Maternal Progesterone Treatment Reduces Maternal Inflammation-Induced Fetal Brain Injury in a Mouse Model of Preterm Birth.

Maternal natural vaginal progesterone (nVP) administration has been shown to reduce the risk of preterm birth (PTB). The largest randomized trial of nVP for PTB (OPPTIMUM) noted a sonographic reduction in neonatal brain injury following nVP treatment. We investigated the neuroinflammatory protective effect of maternal nVP in a mouse model for maternal inflammation. Pregnant mice (n = 24) were randomized to nVP (1 mg/day) or vehicle from days 13-16 of gestation. At days 15 and 16, lipopolysaccharide (30 µg) or saline were administered. Mice were sacrificed 4 h following the last injection. Fetal brains and placentas were collected. Levels of NF-κB, nNOS, IL-6, and TNFα were determined by Western blot. Maternal lipopolysaccharide significantly increased fetal brain levels of IL-6 (0.33 ± 0.02 vs. 0.11 ± 0.01 u), TNFα (0.3 ± 0.02 vs. 0.10 ± 0.01 u), NF-κB (0.32 ± 0.01 vs. 0.17 ± 0.01 u), and nNOS (0.24 ± 0.04 vs. 0.08 ± 0.01 u), and reduced the total glutathione levels (0.014 ± 0.001 vs. 0.026 ± 0.001 pmol/µl; p < 0.01) compared with control. Maternal nVP significantly reduced fetal brain levels of IL-6 (0.14 ± 0.01 vs. 0.33 ± 0.02 u), TNFα (0.2 ± 0.06 vs. 0.3 ± 0.02 u), NF-κB (0.16 ± 0.01 vs 0.32 ± 0.01 u), and nNOS (0.14 ± 0.01 vs 0.24 ± 0.04 u), and prevented the reduction of fetal brain total glutathione levels (0.022 ± 0.001 vs. 0.014 ± 0.001 pmol/µl; p < 0.01) to levels similar to controls. A similar pattern was demonstrated in the placenta. Maternal nVP for PTB may protect the fetal brain from inflammation-induced brain injury by inhibiting specific inflammatory and oxidative pathways in both brain and placenta.

Comparison between Lornoxicam and Paracetamol for Pain Management after Dilation and Curettage for Abortion.

BACKGROUND: Management of postoperative pain has become a growing concern, even for minor gynecological procedures. Proper postoperative pain management has been shown to lead to earlier mobilization, shortened hospital stay, and increased patient satisfaction. The optimal means of reducing the pain of pregnancy termination has not yet been determined. OBJECTIVES: To compare the efficiency in pain management of two drugs, lornoxicam and paracetamol, given intravenously postoperatively to women who underwent abortion with dilation and curettage. METHODS: The cohort comprised 80 women scheduled for dilation and curettage for pregnancy termination at 6-12 gestational weeks. The anesthesiologist gave 1000 mg paracetamol or 20 mg lornoxicam soon after starting the procedure, according to a randomization table. The medical staff and the patients were blinded to the drug that was administered. Pain levels were evaluated by a 10 cm visual analogue scale (VAS) at 15, 30, 60, 90, and 120 minutes following arrival at the postoperative care unit. RESULTS: Mean levels of pain decreased from 60 minutes postoperative until the end of recording, reaching minimum levels at 120 minutes: 0.8 ± 0.19 and 1.5 ± 0.28, for lornoxicam and paracetamol, respectively. The differences between the groups were statistically significant (P < 0.05 from 60 minutes after the procedure until the time of discharge. CONCLUSIONS: Compared to women who received paracetamol, women who received lornoxicam after dilation and curettage for termination of pregnancy reported lower levels of pain, from 30 minutes postoperative until the time of discharge following the procedure.

Methylphenidate attenuates the response to cold pain but not to aversive auditory stimuli in healthy human: a double-blind randomized controlled study.

