First case of acute cholestatic hepatitis attributed to oseltamivir in a young girl with ah1n1 influenza.

Abstract: Oseltamivir caryboxylase is a potent inhibitor of the enzyme neuramidase of the influenza virus particle and it is active against both influenza A and B viruses. Oseltamivir is indicated for therapy or post-exposure prevention of influenza A and B. Side effects are uncommon and include mild nausea, gastrointestinal upset, dizziness and headache. Despite its widespread use, oseltamivir has not been associated with clinically apparent liver injury. To the best of our knowledge, this is the first case report in the literature linking the development of acute hepatitis to the consumption of oseltamivir in a patient suffering from influenza H1N1 infection.

Time course of total and distrectual weight gain after refeeding in anorexia nervosa.

Anorectic patients who achieve complete recovery from the eating disorder can obtain a favorable psychosocial outcome but the long-term nutritional outcome is ill-defined. We investigated the time course of total and distrectual body composition during and after refeeding in 32 female patients with anorexia nervosa. Patients were enrolled at their lowest weight (T0) and re-examinated after a 15% weight gain (at a mean of 3 months, T1; n=17) and after 3 years of stable weight recovery (T2; n=8). At T2 patients were compared to a control group of 8 healthy females matched for age and body mass index. All subjects underwent dual X-ray absorptiometry and anthropometry at each visit. At T0, the 32 subjects were at 61%+/-8% of ideal body weight (IBW) with severe reductions in fat mass (FM; 7.1%+/-4.5%), fat free mass (FFM) and bone mineral content (BMC). At T2, the 8 subjects had gained 40% of initial weight, but remained at 85.1%+/-7.7% of IBW ( p<0.01 vs. controls), with a percent FM comparable to that of controls and an absolute FFM still deficient. BMC did not improve at T2 and remained 79% of that in controls. FM depletion was more severe in the limbs than in the trunk and at T2 the trunk/limb FM ratio remained greater than that in controls. These data strongly suggest that continued nutritional surveillance and support is necessary throughout these patients' lives, even after correction of the psychiatric illness and of severe underweight.

Short-term effects of exercise on body water distribution of severely obese subjects as determined by bioelectrical impedance analysis.

We have previously shown that a short-term weight (Wt) reduction programme consisting of energy restriction, physical activity and psychological counselling, produces physiological changes of body water distribution (BWD) in obese subjects as detected by bioelectrical impedance analysis. The present study was aimed at testing the contribution of diet and physical activity to the observed changes in BWD. A number of 96 obese inpatients were consecutively enrolled in the study at our Obesity Clinic. During a 3-wk period, they underwent a body Wt reduction programme comprising the same dietary strategy and psychological counselling. The programme differed as far as physical activity is concerned, with 52 subjects randomized to a baseline exercise programme (BEP), 22 to a cardiovascular exercise programme (CEP) and 22 to a cardiovascular and strength programme (CSP). Absolute and percent Wt reduction was significantly higher in CSP than BEP subjects (p < 0.05) and the same hold for the changes in impedance (Z) at frequencies of 5, 50 and 100 kHz (p < 0.05). The change in the Z5/Z100 ratio did not show however any between-group difference (p = NS). The average values of Z changes were 1.5 to 2 times higher in CEP and 5.0 to 5.5 times higher in CSP than BEP subjects. We conclude that the type of exercise performed does influence the absolute changes of total body water and extracellular water but not BWD in severely obese subjects undergoing Wt loss.

Lower limb alactic anaerobic power output assessed with different techniques in morbid obesity.

