Assessment of timed bacteriostatic and bactericidal activities of cephalothin against gram-positive and gram-negative bacteria

The comparative bacteriostatic and bactericidal activities of cephalothin were assessed in broth medium with special reference to the period of exposure of microbes to the drug. The bacteriostatic concentration with a brief period of exposure (6 h) was lower than the conventional MIC for Escherichia coli and Klebsiella sp. When the period of exposure was prolonged (18-42 h), the bacteriostatic concentration almost corresponded with the MIC. In contrast to these gram-negatives, the bacteriostatic concentration with a brief period of exposure roughly corresponded with the MIC for strains of Staphylococcus aureus and was higher for enterococcus. When a comparison of the bacteriostatic and the bactericidal concentrations was used as the criterion for assessment, the mode of action of cephalothin appeared to be bactericidal to most of the gram-negatives. This drug was bacteriostatic to a number of strains of gram-positives, in particular to enterococcus, especially when microbes were exposed to the drug over a brief period of time.     

Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor

Human CYP2C9 is important in the metabolism of numerous clinically used drugs such as the anticoagulant warfarin, the anticonvulsant phenytoin, antidiabetic drugs such as tolbutamide and glipizide, the hypertensive agent losartan, and numerous nonsteroidal anti-inflammatory drugs. Several studies have reported that certain drugs such as rifampicin and phenobarbital induce CYP2C9, but the molecular basis for this induction remains unknown. In the present study, we demonstrate that the human pregnane X receptor (hPXR) mediates induction of CYP2C9 by the prototype drugs rifampicin, hyperforin (found in St. John's Wart), and phenobarbital. Deletion and mutagenesis studies with luciferase reporter constructs showed that a functional PXR-responsive element located -1839/-1824 base pairs upstream from the translation start site was the primary binding site mediating the rifampicin induction of CYP2C9. This site was previously described as a constitutive androstane receptor-responsive element (CAR-RE). Mutational analysis of 3- and 12-kilobase CYP2C9 promoter fragments indicated that this proximal binding site was essential for rifampicin inducibility, although a cooperative effect could be attributed to a second CAR-RE located at -2899/-2883. In summary, we have demonstrated rifampicin induction of CYP2C9 promoter constructs that is consistent with the magnitude of induction of CYP2C9 protein and mRNA reported in vivo and in primary human hepatocytes, and we have identified the cis-element essential for this response. This is the first report to demonstrate that the nuclear receptor PXR mediates induction of CYP2C9 with rifampicin, phenobarbital, and hyperforin.     

Sepsis and gas-forming splenic abscess by Clostridium septicum in a patient with type 2 diabetes

Clostridium infections are rare but frequently associated with malignancy, and mortality approaches 100% if care is not rendered within 12 to 24 h. These infections are associated with various medical problems including diabetes mellitus. In this report, we describe a unique case of sepsis and a gas-forming splenic abscess caused by Clostridium septicum in a type 2 diabetes patient which was treatable solely with antibiotics.     

Delivery of an Angiogenic Gene into Ischemic Muscle by Novel Bubble Liposomes Followed by Ultrasound Exposure

Purpose  

To develop a safe and efficient gene delivery system into skeletal muscle using the combination of Bubble liposomes (BL) and ultrasound (US) exposure, and to assess the feasibility and the effectiveness of BL for angiogenic gene delivery in clinical use.     

Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver

The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma.