Is obesity an outcome of gonadotropin-releasing hormone agonist administration? Analysis of growth and body composition in 110 patients with central precocious puberty

Concern has been raised that children with central precocious puberty (CPP) are prone to the development of obesity. Here we report longitudinal height, weight, and body mass index (BMI) data from 96 girls and 14 boys with CPP before, during, and after GnRH agonist (GnRHa) administration. Skinfold thickness (n = 46) and percent body fat by dual energy x-ray absorptiometry (n = 21) were determined in subsets for more accurate assessment of body composition and to validate the use of the BMI SD score as an index of body fatness in our subjects. Before the initiation of therapy (PRE), the girls with CPP had a mean BMI SD score for chronological age (CA) of 1.1+/-0.1 and for bone age (BA) of 0.1+/-0.1. By the end of the study, 12-24 months after the discontinuation of GnRHa, the mean BMI SD score was 0.9+/-0.1 for CA and 0.6+/-0.1 for BA. At the visit when GnRHa was discontinued, 41% and 22% of the girls had a BMI SD score for CA more than the 85th and 95th percentiles, respectively, indicating that obesity was present at a high rate among our subjects; the BMI SD score for CA at the PRE visit was its strongest predictor. Indeed, 86% of the girls with BMI SD score for CA above the 85th percentile when GnRHa was discontinued also had BMI SD score for CA above the 85th percentile at the PRE visit. The proportion of boys with elevated BMI SD score for CA was also high. Fifty-four percent and 31% of the SD scores were greater than the 85th and 95th percentiles after 36 months of GnRHa therapy; the BMI SD score for CA PRE had been above the 85th percentile in 71% of these overweight subjects. Obesity occurs at a high rate among children with CPP, but does not appear to be related to long term pituitary-gonadal suppression induced by GnRHa administration. Children with CPP should have a baseline BMI SD score calculated, and those at risk for obesity should be counseled appropriately.     

Is 18F-FDG-PET suitable for therapy monitoring after palliative photodynamic therapy of non-resectable hilar cholangiocarcinoma?

BACKGROUND: If existing biliary drainage is insufficient, photodynamic therapy (PDT, laser treatment after application of a photosensitizer) is an already established adjunct to palliative therapy for progressing hilar cholangiocarcinoma (Klatskin tumours), since it prolongs survival and improves quality of life. Experimental studies of other tumour entities showed that (18)F-FDG-PET ( (18)F-fluorodeosxyglucose-positron emission tomography) may play a role in monitoring tumour response to PDT. Furthermore, previous studies have revealed a high accuracy of this method for the detection of hilar cholangiocarcinoma. Therefore, the aim of the present study was to investigate the feasibility of (18)F-FDG-PET as a follow-up screening method in patients with hilar cholangiocarcinoma who underwent PDT. PATIENTS AND METHODS: 10 patients were examined by (18)F-FDG-PET before and 4 - 6 weeks after PDT. The following parameters were evaluated: maximum and mean SUV in the tumour, the ratio of maximum SUV in the tumour and mean SUV in the liver, the vital tumour volume, as well as bilirubin and CA 19 - 9 levels. RESULTS: All tumours were detected by (18)F-FDG-PET. Within a period of 4 - 6 weeks after PDT the cholestasis parameter bilirubin decreased significantly. However, SUV-associated parameters did not show a significant change after treatment while the estimated vital tumour volume even increased. DISCUSSION: PDT does not effect a relevant reduction of tumour mass in non-resectable hilar cholangiocarcinoma. However, PDT leads to a significant reduction of cholestasis. If (18)F-FDG-PET is suitable for monitoring the effect of new palliative therapeutic approaches, like brachytherapy, the use of modern chemotherapeuticals, COX-2 and receptor-tyrosine kinase inhibitors, perhaps also in combination with PDT, has to be further investigated.     

Are steroids obligatory mediators of luteinizing hormone/human chorionic gonadotropin-triggered resumption of meiosis in mammals?