Short-term alactic anaerobic performance in jumping (5 consecutive jumps with maximal effort), sprint running (8 m) and stair climbing (modified Margaria test) were measured in 75 obese subjects (BMI: 40.3+/-5.0 kg/m2) and in 36 lean control subjects (BMI: 22.4+/-3.2 kg/m2) of the same age and gender distribution. The results show that obese subjects attained a significantly lower specific (per unit body mass) power output both in jumping (W(spec,j); p<0.001) and stair climbing (W(spec,s); p<0.001) and run at a significantly lower average velocity (v; p<0.001) during sprinting. In spite of the different motor skillfulness required to accomplish the jumping and climbing tests, W(spec,s) (and hence the vertical velocity in climbing, v(v)) was closely correlated with W(spec,j) (R2=0.427, p<0.001). In jumping, although the average force during the positive work phase was significantly higher in obese subjects (p<0.001), no difference between the 2 groups was detected in absolute power. In stair climbing the absolute power output of obese resulted significantly higher (18%) than that of lean controls (p<0.001). In sprint running, the lower average horizontal velocity attained by obese subjects also entailed a different locomotion pattern with shorter step length (L(s); p<0.001), lower frequency (p<0.001) and longer foot contact time with ground (T(c,r); p<0.001). W(spec,j) seems to be a determinant of the poorer motor performance of obese, being significantly correlated with: I) the vertical displacement of the centre of gravity (R2=0.853, p<0.001) in jumping; II) with v(v) in stair climbing; and III) with T(c,r) (R2=0.492, p<0.001), L(s) (R2=0.266, p<0.001) and v (R2=0.454, p<0.001) in sprinting. The results suggest that obese individuals, although partially hampered in kinetic movements, largely rely on their effective specific power output to perform complex anaerobic tasks, and they suffer from the disproportionate excess of inert mass of fat. Furthermore, in view of the sedentary style of life and the consequent degree of muscle de-conditioning accompanying this condition, it may prove useful to implement rehabilitation programs for obesity with effective power training protocols.

Short-term changes of cardiovascular risk factors after a non-pharmacological body weight reduction program.

OBJECTIVE: To test the short-term effectiveness of a 3 week hospital-based body weight reduction (BWR) program on selected coronary heart disease (CHD) risk factors in obese subjects. DESIGN: Intervention study to assess the modifications in CHD risk factor scores estimated according to Framingham risk factor categories (age, total cholesterol, high density lipoprotein (HDL) cholesterol, blood pressure, diabetes and smoking). SETTING: 3rd Division of Metabolic Diseases, Italian Institute for Auxology, Piancavallo (VB), Italy. SUBJECTS: Two-hundred and sixty-eight obese patients (43 men, 225 women, age range 19-81 y; body mass index (BMI) range 30-67). INTERVENTION: The BWR program consisted of a 3 week integrated energy-restricted diet (1200-1800 kcal/day), associated with moderate aerobic exercise, psychological counselling and educational lectures. RESULTS: Substantial reductions of total cholesterol (16.7%), HDL cholesterol (14.8%), systolic (11.2%) and diastolic blood pressure (8.7%) were observed at the end of the intervention, even with relatively moderate decrease in weight (4.1%) and in persistence of elevated BMI (over 40 kg/m2). The mean CHD Framingham score decreased by 16.1%, from 7.8 to 6.2. The BWR-induced changes were similar in both sexes, and across strata of age and BMI. CONCLUSIONS: The full-time participation of the patients in the hospital-based, integrated BWR program may explain the positive clinical outcome in all the subgroups considered, although the long-term results need to be quantified. SPONSORSHIPS: Partially supported by Progetti di Ricerca Corrente, Istituto Auxologico Italiano, IRCCS, Milan, Italy.

Plasma and urinary GH following a standardized exercise protocol to assess GH production in short children.

