Progressive and regressive changes in the nucleus pulposus. Part I. The neonate

Magnetic resonance (MR) imaging, correlated with anatomic sections, was used to characterize the progressive and regressive changes in the nucleus pulposus in neonates. The spines of five fetuses and five full-term infants between 16 and 40 weeks old were studied. In anatomic sections, the nucleus pulposus was sharply demarcated from the anulus fibrosus, Sharpey fibers were conspicuous, and a plate of primitive notochord was evident in the equator of the disk. On long repetition time (TR)/long echo time (TE) or long TR/short TE MR images, Sharpey fibers (low signal intensity) and notochord (low signal intensity) could be differentiated from the high-signal-intensity nucleus pulposus and anulus fibrosus. The major differences between the fetal and infant spines were the amount of notochord in the disk and ossification in the vertebral body.     

Variables that predict the success of labor induction

BACKGROUND. To analyze the clinical and sonographic variables that affect the success of labor induction. METHODS. Bishop score, cervical length, and parity were studied in 196 pregnant women in the prediction of successful vaginal delivery within 24 hr of induction. Logistic regression and segmentation analysis were performed. RESULTS. Cervical length [odds ratio (OR) 1.089, P<0.001], Bishop score (OR 0.751, P=0.001), and parity (OR 6.85, P<0.001) predict the success of labor induction. The best cut-off points for cervical length were <16.5, 16.5--27, and >27 mm (P=0.0016). In the analysis of the Bishop score, we also obtained three discriminatory points, 0, 1--4, and >4 (P=0.0006), that best predict the labor induction. Finally, in a global analysis of the variables studied, the best statistic sequence that predicts the labor induction was found when we introduced parity in the first place. The success of labor induction in nulliparous was 50.77 and 83.33% in multiparous (P=0.0001). CONCLUSIONS. Cervical length, Bishop score, and parity predict the success of labor induction.     

Gene therapy for diabetic peripheral neuropathy: A randomized,placebo‐controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor

AbstractVM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3‐1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3‐1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3‐1 was change from baseline in the mean 24‐h Numerical Rating Scale (NRS) pain score. In DPN 3‐1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well‐tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3‐1. In DPN 3‐1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3‐1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3‐1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long‐lasting pain‐relieving effects of VM202 observed in DPN 3‐1b warrant another rigorous phase III study. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Nonviral gene therapy can be used safely and practically to treat DPN.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.     

Can EPS Development Be Avoided with Early Interventions? The Potential Role of Tamoxifen—A Single-Center Study

♦ Background: Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Identification of patients at high risk for EPS (“EPS-prone”) and delivery of appropriate interventions might prevent its development. Our aim was to evaluate the clinical characteristics and outcomes of all EPS and EPS-prone patients diagnosed at our PD unit.♦ Methods: For a 30-year period representing our entire PD experience, we retrospectively identified all patients with EPS (diagnosed according to International Society for Peritoneal Dialysis criteria) and all patients defined as EPS-prone because they met at least 2 established criteria (severe peritonitis, PD vintage greater than 3 years, severe hemoperitoneum, overexposure to glucose, and acquired ultrafiltration failure).♦ Results: Of 679 PD patients, we identified 20 with EPS, for an overall prevalence of 2.9%. Mean age at diagnosis was 50.2 ± 16.4 years, with a median PD time of 77.96 months (range: 44.36 - 102.7 months) and a median follow-up of 30.91 months (range: 4.6 - 68.75 months). Of patients with EPS, 10 (50%) received tamoxifen, 10 (50%) received parenteral nutrition, and 2 (10%) underwent adhesiolysis, with 25% mortality related to EPS. Another 14 patients were identified as EPS-prone. Median follow-up was 54.05 months (range: 11.9 - 87.04 months). All received tamoxifen, and 5 (36%) received corticosteroids; none progressed to full EPS. We observed no differences in baseline data between the groups, but the group with EPS had been on PD longer (84 ± 53 months vs 39 ± 20 months, p = 0.002) and had a higher cumulative number of days of peritoneal inflammation from peritonitis (17.2 ± 11.1 days vs 9.8 ± 7.9 days, p = 0.015). Overall mortality was similar in the groups. The incidence of EPS declined during our three decades of experience (5.6%, 3.9%, and 0.3%).♦ Conclusions: Being a serious, life-threatening complication of PD, EPS requires high suspicion to allow for prompt diagnosis and treatment. Early detection of EPS-prone states and delivery of appropriate intervention might prevent EPS development. Tamoxifen seems to be a key strategy in prevention, but caution should be used in interpreting our results. Additional randomized controlled studies are needed.     

Desmoplastic fibroma of the proximal ulna

A young man presented with desmoplastic fibroma in the proximal ulna. This rare tumour was treated by curettage and bone grafting.     

Resistance of Copenhagen rats to chemical induction of glutathione S- transferase 7-7-positive liver foci

Copenhagen (Cop) rats are completely resistant to the chemical induction of mammary adenocarcinomas, but their susceptibility to hepatocarcinogenesis is virtually unknown. Rat liver is a well- characterized and easily manipulated tissue in which to study carcinogenesis. Therefore, if Cop rats are resistant to hepatocarcinogenesis, studies into resistance mechanisms may be feasible. Male Cop and F344 rats, 7-8 weeks old, were initiated using either N-nitrosodiethylamine (DEN) (200 mg/kg, i.p.) or a two-thirds partial hepatectomy (PH) followed by N-methyl-N-nitrosourea (MNU) (60 mg/kg, i.p.). The rats were then promoted using a modified resistant hepatocyte (RH) protocol (a combination of four doses of 2- acetylaminofluorene (2-AAF) and a single dose of CCl4 that provides a selective mitotic stimulus for initiated cells). Six weeks after initiation the rats were killed and liver sections were stained for glutathione S-transferase 7-7 (GST 7-7), a marker for putative preneoplastic hepatocytes. Cop rats were found to be highly resistant, having a approximately 9- and approximately 27-fold smaller percentage of liver area occupied by GST 7-7-positive foci than susceptible F344 rats following initiation by DEN and MNU respectively. Furthermore, gross liver nodules did not form in any of the Cop rats, whereas all F344 rat livers contained nodules. Hepatic necrosis caused by DEN during initiation, and CCl4 during promotion is necessary to stimulate compensatory hepatocyte division. We demonstrated that these agents do indeed increase serum transaminase levels and produce histologic evidence of necrosis in Cop rats. In order for liver foci to grow rapidly in the RH protocol, the surrounding normal hepatocytes must be mito-inhibited by 2-AAF. We found that the degree of mito-inhibition of normal hepatocytes by 2-AAF is the same in Cop and F344 rats. These results show that the Cop rat is highly resistant to the chemical induction of putative preneoplastic liver foci and nodules.