It is unclear how tau gene mutations cause frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17), but those in exon 10 (E10) or the following intron may be pathogenic by altering E10 splicing, perturbing the normal 1:1 ratio of four versus three microtubule-binding repeat tau (4R:3R tau ratio) and forming tau inclusions. We report on a 55-year old woman with frontotemporal dementia and a family history of FTDP-17 in whom we found a novel E12 (Glu342Val) tau gene mutation, prominent frontotemporal neuron loss, intracytoplasmic tau aggregates, paired helical tau filaments, increased 4R tau messenger RNA, increased 4R tau without E2 or E3 inserts, decreased 4R tau with these inserts, and a 4R:3R tau ratio greater than 1 in gray and white matter. Thus, this novel Glu342Val mutation may cause FTDP-17 by unprecedented mechanisms that alter splicing of E2, E3, and E10 to preferentially increase 4R tau without amino terminal inserts and promote aggregation of tau filaments into cytopathic inclusions.

Our previous study showed a higher exposure of berberine, palmatine, coptisine, epiberberine and jatrorrhizine in 6-week streptozotocin (STZ)-induced diabetic rats, after oral administration of Coptidis Rhizoma extract. The aim of the present study was to investigate whether the function and expression of intestinal P-glycoprotein (P-GP) was downregulated in STZ-induced diabetic rats and if the impairment of P-GP function and expression contributed to the exposure increase of the five protoberberine alkaloids. Plasma concentration-time profiles of the drugs in the portal vein were obtained after oral administration of Coptidis Rhizoma extract. The effective permeability of the drug across duodenum and ileum were measured using in situ single-pass intestine perfusion. P-GP function in the rat intestine was assessed by measuring the absorption of rhodamine 123 (Rho123). P-GP levels were evaluated using Western blots. It was found that the C(max) and AUC(0-8) values of five alkaloids in the portal vein of diabetic rats were significantly higher than those in the control rats. Diabetic rats also exhibitd a higher level of Rho123 in the portal vein, which showed impairment of P-GP function. A higher effective permeability of the tested drug was found in the duodenum of diabetic rats using in situ single-pass intestine perfusion, indicating that berberine and Rho123 transported more easily across the intestinal barrier of diabetic rats. A lower level of P-GP protein was found in the duodenum, jejunum and ileum of the diabetic rats as compared with age-matched control rats. All these results suggested that the function and expression of P-GP were impaired in the intestine of STZ-induced diabetic rats which, at least partly, contributed to the exposure increase of the five protoberberine alkaloids.

This paper describes the structure of optimal policies for discounted periodicreview single-commodity total-cost inventory control problems with fixed ordering costs for finite and infinite horizons. There are known conditions in the literature for optimality of (s t , S t ) policies for finite-horizon problems and the optimality of (s, S) policies for infinite-horizon problems. The results of this paper cover the situation, when such assumption may not hold. This paper describes a parameter, which, together with the value of the discount factor and the horizon length, defines the structure of an optimal policy. For the infinite horizon, depending on the values of this parameter and the discount factor, an optimal policy either is an (s, S) policy or never orders inventory. For a finite horizon, depending on the values of this parameter, the discount factor, and the horizon length, there are three possible structures of an optimal policy: (i) it is an (s t , S t ) policy, (ii) it is an (s t , S t ) policy at earlier stages and then does not order inventory, or (iii) it never orders inventory. The paper also establishes continuity of optimal value functions and describes alternative optimal actions at states s t and s. by Bensoussan [2], Beyer et al. [4], Porteus [22], Simchi-Levi et al. [26], and Zipkin [30], see also Katehakis et al. [20] and Shi et al. [25] for recent results for continuous review models.Recently developed general optimality conditions for discrete-time Markov Decision Processes (MDPs) applicable to inventory control problem are discussed in the tutorial by Feinberg [9]. Here, we mention just a few directly relevant references. Scarf [23] introduced the concept of K-convexity to prove the optimality of (s, S) policies for finite-horizon problems with continuous demand. Zabel [28] indicated some gaps in Scarf [23] and corrected them. Iglehart [19] extended the results in Scarf [23] to infinite-horizon problems with continuous demand. Veinott and Wagner [27] proved the optimality of (s, S) policies for both finite-horizon and infinite-horizon problems with discrete demand. Zheng [29] provided an alternative proof for discrete demand. Beyer and Sethi [5] completed the missing proofs in Iglehart [19] and Veinott and Wagner [27]. In general, (s, S) policies may not be optimal. To ensure the optimality of (s, S) policies, the additional assumption on backordering cost function (see Condition 3.3 below) is used in many papers including Iglehart [19] and Veinott and Wagner [27]. Relevant assumptions are used in Schäl [24], Heyman and Sobel [15], Bertsekas [3], Chen and Simchi-Levi [6, 7], Huh and Janakiraman [17], and Huh et al. [18]. As shown by Veinott and Wagner [27] for problems with discrete demand and Feinberg and Lewis [14] for an arbitrary distributed demand, such assumptions are not needed for an infinite-horizon problem, when the discount factor is close to 1.For problems with linear holding costs, according to Theorem 8.3.4, p. 126], finite-horizon undiscounted value functions are continuou...