The glass transition and sub-T(g)-relaxation in pharmaceutical powders and dried proteins by thermally stimulated current

The main goal of the study was to evaluate the applicability of thermally stimulated current (TSC) as a measure of molecular mobility in dried globular proteins. Three proteins, porcine somatotropin, bovine serum albumin, and immunoglobulin, as well as materials with a strong calorimetric glass transition (T(g)), that is, indomethacin and poly(vinypyrrolidone) (PVP), were studied by both TSC and differential scanning calorimetry (DSC). Protein/sugar colyophilized mixtures were also studied by DSC, to estimate calorimetric T(g) for proteins using extrapolation procedure. In the majority of cases, TSC detected relaxation events that were not observed by DSC. For example, a sub-T(g) TSC event (beta-relaxation) was observed for PVP at approximately 120 degrees C, which was not detected by the DSC. Similarly, DSC did not detect events in any of the three proteins below the thermal denaturation temperature whereas a dipole relaxation was detected by TSC in the range of 90-140 degrees C depending on the protein studied. The TSC signal in proteins was tentatively assigned as localized mobility of protein segments, which is different from a large-scale cooperative motions usually associated with calorimetric T(g). TSC is a promising method to study the molecular mobility in proteins and other materials with weak calorimetric T(g).     

Comparison of the prognostic value of SPECT after nitrate administration and metabolic imaging by PET in patients with ischaemic left ventricular dysfunction

Purpose We compared the prognostic value of ^99mTc-tetrofosmin single-photon emission computed tomography (SPECT) after nitrate administration and positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) in patients with ischaemic left ventricular (LV) dysfunction. Methods Eighty-nine patients with previous myocardial infarction and LV dysfunction (LV ejection fraction 33 ± 10%) underwent ^99mTc-tetrofosmin SPECT under control conditions (baseline) and after sublingual administration of 10 mg of isosorbide dinitrate (nitrate). Within 1 week, all patients underwent PET imaging with ¹⁸F-FDG. Four patients were excluded because of inadequate FDG uptake caused by severe diabetes. Follow-up data were obtained by phone contact with patients and by review of hospital or physicians’ records. Cardiac death, myocardial infarction and late revascularisation for unstable angina were considered as events. Follow-up data were not available in three patients. Follow-up was 96% complete at a mean period of 29 ± 19 months. Results At baseline SPECT, 59 (72%) patients had evidence of viable myocardium, while 23 did not. Of these latter patients, 12 (52%) demonstrated viable myocardium after nitrate and 13 (56%) had preserved metabolic activity. Cardiac events (cardiac death, myocardial infarction and late revascularisation for unstable angina) occurred in 24 (29%) patients. Event-free survival was similar in patients with and patients without viable myocardium at baseline SPECT (p = 0.8). In contrast, event-free survival was lower in patients with viable myocardium at nitrate SPECT and PET compared to those without viable myocardium (both p<0.05). Conclusion In patients with ischaemic LV dysfunction, the prognostic value of SPECT imaging after nitrate is comparable to that of PET metabolic imaging.     

Past, present, and future prospects of medication-overuse headache classification

The 1988 classification by the International Headache Society (IHS) first defined drug-induced headache as a specific disorder, belonging to secondary headaches, subtype 8.2 (headache induced by chronic substance use or exposure). In 2004 ICHD-II, this definition was replaced by medication-overuse headache (MOH). It was established that a definite diagnosis of MOH required the improvement of the disorder after cessation of medication overuse. The specific characteristics of the various subforms were also indicated. Later revisions have first eliminated these headache characteristics and then the diagnosis of probable MOH. The diagnosis of MOH has therefore become more useful to clinical aims. However, the last revision has eliminated the need to prove that the disorder is caused by drugs, that is, the headache improves after cessation of medication overuse. The classification of MOH as a secondary headache has therefore been modified, too. Clinical trials can consequently include in the same group patients with primary headache and drug overuse and patients with MOH.
We therefore propose to continue to use the diagnosis of probable MOH to research aims. We also propose to modify the classification of MOH subforms according to the presence or absence of a dependence-producing property of overused drugs. This will allow to better analyze the role of the various medications in inducing chronic headache and the outcomes of treatments.     