Plasma and urinary GH responses following acute physical exercise were evaluated in 19 short-statured children (12 males, 7 females, median age: 11.4 yr, age range: 6.1-14.5 yr, Tanner stage I-III, height < or = 3rd centile for age; 7 with familial short stature, FSS; 8 with constitutional growth delay, CGD; 4 with GH deficiency, GHD) and 7 normally growing, age- and sex-matched control children (4 males, 3 females, median age 11.0 yr, range: 7.2-13.1 yr, Tanner stage I-III). All patients and controls underwent a standardized exercise protocol (consisting of jogging up and down a corridor for 15 min, strongly encouraged to produce the maximum possible effort, corresponding to 70-80% of the maximal heart rate) after an overnight fasting. Samples for plasma GH determinations were drawn at 0 time (baseline), at 20 min (5 min after the end of exercise) and at 35 min (after 20 min of rest); urine samples were collected before (0 time) and at 40, 80 and 120 min after exercise. The distance covered by children with GHD during the test was significantly lower (p<0.05) than in the other groups of patients and controls. No differences in the pattern of plasma GH responses after physical exercise were found between children with FSS, CGD and healthy controls, the maximum percent increase (vs baseline) being evident at 20 min (median, FSS: +1125%; CGD: +1271%; controls: +571%). Children with GHD showed a smaller percent increase (+94%) of plasma GH, significantly lower (p<0.01) than those recorded in the other groups. A significant percent increase (p<0.01) of baseline urinary GH following exercise was found in children with FSS (median: +34%), CGD (+18%) and controls (+44%). Children with FSS and CGD showed a gradual increase of urinary GH, reaching the maximum at 80 min, while healthy controls had a more evident and precocious increase (maximum at 40 min). Urinary median GH levels did not change following physical exercise in children with GHD (-5%, not significant). A significant correlation was found between the maximal percent increase (vs baseline) of plasma and urinary GH following physical exercise (r=0.7, p<0.001). In conclusion, our results show that: 1) plasma and urinary GH responses (as well as the distance covered and the number of steps, i.e. the physical performance) to a standardized exercise protocol are similar in children with FSS, CGD and in normal-statured controls, being unable to differentiate among the "normal variants" of growth; 2) children with GHD, unable to accomplish the same performance of the other three groups, show significantly reduced plasma and urinary GH responses following physical exercise. Although the determination of GH responses to pharmacological stimuli remains the definitive tool for the diagnosis of GHD, these preliminary results seem to suggest a potential role of urinary (and plasma) GH response to a standardized exercise protocol as a safe, acceptable first screening test for GH sufficiency also in children, as previously reported in adults.

Effects of 12-month GH treatment on bone metabolism and bone mineral density in adults with adult-onset GH deficiency.

Serum bone-Gla protein (BGP), bone alkaline phosphatase (B-AP), and C-terminal cross-linked telopeptide of type I collagen (ICTP) levels were evaluated in 18 adults with acquired GH deficiency (GHD, 14 males and 4 females, age range: 25-59 yr) before, at 3, 6, 9 and 12 months of rec-GH treatment (0.125 IU/kg/week for the first month, followed by 0.25 IU/kg/week for 11 months) and 6 months after the withdrawal of therapy. Total body bone mineral density (BMD, g/cm2) was measured with dual energy X-ray absorptiometry (Hologic QDR 1000/W) before, at 12 months of GH treatment and 6 months after its withdrawal. Before treatment, BGP (mean+/-SE: 5.1+/-0.4 ng/ml), B-AP (59.4+/-6.5 IU/l), ICTP (3.1+/-0.3 ng/ml) levels of patients were similar to in healthy controls (BGP: 5.4+/-0.1 ng/ml; B-AP: 58.2+/-2.0 IU/l; ICTP: 4.1+/-0.3 ng/ml). GH treatment caused a significant increase of BGP, B-AP, ICTP levels, the maximal stimulation of bone resorption, occurring after 3 months of GH treatment, while the maximal effect on bone formation being evident later (at 6th month). A slight decline in BGP, B-AP, T-AP and ICTP levels occurred at 9-12 months of therapy, although the values remained significantly higher than in basal conditions and with respect to healthy controls. Before treatment, mean total body BMD of patients (1.110+/-0.027 g/cm2, range: 0.944-1.350 g/cm2) was not significantly different (z-score: +0.47+/-0.31, NS) from that observed in healthy controls (1.065+/-0.008 g/cm2, range: 1.008-1.121 g/cm2). GH therapy was associated with a significant reduction of mean total body BMD values (6th month: -1.8+/-0.5%, p<0.01; 12th month: -2.1+/-1.0%, p<0.05 vs baseline), particularly evident in the first six months of treatment. Six months after the withdrawal of GH therapy, BGP (5.9+/-0.5 ng/ml), B-AP (57.3+/-7.0 IU/l) and ICTP (3.2+/-0.1 ng/ml) levels returned similar to those recorded before treatment, while total BMD increased (+1.5+/-0.7, p<0.05), remaining however slightly lower than in basal conditions (-0.6+/-1.2, NS). In conclusion, our study shows that: a) acquired GHD in adulthood is associated with both normal bone formation/resorption indexes and normal total body BMD; b) GH therapy causes a significant rise of bone formation/resorption markers (earlier and greater for bone resorption); c) one-year GH therapy is associated with a reduction of total body BMD values, particularly evident in the first 6 months of treatment; d) the effects of GH therapy on bone turnover are transient, being completely reverted six months after the withdrawal of GH therapy; e) the increase of total body BMD (up to baseline values) after GH withdrawal might be explained as consequence of persisting effects of previous GH stimulation on bone remodeling.

