Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.

Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.

Generalized peritonitis is a common surgical emergency in India, the 'Tropical Spectrum' of generalized peritonitis being different from the western spectrum. A total 155 cases of generalized peritonitis were surgically treated at the All India Institute of Medical Sciences between 1981 and 1987, all patients undergoing peritoneal toilet with drainage after the cause of their peritonitis had been treated. The most common cause of peritonitis was peptic ulcer perforation, with simple closure being associated with a 2 per cent mortality, while typhoid perforation was the second most common cause. The diagnosis was clinical, supported by the operative findings of a terminal ileal perforation while bacteriological, serological and histopathological confirmation was retrospective. Appendicular perforations were less common than in the west but the clinical picture was the same. Tubercular perforations were not uncommon with a previous history of subacute intestinal obstruction and evidence of tuberculosis on chest X-ray suggesting the diagnosis. Ruptured amebic liver abscess was the most common hepatobiliary cause of generalized peritonitis with drainage of the abscess producing good results. The average hospital stay was 15 days with an overall mortality of 8 per cent.

Pantothenate kinase catalyzes the key regulatory step in CoA biosynthesis in bacteria and mammals (1-3). In mammals, there are four distinct kinases that exhibit tissue-specific expression as follows: PANK1␣ and PANK1␤ are splice variants of the PANK1 gene, and PANK2 and PANK3 are encoded by the PANK2 and PANK3 genes, respectively (4, 5). The kinase isoforms possess almost identical catalytic cores but differ in their amino termini that direct the enzymes to different subcellular compartments (6). Isoform 1␣ is targeted to the nucleus, whereas isoform 1␤ is associated with endosomes in humans and mice. Isoform 2 of mice is cytosolic, but the PANK2 gene in humans encodes a protein with both nuclear localization and mitochondrial targeting sequences. Isoform 3 is cytosolic in both species. All pantothenate kinases operate by a compulsory ordered mechanism with ATP⅐Mg 2ϩ as the leading substrate followed by pantothenate ( Fig. 1) (7). The principal mechanism for controlling mammalian pantothenate kinase activity is through feedback inhibition by acetyl-CoA, and the isoforms differ in their sensitivity to this regulator ( Fig. 1) (4, 8, 9). The 1␣ and 1␤ isoforms are least sensitive to inhibition, whereas isoforms 2 and 3 are more potently inhibited by acetyl-CoA. Acetyl-CoA inhibition is competitive with ATP⅐Mg 2ϩ , but acetyl-CoA binds far more tightly than ATP (10). Acyl-carnitines antagonize the inhibition of pantothenate kinases by acetyl-CoA (8).The importance of pantothenate kinase to mammalian physiology is highlighted by the phenotypes of knock-out mice and their connection to human disease. Isoform 1 is most highly expressed in the liver, and Pank1 Ϫ/Ϫ mice have lower total hepatic CoA and exhibit fatty acid ␤-oxidation and glucose homeostasis defects in the fasted state (11). In addition, Pank1 Ϫ/Ϫ Lep Ϫ/Ϫ mice have dramatically lower blood glucose and insulin levels compared with their diabetic Lep Ϫ/Ϫ counterparts, which highlights the connection between isoform 1 and glucose homeostasis (12). Consistent with this, an association between polymorphisms in the PANK1 gene and insulin levels was uncovered in a cohort of individuals in Finland (13). It has also been shown that the severe neurodegenerative disease pantothenate kinase-associated neurodegeneration arises from mutations in the human PANK2 gene (14). Unfortunately, Pank2 Ϫ/Ϫ mice do not recapitulate the pantothenate kinaseassociated neurodegeneration disease phenotype (15,16), and this may be due either to differences in the levels of isoform expression in mouse and human brains or to the fact that human PANK2 accumulates in the intra-membrane space in mitochondria, whereas mouse isoform 2 is cytosolic (9). Finally, Pank1 Ϫ/Ϫ Pank2 Ϫ/Ϫ double knock-out mice are unable to metabolize fats and ketones resulting in early postnatal death (16), and Pank1 Ϫ/Ϫ Pank3 Ϫ/Ϫ and Pank2 Ϫ/Ϫ Pank3 Ϫ/Ϫ double knock-out mice are both embryonic lethal. A chemical knockout of all pantothenate kinases in adult mice resulted in an 80% reduction in hepatic CoA levels a...

Chronic wound management is a difficult area in surgical practice. A wide range of dressings have been recommended for the management of chronic wounds. The present meta-analysis was undertaken to determine the effectiveness of hydrocolloid dressing (HCD) in the healing of chronic wounds compared with conventional gauze dressing. All available controlled clinical trials published before December 2001 that compared HCD to conventional gauze dressing in the healing of chronic wounds were systematically reviewed. We identified and analysed 12 randomized trials (11 published; 1 unpublished) comprising 693 patients with 819 ulcers. The overall odds ratio under the fixed effect model was 1.72, that is, 72% more ulcers healed completely with HCD than with conventional gauze dressing. This result was both clinically and statistically significant.