Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial

CONTEXT: Metformin is successfully used in the treatment of cycle disorders and anovulation in women with polycystic ovary syndrome (PCOS). No data of the exact point and the impact of insulin resistance (IR) on metformin's efficacy exist. OBJECTIVE: The objective of the study was to evaluate the early potential effects of metformin treatment, their time of onset, and the role of IR on metformin's efficacy. DESIGN: This was a prospective randomized, double-blind, placebo-controlled trial. SETTING: The study was conducted at the University of Heidelberg, Heidelberg, Germany. PATIENTS: The patient population was 45 oligo-/anovulatory PCOS women with typical ovaries. INTERVENTIONS: Women were stratified for IR (32 of 13) and then randomly allocated to receive either metformin (n = 22) or placebo (n = 23) and were assessed before and every 4 wk within a treatment period of 12 wk. MAIN OUTCOME MEASURES: Menstrual disturbance and markers of insulin metabolism were measured. RESULTS: The main outcome criterion menstrual disturbance was successfully improved in the metformin-treated group, depending on IR (12 of 15 vs. three of 17), whereas women without IR (four of seven vs. four of six) had no significant amelioration of their menstrual irregularities (P < 0.05). Estradiol levels increased continuously only in the treatment group (P < 0.005), indicating an improvement of ovulatory function. Sixty-seven percent of metformin-treated women had at least one ovulation, compared with only 45% in the placebo group, shown by biphasic body temperature curves. Insulin sensitivity improved within 4 wk after beginning of metformin as shown by an increased area under the curve glucose to insulin ratio, compared with baseline (P < 0.005). CONCLUSIONS: IR is a baseline predictor of clinical efficacy in metformin treatment in PCOS women measured by improved menstrual cyclicity and ovulatory function.     

Independent risk factors for postoperative shivering

Postoperative shivering (PAS) is uncomfortable for patients and potentially risky. In this observational trial we sought to identify independent risk factors for PAS after general anesthesia. Potential risk factors for PAS were recorded in 1340 consecutive patients. Signs of shivering, peripheral and core temperature, and thermal comfort were recorded in the postanesthetic care unit. The data were split into an evaluation data set (n = 1000) and a validation data set (n = 340). The first was used to identify independent risk factors for PAS and to formulate a risk score using backward-elimination logistic regression analysis. The proposed model was subsequently tested for its discrimination and calibration properties using receiver operating characteristic (ROC)-curve analysis and linear correlation between the predicted and the actual incidences of PAS in the validation group. The incidence of PAS was 11.6%. There were three major risk factors: young age, endoprosthetic surgery, and core hypothermia, with age being the most important. The risk score derived from this analysis had a reasonable discriminating power, with an area under the ROC-curve of 0.69 (95% confidence interval, 0.60-0.78; P < 0.0001). Furthermore the equation of the calibration curve (y = 0.69x + 6; R2= 0.82; P < 0.05) indicated a good and statistically significant agreement between predicted and actual PAS incidence. Postoperative shivering can be predicted with acceptable accuracy using the four risk factors identified in the present study. The presented model may serve as a clinical tool to help clinicians to rationally administer prophylactic antishivering drugs.     

Molekularbiologische Erklärungsansätze einer Lymphknotenmetastasierung

Zusammenfassung Die Metastasierung von Tumorzellen solider Tumoren in die regionalen Lymphknoten ist ein wichtiger Schritt in der Progression der Erkrankung und stellt bei vielen Tumoren einen entscheidenden prognostischen Faktor dar. Während der prognostische Wert des Lymphknotenbefalls bereits früh erkannt wurde, so wurde erst durch die Zunahme der molekularen Kenntnisse der Mechanismen, die zu einer lymphogenen Tumorzellausbreitung führen, ein beginnendes Verständnis des Systems der lymphogenen Metastasierung ermöglicht. Hierbei spielen Faktoren eine Rolle, die von den Zellen des Primärtumors gebildet werden und eine Proliferation von Lymphgefäßen in den Primarius induzieren.Die vaskulären endothelialen Wachstumsfaktoren (VEGF) wurden als Schlüsselmoleküle dieses Prozesses identifiziert. Zudem gibt es Hinweise, dass die Familie der Chemokinrezeptoren an Tumorzellen Schlüsselschritte der lymphogenen Metastasierung wie Migration, Invasion und Proliferation steuern. In jüngster Zeit entwickeln sich therapeutische Möglichkeiten der Hemmung der lymphogenen Tumorzellausbreitung durch selektive Inhibition von Wachstumsfaktorrezeptoren oder Chemokinrezeptoren.Das zunehmende Verständnis dieser molekularen Mechanismen der lymphatischen Metastasierung wird die Entwicklung neuer diagnostischer und therapeutischer Ansätze in der Therapie von Tumorpatienten ermöglichen.     

Verbessern intravenöses Fentanyl oder Midazolam vor Durchführung einer peripheren Regionalanästhesie Patientenakzeptanz und Kooperativität bei der Katheteranlage?