Effects of a 16-week progressive high-intensity strength training (HIST) on indexes of bone turnover in men over 65 years: a randomized controlled study.

The aim of the present study was to evaluate the effects of a 16-week progressive high-intensity strength training (HIST) program on peripheral markers of bone turnover (bone Gla protein, BGP; bone alkaline phosphatase, B-AP; N-terminal propeptide of type I procollagen, PINP; C-terminal cross-linked telopeptide of type I collagen, ICTP) in healthy, elderly men over 65 yr of age. Thirty healthy men (aged 65-81 yr), performing light to moderate daily physical activity, were randomly divided into two groups. Group 1 (no.=16) followed a supervised 16-week progressive HIST program, while subjects of group 2 (no.=14), used as controls, were requested to maintain their habitual level of physical activity for 16 weeks. HIST program consisted of 6 different sets of exercise (2 involving the major muscle groups of the lower limb and 4 involving those of the upper limb). Three sessions/ week, during which 10 repetitions of each exercise set were completed, were performed. Lower limb exercises shifted from 50 to 80% of the one maximal repetition (1 MR) during the first month of the protocol and were thereafter maintained at an intensity of 80% 1 MR throughout the training. Upper limb exercises shifted from 40 to 65% of 1 MR with a similar pattern. All sessions were preceded by 15 min of cycloergometer exercise at 50% of maximal oxygen uptake and by a warm-up of 15 repetitions at 20% of 1 MR of each exercise set. The HIST program did not significantly change BGP (mean SE, before: 15.6 +/- 1.2 microg/l vs after: 16.0 +/- 1.2 microg/l, NS) and PINP levels (before: 44.6 +/- 6.7 microg/l vs after: 43.1 +/- 6.0 microg/l, NS). On the contrary, serum B-AP significantly increased (before: 50.2 +/- 6.1 IU/l vs after: 62.3 +/- 7.0 lU/l, p<0.001) and serum ICTP slightly reduced (before: 4.0 +/- 0.3 microg/l vs after: 3.8 +/- 0.3 microg/l, p<0.05). When bone turnover was expressed as the ratio between bone formation to bone resorption (B-AP/ICTP ratio), a significant improvement in this ratio was found in all subjects of group 1 (before: 12.9 +/- 1.3 lU/microg vs after: 17.3 +/- 1.5 IU/microg, p<0.0001), while no significant changes were observed in Group 2. No significant changes of IGF-I levels were observed after the HIST program (before: 94.9 +/- 9.4 microg/l vs after: 89.9 +/- 9.7 microg/l). No significant changes of BGP, PINP, B-AP, ICTP, B-AP-ICTP ratio and IGF-I levels were observed in controls (group 2) during the 16 weeks of observation. Although the positive effects of a progressive HIST program on B-AP levels and B-AP-ICTP ratio seem promising, the support of bone mass measurement and the determination of other bone markers are requested to better identify exercise protocol (duration, intensity) for elderly people.