Steroids mediate the gonadotropic stimulus of oocyte maturation in fish and amphibians. Such a role of steroids in mammals has not been confirmed until recently. A series of studies presented data suggesting that steroids might be involved in meiosis of mouse oocytes. Here we examined this suggestion using in vitro cultures of rat and mouse follicle-enclosed oocytes (FEOs) and cumulus-enclosed oocytes (CEOs). In FEOs that mature only in response to gonadotropins or other stimuli, we tested the ability of steroids to trigger meiosis and whether addition of steroid receptor antagonists blocks LH/human chorionic gonadotropin stimulation of meiosis. In CEOs that mature spontaneously, we tested whether steroid antagonists block maturation and whether steroids overcome the inhibition of maturation by hypoxanthine (Hx), a mild inhibitor of meiotic resumption. The progesterone antagonists mifepristone (RU 486) and Organon 31710 as well as the estrogen antagonist faslodex did not prevent LH-triggered maturation of rat or mouse FEOs or the spontaneous maturation of CEOs. In accordance, the progesterone agonist promegestone (R5020) and estradiol did not stimulate the resumption of meiosis in rat and mouse FEOs, and both did not overcome the Hx inhibition of meiosis in rat and mouse CEOs. Flutamide, an androgen antagonist, did block meiosis in rat FEOs, but this action could not be affected by adding dihydrotestosterone, suggesting that it was not androgen receptor mediated. Flutamide did not affect spontaneous maturation of rat CEOs, and dihydrotestosterone could not stimulate meiosis inhibited by Hx. Thus, in contrast to lower vertebrates, in mammals, steroids do not seem to serve as an obligatory signal by which the somatic cells of the follicle transfer the gonadotropic stimulation of meiosis to the oocyte.     

What is the role of therapeutic drug monitoring in antifungal therapy?

Despite an expanding number of therapeutic options for treating invasive fungal infection (IFI), the mortality rate from these infections remains high. Many risk factors for poor outcome from IFI (eg, the compromised immune status of the host) are not modifiable by the treating clinician. Thus, elevated interest exists in any modifiable factor that might improve outcome. Many of the new antifungal agents have marked variability in drug concentration based on either inconsistent absorption or elimination, leading to very wide interpatient variability. Many agents also have a narrow therapeutic index, meaning a small range between drug levels too low to achieve the desired clinical benefit and high enough to produce unwanted or toxic effects. Therefore, therapeutic drug monitoring is useful to maximize efficacy while minimizing drug toxicity of some antifungal agents.     

Is excessive weight gain after ablative treatment of hyperthyroidism due to inadequate thyroid hormone therapy?

There is controversy about the correct dose and form of thyroid hormone therapy for patients with hypothyroidism. Despite restoration of serum thyrotropin (TSH) concentrations to normal, many patients complain of excessive weight gain. We have compared weight at diagnosis of hyperthyroidism with that when euthyroid, evidenced by a stable, normal serum TSH concentration, with or without thyroxine (T4) replacement therapy, in patients treated with an 18-month course of antithyroid drugs (43 patients), surgery (56 patients), or 13I (34 patients) for Graves' disease. In addition, weights were recorded before and after treatment of 25 patients with differentiated thyroid carcinoma by total thyroidectomy, 131I, and long-term T4 suppressive therapy, resulting in undetectable serum TSH concentrations. Mean weight gain in patients with Graves' disease who required T4 replacement therapy following surgery was significantly greater than in those of the same age, sex, and severity of hyperthyroidism rendered euthyroid by surgery (3.9 kg) (p < 0.001) or at the end of a course of antithyroid drugs (4.1 kg) (p < 0.001). Weight gain was similar in those requiring T4 replacement following surgery or 131T therapy (10.4 versus 10.1 kg). In contrast, ablative therapy combined with suppression of TSH secretion by T4 in patients with differentiated thyroid carcinoma did not result in weight gain. The excessive weight gain in patients becoming hypothyroid after destructive therapy for Graves' disease suggests that restoration of serum TSH to the reference range by T4 alone may constitute inadequate hormone replacement.     

What does a single determination of malaria parasite density mean? A longitudinal survey in Mali

Temporal variations of blood parasite density were evaluated in a longitudinal study of young, asymptomatic men in a village with endemic malaria in Mali (West Africa). Our main intention was to challenge the value of a single measure of parasite density for the diagnosis of malaria, and to define the level of endemicity in any given area. Parasitaemia and body temperature were recorded three times a day in the wet season (in 39 subjects on 12 days) and in the dry season (in 41 subjects on 13 days). Two thousand nine hundred and fifty seven blood smears (98.5% of the expected number) were examined for malaria parasites. We often found 100-fold or greater variations in parasite density within a 6-hour period during individual follow-up. All infected subjects had frequent negative smears. Although fever was most likely to occur in subjects with a maximum parasite density exceeding 10000 parasites/mm3 (P = 0.009), there was no clear relationship between the timing of these two events. Examples of individual profiles for parasite density and fever are presented. These variations (probably due to a 'sequestration-release' mechanism, which remains to be elucidated) lead us to expect a substantial impact on measurements of endemicity when only a single sample is taken. In this study, the percentage of infected individuals varied between 28.9% and 57.9% during the dry season and between 27.5% and 70.7% during the wet season. The highest rates were observed at midday, and there were significant differences between days. Thus, high parasite density sometimes associated with fever can no longer be considered as the gold standard in the diagnosis of malaria. Other approaches, such as decision-making processes involving clinical, biological and ecological variables must be developed, especially in highly endemic areas where Plasmodium infection is the rule rather than the exception and the possible causes of fever are numerous.     