BACKGROUND: The procedure of placing a catheter for continuous regional anaesthesia is often associated with fear and pain in the patient. Thus, we evaluated the use of midazolam and fentanyl to improve patient's comfort and cooperation. METHODS: After an oral dose of 20 mg clorazepate, 174 patients receiving peripheral nerve catheters for regional anaesthesia where randomized into 3 groups to receive either intravenous placebo, 3 mg midazolam or 0.1 mg fentanyl immediately before catheter placement in a double-blind manner. Stepwise regression analysis was used to identify factors associated with patient's assessment of subjective discomfort (measured using a VAS 0-10) during the procedure. Amnesia was evaluated 24 h later. The anaesthetist rated patient's cooperation during catheter placement. RESULTS: Female sex and longer duration of catheter placement had significant negative impact on patient's comfort, whereas fentanyl showed an improvement. Age, body mass index, midazolam and the type of catheter had no influence. The following day 27% of the midazolam group, 6% of the placebo group and 9% of the fentanyl patients did not remember catheter placement. Patient's cooperation was poor in 26% of the midazolam patients but only in 9% of the placebo and 3% of the patients receiving fentanyl. Of the placebo patients 18.4% had to be supplemented with fentanyl because they found the procedure of catheter placement unbearable. No side effects occurred in either group. CONCLUSION: As patient's comfort and cooperation were significantly improved by fentanyl, we recommend fentanyl to facilitate catheter placement for regional anaesthesia.     

Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study

PURPOSE: Sildenafil is the oral phosphodiesterase-5 inhibitor that revolutionized treatment for erectile dysfunction. We investigated a potential association of the G protein beta 3 subunit (GNB3) C825T polymorphism, a determinant of intracellular signal transduction, with the drug response to sildenafil in patients with erectile dysfunction. MATERIALS AND METHODS: In 113 men with erectile dysfunction and 111 healthy male controls genotype status of the GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction analysis. Patients with erectile dysfunction received sildenafil at a dose of 25 to 100 mg. according to the individual erectile response. Drug response was measured by interviewing the patient according to the erection scale of 0 to 5. RESULTS: The GNB3 genotype distribution of patients with erectile dysfunction exactly matched that of healthy controls. Analysis of the response to sildenafil revealed a significant association of C825T allele status with the erectile response to sildenafil. In the group with TT genotype we observed a 90.9% response but only a 50.9% and 48.9% response in patients with the CC and TC genotype, respectively. The odds ratio for a positive erectile response was 10.0 (95% CI 1.2 to 81.1) for patients with the TT versus the TC/CC genotype (p = 0.01). CONCLUSIONS: The response to sildenafil is significantly associated with GNB3 C825T genotype status in patients with erectile dysfunction.     

Optimization and characterization of a sphingomyelin/cholesterol liposome formulation of vinorelbine with promising antitumor activity

Vinorelbine (VRL) is a particularly lipophilic member of the vinca alkaloids which, as a class of drugs, exhibit improved cytotoxicity and therapeutic activity through increased duration of exposure. Here, we describe and optimize a sphingomyelin/cholesterol (SM/Chol) liposome formulation of VRL to maximize in vivo drug retention, plasma circulation time, and therapeutic activity. VRL was efficiently encapsulated (>90%) into 100 nm liposomes using an ionophore-mediated loading method. VRL retention in SM/Chol liposomes after intravenous injection in mice was dependent on drug-to-lipid ratio (D/L), with higher D/L ratios exhibiting increased drug retention (0.3 > 0.2 > 0.1, wt/wt) and improved pharmacokinetics. Cryo-electron microscopic examination of a high D/L ratio formulation indicated that the intravesicular regions of these liposomes were electron dense compared with empty liposomes. The optimized, high D/L ratio SM/Chol VRL formulation showed promising activity against subcutaneous B16 melanoma tumors compared with VRL or SM/Chol formulations of vincristine or vinblastine. Finally, the stability of the formulation was excellent (<5% drug leakage, >99% intact VRL, no changes in liposome size after 1 year at 2-8 degrees C). The optimized drug retention properties of the SM/Chol formulation of VRL, combined with its promising antitumor activity and pharmaceutical stability, make this formulation an excellent candidate for future clinical development.     

Reduction of severe wrist injuries in snowboarding by an optimized wrist protection device: a prospective randomized trial

BACKGROUND: The benefits of sport are well recognized, but many activities carry a sport-specific injury risk. Snowboarding has become an increasingly popular winter sport in Austria in recent years, with an estimated 900,000 participants annually. Roughly 6,000 of these suffer from injury and up to 2,000 sustain moderate or severe wrist injuries (mainly fractures of the distal radius and epiphysiolyses). METHODS: We conducted a prospective, randomized, controlled trial to test the protective effect of a wrist protector, which differs in position, stiffness, length, and fixation from conventional protectors. Seven hundred twenty-one snowboarders were randomized into two groups. The risk factors and the injuries that occurred were registered by questionnaires and, in case of medical treatment, by medical reports. Time until injury (in half-days) was compared by the proportional hazards model. RESULTS: Nine severe wrist injuries were sustained in the unprotected control group and only one in the protected group (hazard ratio, 0.13; 95% confidence limits, 0.02, 1.04). Twelve snowboarders of the protector group secretly discarded their protectors during the trial (including the snowboarder who suffered the one and only severe wrist injury of this group). A per-protocol analysis was therefore performed, which demonstrated a more accentuated result (p = 0.003). There was no statistically significant increase in the incidence of other types of injury. Experience was shown to be a further protective factor. CONCLUSION: We recommend the use of a wrist protector, particularly for novices participating in this sport. As in other domains of medicine, preventive measures can decrease morbidity also in terms of sport injuries.