Expression of menin gene mRNA in pituitary tumours.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder characterised by the combined occurrence of parathyroid, endocrine pancreas and anterior pituitary tumours. The gene responsible for MEN 1, the menin gene, a putative tumour-suppressor gene located on human chromosome 11q13, has been cloned. To investigate the role of the menin gene in sporadic anterior pituitary tumorigenesis, its mRNA was assessed in a group of pituitary tumours. METHODS: Menin gene expression, along with glyceraldehyde phosphate dehydrogenase (GAPDH) gene expression, has been studied in a group of normal pituitaries and in 23 pituitary tumours not associated with the MEN 1 syndrome. The pituitary tumours included 4 prolactinomas, 11 growth-hormone-secreting tumours and 8 non-functional tumours. Total RNA was extracted from the normal pituitaries and tumours, and cDNA was synthesised with standard reverse transcriptase methods. Duplex polymerase chain reaction (PCR) was standardised in order to quantify the expression of the menin gene using intron-spanning primers across exons 9 and 10 in relation to the 'house-keeping' gene GAPDH. The PCR products were separated on agarose gel and densitometric analysis of the bands allowed semi-quantification. RESULTS: There was no evidence for a change in menin gene expression in any of the pituitary tumours when compared with normal pituitaries. CONCLUSIONS: These studies complement previous work on mutational analysis, and do not suggest a major role for the menin suppressor gene in sporadic pituitary tumorigenesis.

Effect of acute and chronic administration of tamoxifen on GH response to GHRH and on IGF-I serum levels in women with breast cancer.

Tamoxifen, an estrogen antagonist, is usually employed in the treatment of breast cancer. Its mechanism of action is not well known because an antiproliferative effect of the drug has been shown also in estrogen receptor negative tumors, most likely mediated by the inhibition of local growth factors and particularly IGF-I. However, the action of tamoxifen on the GH-IGF-I axis is still open to investigation. We have investigated the influence of acute and chronic treatment with tamoxifen on GH response to GHRH and IGF-I serum levels in six postmenopausal women with metastatic breast cancer. A GHRH test (50 microg i.v. at time 0, GH determinations at 0, 15, 30, 60, 90 and 120 min) was performed (a) basally, (b) 3 h after 40 mg oral administration of tamoxifen and (c) after 8 weeks of 20 mg twice a day oral tamoxifen treatment. IGF-I was measured basally and after chronic tamoxifen therapy. No significant modifications in GH response to GHRH were observed after acute or chronic treatment with tamoxifen vs the basal test. On the contrary, chronic tamoxifen treatment induced a significant decrease in serum IGF-I levels. Basal pretreatment levels of 123+/-18 microg/l were suppressed to 65+/-11 microg/l (mean suppression 47%, P < 0.001). These preliminary data confirm the inhibitory effect of tamoxifen on IGF-I production but seem to exclude the possibility that this effect may be due to an inhibition of GH secretion.

Intracranial and spinal dissemination of an ACTH secreting pituitary neoplasia. Case report and review of the literature.

We report a case of a 52-year-old woman presenting with a recurrence of a large pituitary adenoma with suprasellar extension and an overt Cushing's clinical picture, five years after successful transsphenoidal treatment. After transfrontal ablation of the tumour, followed by external radiotherapy, she was asymptomatic for six years before she exhibited epileptic seizures. A left frontal intracranial neoplasm was diagnosed and removed, and at histological examination it was found to be constituted by a localization of the pituitary ACTH secreting neoplasia. One month later she exhibited spinal dissemination of the ACTH secreting neoplasia which was only partially removed. After four months a Magnetic Resonance Image (MRI) revealed recurrence of the intracranial localization and further spinal dissemination. Because of compressive symptoms, spinal masses with the same histologic features, were partially removed again in three successive surgical operations. Several medical treatments for obtaining the control of corticoid excess, caused by the ACTH overproduction, were tried, but none were satisfactory. Finally a bilateral adrenal venous embolization was performed thus obtaining a critical transient fall of serum cortisol. Five months later the patient died. At necroscopy bilateral adrenal enlargement was found, spinal disseminations were confirmed, and no metastatic lesions were discovered.