The role of the 3′ region of mammalian gonadotropin β subunit gene in the luteinizing hormone to chorionic gonadotropin evolution

CGβ subunits comprise a unique carboxyl-terminal peptide (CTP) that has multiple O-linked glycans and extends serum half-life of the protein. It has evolved by incorporating a previously untranslated region of the LHβ gene into the reading frame. Although CTP-like sequences are encrypted in the LHβ genes of several mammals, the CGβ subunit developed only in primates and equids. To study this restriction in evolution, we examined whether the cryptic CTP decoded from the bovine LHβ gene (boCTP) possesses key characteristics of the human (h) CGβ-CTP. The boCTP does not impede several crucial aspects of hormone biosynthesis, but compared to the hCGβ-CTP, the stretch lacks O-glycans and determinants for circulatory survival. O-glycan deficiency and the associated incapacity to extend serum half-life is a major drawback of the boCTP. This may explain why LH did not evolve into CG in ruminants and consequently alternative mechanisms evolved to delay luteolysis early in gestation.     

Effect of serotonin and β-endorphin on the release of luteinizing hormone in the hen (Gallus domesticus)

Serotonin (5-hydroxytryptamine) and β-endorphin administered into the third ventricle of the hen blocked normal and progesterone-induced ovulation, and suppressed the release of LH in normal and progesterone-injected hens. p-Chlorophenylalanine, an inhibitor of serotonin synthesis, caused the release of LH and diminished the effect of β-endorphin. Naloxone, an antagonist of opiate peptides, diminished the effect of β-endorphin but not the effect of serotonin. The results suggest that both serotonin and β-endorphin are involved in the control of LH release in the hen as an inhibitory agent, and serotonin is predominant while β-endorphin is subsidiary to the inhibition of the LH release.     

Does cortisol acting via the type II glucocorticoid receptor mediate suppression of pulsatile luteinizing hormone secretion in response to psychosocial stress?

This study assessed the importance of cortisol in mediating inhibition of pulsatile LH secretion in sheep exposed to a psychosocial stress. First, we developed an acute psychosocial stress model that involves sequential layering of novel stressors over 3-4 h. This layered-stress paradigm robustly activated the hypothalamic-pituitary-adrenal axis and unambiguously inhibited pulsatile LH secretion. We next used this paradigm to test the hypothesis that cortisol, acting via the type II glucocorticoid receptor (GR), mediates stress-induced suppression of pulsatile LH secretion. Our approach was to determine whether an antagonist of the type II GR (RU486) reverses inhibition of LH pulsatility in response to the layered stress. We used two animal models to assess different aspects of LH pulse regulation. With the first model (ovariectomized ewe), LH pulse characteristics could vary as a function of both altered GnRH pulses and pituitary responsiveness to GnRH. In this case, antagonism of the type II GR did not prevent stress-induced inhibition of pulsatile LH secretion. With the second model (pituitary-clamped ovariectomized ewe), pulsatile GnRH input to the pituitary was fixed to enable assessment of stress effects specifically at the pituitary level. In this case, the layered stress inhibited pituitary responsiveness to GnRH and antagonism of the type II GR reversed the effect. Collectively, these findings indicate acute psychosocial stress inhibits pulsatile LH secretion, at least in part, by reducing pituitary responsiveness to GnRH. Cortisol, acting via the type II GR, is an obligatory mediator of this effect. However, under conditions in which GnRH input to the pituitary is not clamped, antagonism of the type II GR does not prevent stress-induced inhibition of LH pulsatility, implicating an additional pathway of suppression that is independent of cortisol acting via this receptor.     

Is continuous transcutaneous monitoring of PCO2 (TcPCO2) over 8 h reliable in adults?

