5Al₅O₁₂ oxide with a garnet structure obtained by the spark plasma sintering (SPS) method has been studied. The tests were carried out in distilled water under hydrothermal conditions in an autoclave and, for comparison, in a static mode at room temperature. The mechanism of leaching of Y and Nd from the ceramics was investigated. It has been shown that at “low” temperatures (25 and 100 °C), the destruction of pores occured, and the intensity of the leaching process was limited by the diffusion of ions from the inner part of the sample to the surface. At “high” test temperatures (200 and 300 °C), intense destruction of the ceramic grain boundaries was observed. It was assumed that the accelerated leaching of neodymium is due to the formation of grain-boundary segregations of Nd³⁺ in sintered ceramics.     

Mechanistic study of 1,1-dimethylhydrazine transformation over Pt/SiO2 catalyst

Catalytic oxidation of 1,1-dimethylhydrazine (UDMH) with molecular oxygen over Pt/SiO₂ was studied by in situ FTIR spectroscopy coupled with online MS monitoring of the gas phase. An unusual two-step oxidation process was detected in experiments with the pulse UDMH feeding: initial UDMH oxidation over a fresh platinum surface quickly terminates due to the blockage of active sites; a time-separated second oxidation step corresponds to combustion of the surface residue. This residue consists of C N nitrile groups formed via decomposition of the products of non-oxidative UDMH conversion, such as dimethylamine. The two-step oxidation picture is observed over a broad range of reaction temperatures and oxygen to UDMH ratios.

Unusual two-step oxidation process of 1,1-dimethylhydrazine on Pt/SiO₂ catalyst.     

Molecular and biochemical study of glutaric aciduria type 1 in 49 Russian families: nine novel mutations in the GCDH gene

Metabolic Brain Disease - Glutaric aciduria type 1 (GA1, deficiency of glutaryl CoA dehydrogenase, glutaric acidemia type 1) (ICD-10 code: E72.3; MIM 231670) is an autosomal recessive disease...