INTRODUCTION: We recently showed that the psycho-stimulant norepinephrine-dopamine reuptake inhibitor methylphenidate (MP) prolonged cold pain threshold and tolerance in adults with attention-deficit hyperactivity disorder (ADHD). OBJECTIVES: The objectives of the present study were to: (1) examine whether MP has antinociceptive properties in healthy men; (2) test MP's effects on responses to aversive auditory stimuli. The underlying aim was to determine whether MP exerts antinociceptive properties or more generalized, nonspecific attenuating effects on different aversive sensory modalities. METHODS: This double-blind, crossover, randomized placebo-controlled study consisted of 2 sessions one week apart from each other. In each session, pain threshold (seconds) and tolerance (seconds) in response to painful cold stimulation were measured. Additionally, threshold (dB) and tolerance (seconds) to loud aversive auditory stimuli (500 Hz, 2000 Hz and white noise) were also tested prior to and 2 hours following the administration of a single dose of either 20 mg MP or an identical looking placebo. RESULTS: Forty men, 26.1 ± 4.0 (mean ± SD) years were enrolled in the study. Wilcoxon signed-rank test analyses showed that MP, but not the placebo, produced a significant increase in cold pain threshold (from 4.1 ± 2.6 to 5.4 ± 3.1 seconds, P = 0.001 and from 4.5 ± 2.6 to 4.3 ± 2.7 seconds, P = 0.2, respectively) and tolerance (from 57.8 ± 54.0 to 73.8 ± 61.8 seconds, P = 0.001 and from 52.5 ± 53.7 sec to 57.0 ± 52.9 seconds, P = 0.1, respectively). No significant changes were found in any of the auditory parameters. CONCLUSION: These results suggest that MP has an effect on nociceptive pathways rather than a nonspecific, generalized attenuating effect on aversive sensory stimuli.

Clinical analgesia correlates with decline in temporal summation in response to remifentanil infusion in patients with chronic neuropathic (radicular) pain.

BACKGROUND: Animal studies have shown that in addition to their antinociceptive effects, opioids have attenuated the electrophysiological "wind-up" phenomenon. Although effects of opioids on clinical pain and on temporal summation (TS), the human correlatives of this phenomenon, have been tested repeatedly, correlations between these two parameters have not been reported so far. OBJECTIVES: To search for possible correlations between the effects of remifentanil on clinical pain intensity and on the magnitude of TS in patients with chronic pain. DESIGN: A single-blinded prospective study. SETTING: A tertiary care pain clinic. PATIENTS: Thirty-one patients (24 men) with chronic lumbar (radicular) neuropathic pain. INTERVENTION: Intervenous administration of saline followed by remifentanil infusions. MAIN OUTCOME MEASURES: Clinical pain intensity and thermal TS measured at baseline, during infusion of each drug and 20 minutes after termination of remifentnail infusion. RESULTS: Friedman test revealed statistically significant differences in the magnitudes of both clinical pain intensity and TS (x(2(3)) = 73, p < 0.001 and x(2(3)) = 11.38, p = 0.01, respectively). Post hoc analysis (Wilcoxon signed-rank test) showed significant differences between clinical pain intensities measured at all time points but significant reductions in the magnitudes of TS were found only during remifentanil compared to baseline (p = 0.014) and to saline (p = 0.019). The difference in clinical pain between saline and remifentanil positively correlated with the difference in TS measured at the same time points (Spearman's test; r = 0.444, p = 0.012). CONCLUSIONS: These results point to a possible causative relationship between TS and opioid analgesia.

Successful desensitization protocol for hypersensitivity reaction probably caused by dabrafenib in a patient with metastatic melanoma.

Vemurafenib and dabrafenib are both orally bioavailable small molecule agents that block mitogen activated protein kinase signalling in patients with melanoma and BRAF(V600E) mutation. Generalized hypersensitivity reactions to vemurafenib or dabrafenib have not been described. Continuing vemurafenib or dabrafenib therapy despite hypersensitivity reaction is especially important in patients with melanoma and BRAF(V600E) mutation, in whom this mutation plays a critical role in tumour growth. Desensitization protocols to overcome hypersensitivity reactions by gradual reintroduction of small amounts of the offending drug up to full therapeutic doses are available for many anti-cancer agents, including vemurafenib but, to the best of our knowledge, have not been reported for dabrafenib. We describe a patient with metastatic melanoma who developed Type I hypersensitivity reaction to vemurafenib and to subsequent treatment with dabrafenib, and who was successfully treated by drug desensitization which allowed safe prolonged continuation of dabrafenib. The development of hypersensitivity reactions for both dabrafenib and vemurafinib in the current case could be because these drugs have a similar chemical structure and cause a cross-reactivity. However, hypersensitivity reaction to a non-medicinal ingredient shared by the two drugs is also possible. Oral desensitization appears to be an option for patients with hypersensitivity Type I to dabrafenib. This approach may permit clinicians to safely administer dabrafenib to patients who experience hypersensitivity reactions to this life-prolonging medication.

Eradication of carbapenem-resistant Enterobacteriaceae gastrointestinal colonization with nonabsorbable oral antibiotic treatment: A prospective controlled trial.

BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) are emerging. In attempt to eradicate CRE colonization, we conducted a semirandomized, prospective, controlled trial using oral nonabsorbable antibiotics. METHODS: Consecutive hospitalized CRE carriers were studied. Patients whose rectal isolates were gentamicin sensitive but colistin resistant were treated with gentamicin. Patients whose isolates were colistin sensitive but gentamicin resistant were treated with colistin. Patients whose isolates were sensitive to both drugs were randomized to 3 groups of oral antibiotic treatment: gentamicin, colistin, or both. Patients whose isolates were resistant to both drugs, and those who did not consent, were followed for spontaneous eradication. RESULTS: One hundred fifty-two patients were included; 102 were followed for spontaneous eradication for a median duration of 140 days (controls), and 50 received 1 of the 3 drug regimens: gentamicin, 26; colistin, 16; both drugs, 8, followed for a median duration of 33 days. Eradication rates in the 3 treatment groups were 42%, 50%, and 37.5%, respectively, each significantly higher than the 7% spontaneous eradication rate in the control group (P < .001, P < .001, and P = .004, respectively) with no difference between the regimens. No significant adverse effects were observed. CONCLUSION: Oral antibiotic treatment with nonabsorbable drugs to which CRE is susceptible appears to be an effective and safe for eradication of CRE colonization and, thereby, may reduce patient-to-patient transmission and incidence of clinical infection with this difficult-to-treat organism.

Prospective evaluation of the dosing regimen of vancomycin in children of different weight categories.

BACKGROUND: Pharmacokinetics (PK), pharmacodynamics and optimal dosing of vancomycin in obese children is not known. Higher trough levels of vancomycin may improve outcomes. This prospective study evaluated the appropriateness of twice-daily regimen for the adherence to guidelines, among obese and non obese children. METHODS: Children receiving vancomycin, (20 mg/kg BID) were included. Patients were divided into 3 groups. Adequacy was defined as trough level ≥ 10mg/L and AUC/MIC > 400. An alternative-dosing regimen was calculated based on individual PK parameters. RESULTS: Seventy-seven pairs (trough, peak) were taken from 51 children. Mean trough level was 3.36 ± 2.58, only 3% fell in therapeutic range, no statistical difference was observed between obese, normal weight or underweight groups. One child had an AUC/MIC > 400. All children recovered. CONCLUSION: PK properties of all weight groups were similar. More frequent and higher doses are needed to achieve the goals of current guidelines.

Calcium absorption, kinetics, bone density, and bone structure in patients with hereditary vitamin D-resistant rickets.

BACKGROUND: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor gene. Children with HVDRR suffer from severe hypocalcemia and rickets that are treatable with extremely high-dose calcium supplements. Surprisingly, spontaneous recovery of calcium metabolism occurs after the end of puberty without the need for further calcium supplementation. OBJECTIVES: To evaluate the role of vitamin D receptor in intestinal calcium absorption and bone, we investigated intestinal fractional calcium absorption (FCA), bone calcium accretion (Vo+), bone mineral density (BMD), and bone structure parameters in HVDRR patients from infancy into adulthood. PATIENTS AND METHODS: Seventeen HVDRR patients aged 1.5-37 yr were investigated. FCA and Vo+ were determined by stable-calcium isotopes. BMD was determined by dual-energy x-ray absorptiometry and bone structure by high-resolution magnetic resonance imaging. RESULTS: FCA in patients aged 1.5-17 yr was 34.9 ± 11.2% compared with 57.3 ± 2.0% in age-matched controls (P < 0.00004), whereas in patients aged 18-26 yr, it was 82.0 ± 7.8 and 53.6 ± 1.2% in controls (P < 0.001). FCA of patients older than 29 yr was comparable to controls. Patients aged 18-26 yr had higher Vo+ than controls (P < 0.02). Patients under 18 and over 29 yr of age had Vo+ comparable to controls. Femoral-neck BMD Z-score was -2.38 ± 0.3 in patients under 18 yr and 0.28 ± 0.87 in postpubertal patients (P < 0.0001). Bone structure by high-resolution magnetic resonance imaging and bone parameters of HVDRR patients and controls were similar. CONCLUSIONS: Evidence from HVDRR patients reveals that calcium absorption is highly vitamin D dependent during infancy until the end of puberty, after which there is a period of about 10 yr in which mechanisms other than vitamin D-dependent ones are substantially involved in calcium absorption.

Opioid consumption in a tertiary hospital setting over an 8-year timeframe--a potential resource for tracking trends in pain management.