Monitoring of non-invasive ventilation (NIV) in a non-intensive care unit (non-ICU) setting requires a method of evaluating nocturnal PaCO2, such as transcutaneous CO2 monitoring (TcPCO2). However, changing the probe site after 4 h and recalibrating (as recommended) is time-consuming and impractical. Continuous (8-h) TcPCO2 monitoring at a lower electrode temperature (43 degrees C) in this setting has never been formally studied. Patients under intermittent NIV were studied (n = 28, aged 69 +/- 9 years, PaO2: 71 +/- 13 mmHg, PaCO2: 49 +/- 9 mmHg). After calibration and stabilization of TcPCO2 (Radiometer Tina TCM3 capnograph), arterial blood gases (ABG) were measured and compared with transcutaneous readings. In 10 patients who underwent continuous 8-h TcPCO2 recording, ABGs were also measured after 4 and 8 h. The correlation between TcPCO2 and PaCO2 was highly significant (r2 = 0.92, P<0.0001). Mean (TcPCO2 PaCO2) gradient (bias) was: -2.8 +/- 3.8 mmHg; limits of agreement were: (-10.4; +4.8 mmHg). TcPCO2-PaCO2 gradient was lowest (i.e. within-bias +/- 2 mmHg) between 40 and 54 mmHg, increasing below and above these values. Over 8 h, no significant drift of the TcPCO2 signal occurred (ANOVA). No discomfort or skin lesion was noted. In conclusion, with an electrode temperature of 43 degrees C, 8-h continuous monitoring of TcPCO2 was well tolerated, without any local side-effects or significant drift of TcPCO2 signal; when compared to previous reports, lowering the electrode temperature did not decrease performance for CO2 monitoring.     

Methotrexate as single therapy in Crohn's disease: Is its long-term efficacy limited?

OBJECTIVE: To determine the efficacy and patient tolerance of parenteral methotrexate in the treatment of Crohn's disease at a dose of 25mg per week for three months, then at 15-25mg per week as maintenance therapy. PATIENTS AND METHODS: Thirty-five patients (27 women, eight men; mean age 36 years) with steroid-dependent Crohn's disease were included in the study after failure of azathioprine in 34 cases. Clinical remission was defined as a Harvey-Bradshaw disease-activity index less than or equal to 4 and complete weaning from steroids. RESULTS: At the end of the three-month induction treatment, the Harvey-Bradshaw index decreased significantly (4.6+/-2.9 versus 9.4+/-5.2; P=0.0001), as did serum CRP (24+/-27 versus 43+/-45 mg/L; P=0.01) and prednisone dose (5.63+/-7.3 versus 21.1+/-18.7 mg/L; P=0.00001). The mean maintenance dose of methotrexate was 20.3+/-3.8 mg per week. The rate of clinical remission was 50% at three months and 28% at one year and two years. Nine patients had an adverse event attributed to methotrexate that led to drug withdrawal in six cases (17%). CONCLUSION: Our findings suggest that, for steroid-dependent Crohn's disease which has failed to respond to thiopurines, long-term methotrexate remains effective in fewer than one in three patients.     

Is the outcomes of early ST-segment resolution after thrombolytic therapy in acute myocardial infarction always favorable?

AIMS: To determine whether the magnitude of ST-segment resolution after thrombolytic therapy (TT) predicts short- and long-term outcomes in an unselected population of patients with an acute myocardial infarction (AMI). BACKGROUND: Recent studies suggest that resolution of ST-segment elevation (STE) on the 2-hour post-TT electrocardiogram (ECG) is a useful predictor of prognosis. However, these studies were restricted to clinical trials where only 15% to 20% of the patients receiving TT were often enrolled. METHODS: The present study evaluated an unselected consecutive group of patients who received TT. All clinical, investigational, and follow-up data had been collected in a prospective manner. The analysis of ECGs was done retrospectively with the reader blinded to the clinical course. STE at 80 milliseconds after the J point was measured on the baseline and 90-minute ECG using a hand-held caliper. The resolution of STE was categorized as complete (>or=70%), partial (30% to <70%), and none (<30%) as has been done in previous studies. RESULTS: Three hundred fifty-two patients (250 men, 102 women; age, mean+/-SEM, 61.8+/-1.0 years; peak creatine kinase, 1938+/-185 micromol/L; door to needle time, 50.0+/-6 minutes, <30 minutes, 50%; <45 minutes, 70%) with AMIs who received TT were included in the study. Inhospital deaths and recurrent AMI/postinfarct angina revealed no significant association with increasing ST-segment resolution (P>.05). A 70% or higher ST-segment resolution was associated with a significantly lower incidence of inhospital congestive heart failure (CHF) and CHF/death (P<.05). Similarly, with a 70% or higher ST-segment resolution, there was a lower incidence in the 1-year outcomes of CHF and death/CHF. However the 1-year occurrences of unstable angina or recurrent AMIs taken singly did not bear a correlation to increasing magnitudes of ST-segment resolution (P>.05). Although as a composite measure, there was an increasing trend with ST-segment resolution. CONCLUSIONS: Magnitude of ST-segment resolution after TT appears to demonstrate a dichotomous relationship to measured outcomes. Although there is a lower incidence of death/CHF with increasing ST-segment resolution, there appears to be a higher likelihood for recurrent AMI/unstable angina.