Women's Recognition of the Spontaneous Onset of Labor

Abstract: Background: Despite extensive research on the onset of labor, almost no data are available on women's perception of labor onset. We undertook a study to assess how women experience spontaneous onset of term labor. Methods: A semistructured questionnaire was given to 235 women admitted in spontaneous labor at term. Women noted when labor had started, whether and when membranes had ruptured, and answered an open question about how labor had announced itself. Two investigators independently subdivided women's experiences on how labor had started into 369 sampling units corresponding to 8 predefined categories. Results: Nearly two‐thirds of the sampling units (63.4%) related to recurrent and nonrecurrent pain, and the ratio between the two types was higher for multiparas than for nulliparas. The number of women and sampling units were identical for each of the following categories: watery fluid (n = 47), blood‐stained loss (n = 33), gastrointestinal symptoms (n = 10) and altered sleep patterns (n = 11); 22 sampling units relating to emotional upheaval were mentioned by 16 women. Although 33.6 percent of women experienced rupture of membranes before admission, only 21.6 percent associated it with their onset of labor, either alone (11.5%) or in association with other categories (10.1%). Conclusions: Although women experience onset of labor in a variety of ways, for most it is a concrete event. Studies on duration of labor should take women's perception of onset of labor as a starting point rather than rely on surrogate measures. (BIRTH 30:4 December 2003)     

GYKI-46 903, a Non-Competitive Antagonist for 5-HT3 Receptors

Abstract: The effects of GYKI-46 903 ((+)endo-4-propionyloxy-6-(4-fluorophenyl)-1-azabicyclo [3.3.1]non-6-ene HCI), on 5-HT₃ receptors have been studied and compared with ondansetron in peripheral organs in vitro and in vivo, and in a receptor binding assay in membranes prepared from rat cerebral cortex. GYKI-46 903 was found to be a non-competitive antagonist at 5-HT₃ receptors present in non-stimulated longitudinal muscle strip of guinea-pig ileum (pD₂’against serotonin=5.54), and also in 5-methoxytryptamine-pretreated electrically stimulated ileal preparations (pD₂’against serotonin=5.26). On the contrary, ondansetron was found to be a competitive antagonist for 5-HT₃ receptors; the pA₂ value against serotonin was 7.40 in non-stimulated ileum, and it was 7.08 in electrically stimulated ileal preparation pretreated with 5-methoxytryptamine. In displacement studies, the pIC₅₀ values of GYKI-46 903 and ondansetron against [³H]granisetron binding to rat cerebral cortex membranes were 6.91 and 8.58 respectively. GYKI-46 903, when administered by intravenous infusion, antagonized the decrease in heart rate evoked by serotonin (Bezold-Jarisch reflex) in anaesthetized rats, and the maximal reversal was less than 50%. This was in striking contrast with ondansetron, which, after intravenous injection, completely antagonized the serotonin-induced bradycardia with an ID₅₀ value of 3.28 ug/kg. These data classify GYKI-46 903 as a non-competitive antagonist for 5-HT₃ receptors.     

Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner

Hyperalgesia is a cardinal symptom of opioid withdrawal. The transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated ion channel expressed on sensory neurons responding to noxious heat, protons, and chemical stimuli such as capsaicin. TRPV1 can be inhibited via μ-opioid receptor (MOR)-mediated reduced activity of adenylyl cyclases (ACs) and decreased cyclic adenosine monophosphate (cAMP) levels. In contrast, opioid withdrawal following chronic activation of MOR uncovers AC superactivation and subsequent increases in cAMP and protein kinase A (PKA) activity. Here we investigated (1) whether an increase in cAMP during opioid withdrawal increases the activity of TRPV1 and (2) how opioid withdrawal modulates capsaicin-induced nocifensive behavior in rats. We applied whole-cell patch clamp, microfluorimetry, cAMP assays, radioligand binding, site-directed mutagenesis, and behavioral experiments. Opioid withdrawal significantly increased cAMP levels and capsaicin-induced TRPV1 activity in both transfected human embryonic kidney 293 cells and dissociated dorsal root ganglion (DRG) neurons. Inhibition of AC and PKA, as well as mutations of the PKA phosphorylation sites threonine 144 and serine 774, prevented the enhanced TRPV1 activity. Finally, capsaicin-induced nocifensive behavior was increased during opioid withdrawal in vivo. In summary, our results demonstrate an increased activity of TRPV1 in DRG neurons as a new mechanism contributing to opioid withdrawal-induced hyperalgesia.     

Hypercalcemia from metastatic pancreatic neuroendocrine tumor secreting 1,25-dihydroxyvitamin D

Malignant hypercalcemia occurs in about 20-30% of patients with cancer, both solid tumors and hematologic malignancies. The secretion of parathyroid hormone-related protein (PTH-rP) is the most common cause and has been shown to be the etiology of hypercalcemia associated with neuroendocrine tumors. Here we report the case of a patient with metastatic pancreatic neuroendocrine tumor who developed hypercalcemia more than 4 years after the initial diagnosis as a result of secretion of 1,25-dihydroxyvitamin D, a mechanism only commonly seen in lymphomas. The successful control of the patient’s disease with capecitabine and temozolomide led to the alleviation of this paraneoplastic syndrome.     