Opioid consumption by countries and health care organizations can be regarded as a marker of the quality of pain management. However, there are only limited data on opioid consumption in hospital settings. Objective and reliable data can be obtained by monitoring direct opioid consumption within a hospital, and then that data can be analyzed for identifying trends and directions to assist in guiding improved pain treatment within the hospital. This article tracks opioid consumption in a tertiary hospital over an 8-year period and by comparing the data to the consumption during the previous decade, it highlights trends and tendencies in the use of opioids as a potential indicator of pain management within this facility.

Successful desensitization protocol for hypersensitivity reaction caused by sunitinib in a patient with a gastrointestinal stromal tumor.

Sunitinib is an orally bioavailable small molecule that inhibits multiple receptor tyrosine kinases. Generalized hypersensitivity reactions (HSR) to sunitinib have not been described. A patient with a gastrointestinal stromal tumor (GIST) who developed a type I HSR to sunitinib and who was successfully treated by drug desensitization is reported. A 51-year-old man with metastatic GIST developed a type I HSR during sunitinib treatment. Four days after treatment initiation, the patient presented to the Emergency Department with acute generalized urticaria and facial and throat swelling. Sunitinib was restarted 1 week later, using a desensitization protocol in which 10 escalating reduced doses, beginning with 0.05 mg, were given following pre-medication with prednisone and promethazine. This protocol was well tolerated and allowed us to continue the treatment, obtaining partial remission of the liver metastasis that was followed by complete resection. Sunitinib was temporarily discontinued before the operation and renewed after surgery by repeating the same desensitization procedure. At the time of this report, sunitinib has been continued for 1 year without evidence of recurrent disease. Oral desensitization appears to be an option for patients with hypersensitivity type I to sunitinib and may permit its safe administration to patients who experience HSR to this life-prolonging medication.

Olive oil-based intravenous lipid emulsion in pediatric patients undergoing bone marrow transplantation: a short-term prospective controlled trial.

BACKGROUND & AIMS: Parenteral nutrition (PN) is an important component of the supportive care of children undergoing bone marrow transplantation (BMT). The study aimed to assess short-term safety and metabolic effects of an olive oil-based (OO) lipid emulsion compared with a MCT/LCT (M/L) emulsion in the clinical setting of pediatric BMT. METHODS: Twenty-eight pediatric BMT patients (age 1-18 years) expected to need PN support for at least 2 weeks, were prospectively enrolled and randomly assigned to receive either OO or M/L lipid emulsions within PN. Clinical and routine laboratory parameters, plasma fatty acids profile, vitamin E and peroxidation status were recorded at baseline and after 14 days of PN. RESULTS: No significant differences were found for hematological parameters, liver enzymes, vitamins, plasma peroxidation status, percentage and time to engraftment. Taking into consideration the baseline fatty acids levels, the OO group showed higher oleic acid (p=0.012), linoleic (p=0.012) and arachidonic acid (p=0.002) enrichment but similar eicosapentanoic and docosahexanoic acids levels compared to the M/L group at day 14. Cholesterol levels decreased significantly in the OO group after 14 days on PN (p=0.017). CONCLUSIONS: OO lipid emulsion was well tolerated, maintained essential fatty acids and peroxidation status, and generated a favorable plasma lipid profile. In this study short-term use of OO intravenous lipid emulsions was safe in children who needed PN support during BMT.

Hyperimmune gammaglobulin for the treatment of West Nile virus encephalitis.

BACKGROUND: West Nile virus, the etiologic agent of West Nile fever, is an emerging mosquito-borne disease. WNV was recognized as a cause of severe human meningoencephalitis in elderly patients during outbreaks in various parts of the world. OBJECTIVES: To analyze WNV encephalitis therapy and its outcome after prescribing hyperimmune gammaglobulin therapy. METHODS: Eight subjects with WNV encephalitis were treated with supportive therapy and 5 days of IVIG 0.4 g/kg/day containing high WNV antibodies obtained from healthy blood donors. RESULTS: Patients who were treated with IVIG as soon as possible exhibited an improvement in their symptoms. All subjects presented with high fever, progressive confusion and headaches, nausea and vomiting. The Glasgow Coma Screen for six patients ranged between 8 and 13 and all were discharged with a score of 15. The remaining two subjects died during their hospitalization. CONCLUSIONS: In severe WNV infection, where the disease affects the central and/or peripheral nervous system, early intervention with IVIG together with supportive treatment is recommended.

Tolerability and feasibility of eptifibatide in acute coronary syndrome in patients at high risk for cardiovascular disease: A retrospective analysis.