Surgical treatment of congenital pseudarthrosis of the clavicle: a report on 17 cases

Congenital pseudarthrosis of the clavicle (CPC) is a rare malformation of uncertain aetiopathogenesis, usually unilateral. Physical examination reveals swelling over the midportion of the clavicle, often asymptomatic; the diagnosis is confirmed by radiology. Treatment is controversial: for many authors the surgical indications are the presence of symptoms, functional impairment or cosmetic deformities. We present a retrospective analysis of 17 children with CPC treated in our institutions: 9 were treated with plate (P) and 8 with Kirschner wire (KW) fixation; a bone graft was used in 12 cases only. Five patients (4 P and 1 KW) needed a second surgical procedure. The surgical treatment led to a very good result in 7 cases, good in 4 cases, fair in 3 cases and poor in 3 other cases. We recommend early treatment of all patients with CPC with resection of the pseudarthrosis, autologous iliac bone grafting and internal fixation with Kirschner wires.     

Thalidomide in combination with oral daily cyclophosphamide in patients with pretreated hormone refractory prostate cancer: a phase I clinical trial

AIM: This is a phase I study investigating the toxicity and the potential efficacy of thalidomide and oral cyclophosphamide in patients with hormone refractory prostate cancer (HRPC), previously treated with docetaxel-based regimens. METHODS: Two dose levels of thalidomide (100 and 200 mg every day) were studied. Patients were accrued to each dose level in cohorts of 3 starting from dose 1 level (100 mg). Thalidomide was started on day 1 at the assigned dose and continued for four consecutive weeks; oral cyclophosphamide (50 mg for day) was given for four consecutive weeks (1 cycle) starting on the same day initiating thalidomide. Toxicity was evaluated every two weeks; changes in prostate-specific antigen (PSA) levels were evaluated every cycle. Treatment was planned for four cycles. RESULTS: Sixteen men were treated. Ten patients in cohort 1, and 6 in cohort 2 were enrolled respectively. Grade 1-2 constipation, peripheral neuropathy and fatigue were the most common side effects, noted in 6 (37.5%), 5 (31.25%) and 3 (19%) patients, respectively. Three patients stopped the treatment at level 2, during the first cycle, for toxicity. Those three patients were evaluable only for toxicity. The MTD was 100 mg thalidomide. Thirteen patients completed two cycles. Two patients (15%) had a >50% decrease in PSA, while in one patient (8%) the PSA decrease was less of 50%. Overall PSA decrease was of 23%. CONCLUSIONS: The oral combination of thalidomide and cyclophosphamide is well tolerated and appears to be associated with biochemical response in this population. Future phase II trials, in pre-treated and untreated patients, are needed to evaluate clinical efficacy of this regimen in HRPC.     

Patients' desire to preserve sexual activity and final decision for a nerve-sparing approach: results from the MIRROR (Multicenter Italian Report on Radical Prostatectomy Outcomes and Research) Study

IntroductionPreservation of sexual function after surgery represents a major issue for patients undergoing radical prostatectomy (RP).AimTo investigate determinants of patients’ desire to preserve sexual activity before RP and surgeons’ final decision to perform a nerve-sparing RP (NSRP).MethodsOverall, 2,408 prostate cancer patients, candidates to RP, from 136 urologic departments across the Italian territory were evaluated in a multicenter prospective observational study. All patients underwent RP, according to single-center indications and procedures.Main Outcome MeasuresAge, body mass index, previous benign prostatic hyperplasia history, preoperative tumor characteristics, quality of life through the Short Form Health Survey (SF-12), and the University of California Los Angeles Prostate Cancer Index (UCLA-PCI), erectile function through the International Index of Erectile Function (IIEF-5), desire to preserve sexual activity, NS operative outcomes, and surgical margins status were recorded.ResultsOverall, 1,667 were interested to preserve sexual activity. Age, physical component summary of SF12 (PCS-12), sexual function score of UCLA-PCI, and IIEF-5 score were the main determinants of such interest. Only 1,246 patients were suitable for a NSRP according to guidelines. Surgeons performed a non-NSRP (NNSRP) in 1,234 patients, a unilateral NSRP in 318 and a bilateral NSRP in 856. Age, bioptical Gleason score, percentage of positive cores, PCS-12, and patient's desire to preserve sexual activity were the main determinants of final decision for a NSRP. Surgeons performed a NSRP in 424 not suitable and in 121 not interested patients. Positive surgical margins in not suitable patients submitted to NSRP were not higher if compared to that obtained after NNSRP in the same subgroup. Limits include lack of oncological and functional follow-up.ConclusionsMost patients are interested to preserve sexual activity. Discrepancies exist among patients’ preferences, guidelines’ indications, and surgeon's final decision. Imbimbo C, Creta M, Gacci M, Simonato A, Gontero P, de Cobelli O, Briganti A, Fulcoli V, Martorana G, Nicita G, Mirone V, and Carmignani G. Patients’ desire to preserve sexual activity and final decision for a nerve-sparing approach: results from the M.I.R.R.O.R. (Multicenter Italian Report on Radical prostatectomy Outcomes and Research) study.