Peculiar response to methylphenidate in adolescent compared to adult rats: a phMRI study

Rationale  Adolescent rodents differ markedly from adults in several neuro-behavioural parameters. Moreover, ‘paradoxical’ responses to psychostimulants have been reported at this age. Objectives  Thus, we investigated the responses of adolescent (post-natal day, PND, 34 to 43) and adult (PND >60) Sprague–Dawley male rats to the psychostimulant drug methylphenidate (MPH). We used pharmacological magnetic resonance imaging (phMRI) performed at 4.7 T under isoflurane anaesthesia. Following anatomical MRI, axial gradient echo images were collected continuously. After baseline recording (32 min), animals received MPH (0 or 4 mg/kg i.p.) and were recorded for further 32 min. Results  Region-specific changes in the blood-oxygenation level dependent (BOLD) signal were evident as a function of age. As expected, among adults MPH induced an increase of BOLD signal in nucleus accumbens (NAcc) and prefrontal cortex (PFC), with no effects in the hippocampus (Hip). Notably, among adolescents, MPH induced a marked and generalised decrease of BOLD signal, which occurred earlier in NAcc and PFC whilst being delayed in the Hip. Any bias in BOLD responses was excluded by the measurement of physiological parameters. Conclusions  The present findings highlight the utility of phMRI in animal models. The peculiar negative BOLD effect found in adolescent rats may be suggestive of a reduced cerebro-vascular feedback and/or an increased MPH-induced neuronal activation. Data are relevant for a better understanding of brain/behavioural regulation during adolescent development. Moreover, a greater understanding of the differences between adult and adolescent drug responses will aid in the development of a more appropriate age-specific treatment strategy. Rossella Canese and Walter Adriani contributed equally to this work.     

Relationship between P-glycoprotein activity measured in peripheral blood mononuclear cells and indinavir bioavailability in healthy volunteers

Indinavir, a HIV-1 protease inhibitor, showed large inter-individual pharmacokinetic variability. It has been proposed as a substrate of P-glycoprotein (P-gp), an efflux transporter, that may contribute to limit indinavir bioavailability. A liquid formulation of indinavir was developed from indinavir capsules in order to study indinavir pharmacokinetics in healthy volunteers. Compartmental and noncompartmental analysis of indinavir plasma concentrations showed high inter-individual variability in terms of area under the curve (AUC) and maximal plasma concentration (C(max)). A significant negative association between AUC normalized to body weight (AUC x weight) and lymphocyte P-gp activity, using Rh123 efflux assay, was observed (p = 0.008; r = -0.75). AUC normalized to elimination rate constant (AUC x beta) also showed a significant negative relationship with lymphocyte P-gp activity (p = 0.03, r = -0.64). Apparent clearance (CL/[F x weight]) and volume of distribution (VD/[F x weight]) showed a positive correlation with P-gp activity. Conversely, elimination rate constant did not correlate with P-gp activity. Although there is not enough evidence of a correlation between lymphocitary and intestinal function of P-gp, our results suggest a relationship between a P-gp phenotype marker, Rh123 efflux assay in lymphocytes, and indinavir bioavailability.     

Hypothermia-induced J waves

A 36 years old woman with acquired immunodeficiency syndrome was admitted to the hospital for pulmonary Mycobacterium Avis Complex infection. Seventy-two hours after the admission she became hypothermic and bradycardic. The ECG showed sinus bradycardia, J waves in leads II, III, aVF, aVR, aVL, V5 and V6 along with QT prolongation and T wave abnormalities. After rewarming the J waves and repolarization abnormalities disappeared. The proposed cellular basis of hypothermia-induced J waves is the accentuation of the spike-and-dome morphology of the action potential of M and epicardial cells.     

Quality of life and seizure control in patients with brain tumor-related epilepsy treated with levetiracetam monotherapy: preliminary data of an open-label study

The aim of this pilot study was to investigate the effects of levetiracetam monotherapy on seizure control, quality of life and neurocognitive performance in patients with brain tumor-related epilepsy. We present here preliminary data from 18 patients with follow-up of 6 months. We evaluated seizure frequency at baseline. We used administered Mini Mental State Examination (MMSE), Karnofsky Performance Status (KPS), Barthel index (BI), QOLIE 31P (V2), EORTC QLQ-C30 and Adverse Events Profile. After 6 months, 16 patients were seizure free (88.9%), 2 (11.1%) had reduction in seizure frequency >50%. Compared to baseline, we observed a worsening of performance (KPS p = 0.011; BI = 0.008) and global lower cognitive performance (MMSE p = 0.011); distress related to seizure frequency (p = 0.003) and medication effects (p = 0.046) were significantly lower. Levetiracetam caused mild and reversible side effects. These preliminary data on LEV monotherapy in patients with brain tumor-related epilepsy show that this antiepileptic drug is efficacious and well tolerated.     