Isotretinoin for the treatment of squamous cell carcinoma arising on an epidermoid cyst

A 63‐year‐old man showed multiple concentric erythemato‐nodular lesions of approximately 1.5–3 cm in diameter, located in the parietal and temporal region. The skin biopsy allowed histological diagnosis of infundibular epidermal cyst associated with chronic granulomatous flogosis; in one of these, a well‐differentiated squamous cell carcinoma arising from the cyst wall was found. The patient received isotretinoin at the daily dosage of 0.5 mg/kg/day for 5 months. During 1‐year follow‐up, laboratory tests, computed tomography scans, and control histology were all in the normal range, with a good improvement of the lesions. Epidermal cysts and squamous cell carcinoma are both commonly encountered in practice. However, the association of epidermal inclusion cysts and squamous cell carcinoma in the skin is very rare. In some cases, including the present one, more potent chemopreventive strategies, such as the use of systemic retinoids, must be considered. Systemic retinoids are the most heavily researched chemopreventive agents and have shown promise for multiple types of cancer, including bladder and head and neck carcinomas. We would like to recommend the possibility to administer retinoids in a squamous cell carcinoma, achieving very satisfactory results; in our case, a complete remission of malignant lesion and an improvement of epidermal cysts were made, without the development of side effects associated with retinoids.     

Obesity induced a leptin‐Notch signaling axis in breast cancer

To investigate whether obesity induces a leptin‐Notch signaling axis in breast cancer (BC), leptin‐induced Notch was determined in human MCF‐7 and MDA‐MB231 and mouse E0771 cells and in E0771‐BC hosted by syngeneic lean and diet‐induced obesity (DIO) C57BL/6J female mice. Lean and DIO mice were treated for 3 weeks with leptin inhibitor (PEG‐LPrA2) 1 week after the inoculation of E0771 cells. Leptin induced Notch1, 3 and 4 in BC cells, but Notch2 expression showed opposite pattern in MCF‐7 compared to MDA‐MB231 cells. Notch loss‐of‐function (DAPT and dominant negative [R218H] RBP‐Jk [CSL/CBF1]) showed that a functional leptin‐Notch signaling axis was involved in the proliferation and migration of E0771 cells. E0771‐BC onset was affected by obesity (lean mice7/10 [70%] vs. DIO mice: 11/12 [92%]; Pearson χ²: p = 0.06]). PEG‐LPrA2 significantly reduced BC growth (untreated: 19/42; [45%] vs. treated: 8/42 [19%]; Pearson χ²: p = 0.008). PEG‐LPrA2 did not influence the caloric intake of mice but increased carcass and/or body weights of lean and DIO mice inoculated with E0771 cells, which could be related to the improvement of health conditions (less aggressive disease). Importantly, BC from obese mice had higher levels of Notch3, JAG1 and survivin than lean mice. Inhibition of leptin signaling reduced protein levels of Notch (NICD1, NICD4, Notch3, JAG1 and survivin) and significantly decreased mRNA expression of Notch receptors, ligands and targets. PEG‐LPrA's effects were more prominent in DIO mice. Present data suggest that leptin induces Notch, which could be involved in the reported higher incidence and aggressiveness and, poor prognosis of BC in obese patients.     

Ritanserin, a serotonin-2 receptor antagonist, improves ultradian sleep rhythmicity in young poor sleepers.

OBJECTIVES: To determine the effect on sleep electroencephalographic (EEG) activity of ritanserin, a serotonin-2 (5-HT2) receptor antagonist in young poor sleepers. METHODS: Eight male subjects underwent two randomized night studies after receiving either a placebo or 5 mg ritanserin administered in the morning. The overnight variations in the delta (0.5-4.0 Hz) and sigma (12.25-15.0 Hz) frequency bands were characterized using a peak analysis which provided a quantitative evaluation of the time-courses in EEG activity. RESULTS: In subjects under ritanserin, slow wave sleep duration and the number of non-rapid eye movement (NREM)-REM sleep cycles were significantly enhanced (P<0.01). The number of peaks in delta activity occurring in the normal 80-120 min range was significantly (P<0.05) increased. Using a delta peak analysis, 4 periods containing or not a significant peak were identified in each subject. A significant increase in delta activity was observed in the areas under the averaged curves during the second and the third periods (P<0.05), while sigma activity decreased under ritanserin during the first, second and third periods (P<0.05). CONCLUSIONS: These results demonstrate that ritanserin increases delta activity, possibly by opposing the inhibitory control of 5-HT2 receptor family. It restores sleep ultradian rhythmicity and improves sleep quality in young poor sleepers.