BACKGROUND: Despite the beneficial effects of glycoprotein (GP) IIb/IIIa antagonists in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI), GP IIb/IIIa antagonists are rarely administered in general internal medicine wards in Israel, where most patients with UA/ NSTEMI are admitted, due to lack of adequate monitoring and safety concerns. OBJECTIVE: The aims of this study were to compare the prevalence of bleeding complications in patients with UA/NSTEMI receiving combination treatment with eptifibatide (a GP IIb/IIIa antagonist), the low-molecular-weight heparin enoxaparin, and acetylsalicylic acid (ASA) versus that in patients receiving enoxaparin and ASA in internal medicine wards in Israel, and to identify risk factors for bleeding complications. METHODS: This retrospective analysis included information from the database at Rambam Medical Center, Haifa, Israel. The database provided information from 4 of the 5 wards (the ward from which data were unavailable did not routinely use eptifibatide). Data were included from patients aged ≥l.8 years who were admitted to the center with a diagnosis of UA/NSTEMI, were at high risk for death and/or nonfatal ischemic events based on American College of Cardiology/American Heart Association guidelines, were to undergo coronary intervention, and who had a Thrombosis in Myocardial Infarction risk score ≥3 (moderate to high risk). Patients in the eptifibatide group received eptifibatide IV (180-µg/kg bolus followed by a continuous infusion of 2 µg/kg · min up to 72 hours), enoxaparin SC (2 mg/kg · d), and ASA (100 mg/d). Patients in the control group received enoxaparin SC (2 mg/kg - d up to 96 hours) and ASA (100 mg/d). The prevalence of bleeding events was assessed using data up to 24 hours after the end of study drug administration. Major bleeding was defined as life-threatening bleeding at any site, intracranial hemorrhage, or bleeding accompanied by a decrease in plasma hemoglobin concentration of 5 g/dL or more. Otherwise, bleeding was considered minor. The risk for bleeding events was assessed using multivariate regression analysis. RESULTS: Data from 105 patients (64 men, 41 women) were included in the analysis. In the eptifibatide and control groups, the mean (SD) ages were 68.7 (11.1) and 74.8 (11.0) years, respectively. These characteristics were statistically similar between the 2 groups. The rates of major bleeding were similar between the eptifibatide and control groups (2 [3.8%] vs 0 patients). The rate of minor bleeding was significantly higher in the eptifibatide group compared with that in controls (11 [21.2%] vs 4 [7.5%] patients; P = 0.03). The incidence of thrombocytopenia was statistically similar between the eptifibatide and control groups (0 vs 2 [3.8%] patients). The risk for bleeding was found to be associated with eptifibatide use (odds ratio, 4.8; 95% CI, 1.29-17.80), whereas an association with treatment was not found in the control group. CONCLUSION: The results of this retrospective analysis suggest that the risk for bleeding complications is higher with combination treatment with eptifibatide, enoxaparin, and ASA compared with that with enoxaparin and ASA in high-risk patients with UA/NSTEMI admitted to internal medicine wards in Israel.

Loss of types XV and XIX collagen precedes basement membrane invasion in ductal carcinoma of the female breast.

Ductal and lobular carcinomas comprise most malignancies of the female breast and the morbidity and mortality associated with breast cancer. During the progression from in situ to invasive stages, tumour cells penetrate the epithelial and vascular basement membranes (BM) to realize full metastatic potential. While the definition of these structures has primarily resulted from analysis of laminin and type IV collagen, characterization of newly discovered BM/BM zone (BMZ) proteins will further elucidate the interactions between tumour cells and the host stroma. We have studied the expression of two non-fibrillar BMZ collagens, the type XV proteoglycan and collagen XIX, in breast cancer where a linear, well-formed BM becomes fragmented and even lost in the progression of epithelial malignancy. In the normal breast, types XV and XIX were found in all BMZ: epithelial, muscle, neural, endothelial, and fat. In in situ lesions, these two collagens, and particularly type XV, were often absent from the BM/BMZ displaying a continuous or just focally disrupted type IV/laminin staining pattern. In contrast, infiltrating ductal carcinomas showed only rare traces of laminin and collagen IV reactivity adjacent to the glands and tumour nests, and similarly there was little if any evidence of types XV and XIX collagen. All four molecules were, however, detected in the interstitium associated with some of the invasive carcinomas. The data suggest that types XV and XIX collagen are lost early in the development of invasive tumours, prior to penetration and eventual dissolution of the epithelial BM. Disappearance of these proteins from the BM/BMZ may signal remodelling of the extracellular matrix to promote tumour cell infiltration.