Antiprogesterone, RU 486, facilitates parturition in cattle.

RU 486, a potent progesterone antagonist with high affinity for progesterone receptor, was used alone or in combination with relaxin in late pregnant cattle to determine its effect on induction of parturition. Cross-bred beef cattle were bred by artificial insemination. An indwelling cannula was inserted into a jugular vein on day 269 (expected term = day 283) for repeated blood sample collection. On day 277, the cattle were assigned randomly to three groups (n = 6 each): group 1 received RU 486 (2 mg/kg BW, im) at 0800 h on days 277 and 278; group 2 received the same RU 486 treatment plus 3000 U relaxin, injected sc at 0800 h on day 278; and group 3 served as controls and received vehicle injection. Parturition occurred 55 h after treatment in group 1 and 53 h after treatment in group 2 compared with 210 h in the controls (P less than 0.01). The calves from treated groups were vigorous at birth, and their birth weights (32 and 33 kg in groups 1 and 2) were less than those of control calves (38 kg; P less than 0.01). There was no incidence of difficult birth (dystocia) with RU 486 treatment compared with that in the controls. Placenta delivery averaged 6.5 h after birth in both RU 486-treated groups and did not differ from the control value (5 h). Plasma progesterone concentrations averaged 8.2 ng/ml during the pretreatment period for all animals. Progesterone started to decrease markedly by 1200 h on day 278, dropped to about 4 ng/ml by 2400 h that same day, and was at basal levels on day 279, the day of calving, in two hormone-treated groups. In sharp contrast, progesterone was maintained at about 6 ng/ml in placebo-treated controls during this period and did not decrease to basal levels until 2 days before parturition on day 286 (P less than 0.01). Peak RU 486 in plasma was 7.2 ng/ml after the first injection and 14.3 ng/ml after the second injection, and averaged 7.9 ng/ml on the day of induced calving (day 279). Peak relaxin was 4.1 ng/ml after hormone injection. The results indicate that RU 486 alone or combined with relaxin precisely controlled the time of parturition in cattle in late pregnancy. Such treatment can be used to facilitate parturition and increase survival rates of neonatal calves without detrimental effects of dystocia, retention of placenta, and delayed postpartum fertility.     

Facile solid‐phase synthesis of C‐terminal peptide aldehydes and hydroxamates from a common Backbone Amide‐Linked (BAL) intermediate*†

Abstract: C‐Terminal peptide aldehydes and hydroxamates comprise two separate classes of effective inhibitors of a number of serine, aspartate, cysteine, and metalloproteases. Presented here is a method for preparation of both classes of peptide derivatives from the same resin‐bound Weinreb amide precursor. Thus, 5‐[(2 or 4)‐formyl‐3,5‐dimethoxyphenoxy]butyramido‐polyethylene glycol‐polystyrene (BAL‐PEG‐PS) was treated with methoxylamine hydrochloride in the presence of sodium cyanoborohydride to provide a resin‐bound methoxylamine, which was efficiently acylated by different Fmoc‐amino acids upon bromo‐tris‐pyrrolidone‐phosphonium hexafluorophosphate (PyBrOP) activation. Solid‐phase chain elongation gave backbone amide‐linked (BAL) peptide Weinreb amides, which were cleaved either by trifluoroacetic acid (TFA) in the presence of scavengers to provide the corresponding peptide hydroxamates, or by lithium aluminum hydride in tetrahydrofuran (THF) to provide the corresponding C‐terminal peptide aldehydes. With several model sequences, peptide hydroxamates were obtained in crude yields of 68–83% and initial purities of at least 85%, whereas peptide aldehydes were obtained in crude yields of 16–53% and initial purities in the range of 30–40%. Under the LiAlH₄ cleavage conditions used, those model peptides containing t‐Bu‐protected aspartate residues underwent partial side chain reduction to the corresponding homoserine‐containing peptides. Similar results were obtained when working with high‐load aminomethyl‐polystyrene, suggesting that this chemistry will be generally applicable to a range of supporting materials.     

Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition

Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high‐risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta‐analysis (3940 melanoma cases and 3620 controls) with two‐side p values of 0.002, (OR = 0.86) and 4.07 × 10^?10 (OR = 0.80), respectively. Exome sequencing revealed a non‐synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma.     

Distraction osteogenesis using a longitudinal corticotomy

Purpose  

The purpose of this study was to evaluate whether the use of a longitudinal corticotomy (S-Z osteotomy) results in more rapid consolidation following distraction osteogenesis of short tibiae.     

Intraoperative local anaesthesia for paediatric postoperative oral surgery pain--a randomized controlled trial

The aim of this study was to improve the pain experience for children following oral surgery under general anaesthesia. To this end, the efficacy and safety of intraoperative local anaesthetic (2% lidocaine with 1:200,000 epinephrine) for postoperative pain control was investigated. In a randomized controlled trial, 142 patients aged 12 years or less, who were scheduled for dental extractions under general anaesthesia, received local anaesthesia or saline intraoral injection after induction of anaesthesia. There was statistically no significant difference between groups for pain scores recorded preoperatively, on waking, at 30 min, at 24h, or for distress scores recorded preoperatively, on waking and at 30 min. 'Severe' pain scores were recorded for 13% of treatment and 12% of control patients and 'very severe' for 13% of treatment and 10% of control patients on waking. These rates were similar at 30 min but reduced at 24h. Lip/cheek biting injuries occurred in one control and three treatment patients. Intraoperative local anaesthesia has been found to be effective for pain control following a range of other surgical procedures, but we did not find it to be effective in reducing postoperative pain or distress in children after oral surgery. Reasons may include unfamiliarity with altered orofacial sensation.     

A double-blind randomized controlled trial investigating the effectiveness of topical bupivacaine in reducing distress in children following extractions under general anaesthesia

OBJECTIVE: This study was designed to investigate the effectiveness of topical bupivacaine (0.25%) in reducing postoperative distress following extraction of teeth under general anaesthesia in children. DESIGN: The study was a double-blind randomized controlled trial. SETTING: The study was conducted in a dental hospital. SAMPLE: The sample comprised 135 children aged between 2 and 12 years of age who were undergoing outpatient general anaesthesia for simple dental extractions. METHODS: The children were randomly allocated to one of two groups: the bupivacaine group (the study group) comprised 68 children whilst the sterile water group (the control group) comprised 67. Following the extraction of their teeth, children had swabs soaked in the appropriate solution placed over the exposed teeth sockets. A five-point face scale was employed by an independent observer to evaluate the distress for each child. Evaluation of distress was made preoperatively, on recovery from the general anaesthetic, and again, 15 min following recovery from the anaesthetic. RESULTS: There were no statistically significant differences between the mean distress scores for the bupivacaine and sterile water groups preoperatively, postoperatively or 15 min postoperatively. For both groups, however, there were significant increases in distress scores between the preoperative and 15 min postoperative assessment scores. CONCLUSION: Extraction of teeth under general anaesthesia does cause distress in children. There is no evidence that topical bupivacaine reduces this distress when compared to sterile water.