Clinical evaluation of the use of exemestane as further hormonal therapy after nonsteroidal aromatase inhibitors in postmenopausal metastatic breast cancer patients

OBJECTIVES:The aromatase inhibitors Anastrozole, Letrozole (type 2 nonsteroidal aromatase inhibitors: n-SAI) and Exemestane (type 1 steroidal aromatase inactivator) are used respectively as first- and second-line hormonal therapy in postmenopausal metastatic breast cancer women. Few clinical data are published on the sequential use of different classes of aromatase inhibitors. METHODS: We report an analysis on 30 postmenopausal metastatic breast cancer women treated between January 2000 and May 2002 in 2 Italian Oncology Institutions with the hormonal sequence n-SAI (Anastrozole, Letrozole) --> Exemestane. RESULTS: When receiving n-SAI (Anastrozole 8 patients and Letrozole 22 patients), 1 out of 30 women achieved a partial response, 20 of 30 patients no change (NC) > or =6 months. The analysis of the entire population treated with Exemestane showed an overall clinical benefit (CB) of 46.6 percent (14/30) with a median duration of 12 months (95%CI 6-25) and a median time to progression (TTP) of 4 months (95%CI 1-25). CONCLUSIONS: These data confirm a partial lack of cross-resistance between n-SAI --> Exemestane given in sequence.     

Squamous-cell carcinoma and osteomyelitis: three cases and a review of the literature

Chronic osteitis and squamous-cell carcinoma is a rare but classically described association. We report three cases of chronic tibial osteitis which developed open leg trauma. During the surveillance, after a latency period of several years, local signs developed leading to biopsy which provided the diagnosis of degenerative carcinomatosis. Search for locoregional extension or metastatic dissemination was negative. All three patients underwent amputation with good results. This small series, together with a review of the literature, enabled us to describe the principle epidemiological and diagnostic features, focusing on early signs. The appropriate management scheme remains to be determined although amputation, which some may consider as a failure, should not be postponed indefinitely.     

Comparison of different culture media and growth conditions for recognition of Arcanobacterium haemolyticum

Detection of Arcanobacterium haemolyticum is based upon typical beta-hemolysis and colony morphology, but it may go undetected if only conventional sheep blood agar media for detection of beta-hemolytic streptococci are used. The influence of different culture media, atmospheres, and times of incubation for the recognition of colonies of 47 isolates of A. haemolyticum was studied. After 48 h of incubation, trypticase soy agar with 5% horse blood in 5% CO(2) was the best medium.     

Brain radiotherapy during treatment with anticonvulsant therapy as a trigger for toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN) is a severe mucocutaneous syndrome that can be occasionally caused by anticonvulsant drugs. In some cases, cranial irradiation may act as a precipitating factor. Thus, in cancer patients who suffer from brain metastases and are administered antiepileptic drugs for seizure prophylaxis, the risk of developing TEN after receiving palliative brain radiotherapy cannot be ignored. We is reported. The case of a young patient with non-small cell lung cancer (NSCLC) treated with prophylactic phenobarbital who developed TEN within a few days of completing cranial radiotherapy for brain metastases is reported. To minimize the risk of TEN in patients undergoing brain radiotherapy, prophylactic anticonvulsant therapy is recommended only after an accurate measurement of the true benefits. Alternatively, discontinuation of antiepileptic treatment before the initiation of brain radiotherapy, or the use of anticonvulsants associated with a lower risk of developing cutaneous reactions might be considered.     

Factors associated with clinically significant hypoglycemia in patients with type 1 diabetes using sensor-augmented pump therapy with predictive low-glucose management: A multicentric study on iberoamerica

Background and aimsDespite using sensor-augmented pump therapy (SAPT) with predictive low-glucose management (PLGM), hypoglycemia is still an issue in patients with type 1 Diabetes (T1D). Our aim was to determine factors associated with clinically significant hypoglycemia (<54 mg/dl) in persons with T1D treated with PLGM-SAPT.Methodology: This is a multicentric prospective real-life study performed in Colombia, Chile and Spain. Patients with T1D treated with PLGM-SAPT, using sensor ≥70% of time, were included. Data regarding pump and sensor use patterns and carbohydrate intake from 28 consecutive days were collected. A bivariate and multivariate Poisson regression analysis was carried out, to evaluate the association between the number of events of <54 mg/dl with the clinical variables and patterns of sensor and pump use.Results188 subjects were included (41 ± 13.8 years-old, 23 ± 12 years disease duration, A1c 7.2% ± 0.9). The median of events <54 mg/dl was four events/patient/month (IQR 1–10), 77% of these events occurred during day time. Multivariate analysis showed that the number of events of hypoglycemia were higher in patients with previous severe hypoglycemia (IRR1.38; 95% CI 1.19–1.61; p < 0.001), high glycemic variability defined as Coefficient of Variation (CV%) > 36% (IRR 2.09; 95%CI 1.79–2.45; p < 0.001) and hypoglycemia unawareness. A protector effect was identified for adequate sensor calibration (IRR 0.77; 95%CI 0.66–0.90; p:0.001), and the use of bolus wizard >60% (IRR 0.74; 95%CI 0.58–0.95; p:0.017).ConclusionIn spite of using advanced SAPT, clinically significant hypoglycemia is still a non-negligible risk. Only the identification and intervention of modifiable factors could help to prevent and reduce hypoglycemia in clinical practice.