Biochemical and biological activity of the anthracycline analog, 4-demethyl-6-0-methyl-doxorubicin

Summary The chromophore-modified derivative of doxorubicin, 4-demethyl-6-0-methyl-doxorubicin, has been tested for antitumor activity in a range of experimental murine tumor systems. In contrast to the inactive 6-0-methyl derivative of daunorubicin, 4-demethyl-6-0-methyl-doxorubicin provided antitumor effects comparable to that of the parent compound. In addition, detailed DNA-interaction studies showed that the doxorubicin derivative retains the ability to bind DNA by the intercalation mechanism. However, the binding affinity was appreciably reduced following structural modification in the anthraquinone chromophore. On the basis of the proposed models of intercalation, these results could be rationalized in terms of steric influence of the bulky methoxy group. The results of this study are in agreement with the correlation already observed between DNA binding and relative antitumor activity of anthracyclines.     

Immunological and echocardiographic evaluation of decellularized versus cryopreserved allografts during the Ross operation.

OBJECTIVE: Compare the immunological and echocardiographic data of decellularized versus cryopreserved allografts used for RVOT reconstruction during Ross operation. METHODS: From 16/01/03 thru 07/10/03, 20 Ross operations were performed using decellularized (n=11) or cryopreserved (n=9) allografts. Echocardiography was done at discharge, 1, 3, 6 and 12 months and annually thereafter. Samples for determination of antibodies against HLA class I and II were obtained preoperatively and at days 5, 10, 30, 90 and 180 postoperatively. These samples were tested by the ELISA method in LAT-M dishes (unspecific) for identification of circulating antibodies and the results expressed as mean sample values (Is=DO/cutoff). If positive, LAT-E (specific) was performed and PRA levels determined. RESULTS: There was no mortality. Cryopreserved allografts showed marked Is values elevations for class I and II antibodies which started at the first month and remained elevated up to 6 months. In contrast, of the patients receiving decellularized allografts, seven remained negative, two patients had only marginal elevation of class I antibodies and two patients showed abnormal elevations of PRA levels. This response happened earlier than in the cryopreserved group, starting on the 5th postoperative day and has returned to baseline levels in one case. Echocardiography showed mild, but significant, elevation of gradients in cryopreserved valves but none in the decellularized. CONCLUSIONS: Decellularized allografts had normal function up to 18 months and showed important reduction of the immunogenic response when compared to cryopreserved valves.     

Botulinum toxin and neuromotor rehabilitation: An integrated approach to idiopathic cervical dystonia.

Currently, the best treatment option for idiopathic cervical dystonia (ICD) is injection of botulinum toxin (BTX) into the affected muscles, whereas rehabilitative approaches have given disappointing results. We evaluated whether the association of an ad hoc rehabilitative program may improve the clinical efficacy of BTX treatment in a single-center, cross-over, controlled study. Forty patients with ICD were randomly assigned to two different treatment groups: (1) BTX type A (BTX-A) plus a specific program of physical therapy (BTX-PT) or (2) BTX-A alone (BTX-0). Patients in the BTX-PT group showed a longer duration of the clinical benefit (118.8 vs. 99.1 days) and needed a lower dose of BTX at reinjection (284.5 vs. 325.5 units). In addition, they showed more marked reductions in their disability in activities of daily living (-9.7 vs. -4.85 points) and subjective pain (-13.35 vs. 6.95 points) scores. Association of BTX-A therapy with a specific program of physical therapy may improve ICD treatment outcome.     

The clinical phenotypes of juvenile bipolar disorder: toward a validation of the episodic-chronic-distinction.

BACKGROUND: Recent research has addressed the issue of subtyping juvenile bipolar disorder (JBD). Accordingly, we set out to find out, in a naturalistic sample of bipolar children and adolescents with mania and mixed mania, whether the most useful subtyping should be based on clinical features (elated vs. irritable) or course (episodic vs. chronic). METHODS: We studied 136 patients, 81 male patients (59.6%) and 55 female patients (40.4%), mean age 13.5 +/- 2.9 years, meeting the DSM-IV diagnosis of bipolar disorder, assessed by a structured clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version [K-SADS-PL]). RESULTS: Regarding course, 77 patients (56.6%) had an episodic course and 59 patients (43.4%) had a chronic course. Patients with chronic course were significantly younger, had an earlier onset of JBD, and presented a more frequent comorbidity with disruptive behavior disorders. According to the prevalent mood disturbance, 75 patients (55.1%) showed an elated and 61 patients (44.9%) showed an irritable mood. Elated mood was more frequent in patients with episodic course, whereas irritable mood was more frequent in the patients with chronic course. CONCLUSIONS: These findings suggest that chronic versus episodic course may be a putative differential feature. Further validation of such a distinction would require prospective studies, temperament evaluation, gender and neurobiologic approaches, and differential psychopharmacologic assignment and response.     

Estimation of salt intake by urinary sodium excretion in a Portuguese adult population and its relationship to arterial stiffness.

BACKGROUND: Portugal has one of the highest mortality rates from stroke, a high prevalence of hypertension and probably a high salt intake level. AIM: To evaluate Portuguese salt intake levels and their relationship to blood pressure and arterial stiffness in a sample of four different adult populations living in northern Portugal. METHODS: A cross-sectional study evaluating 24-hour urinary excretion of sodium (24 h UNa+), potassium and creatinine, blood pressure (BP), and pulse wave velocity (PWV) as an index of aortic stiffness in adult populations of sustained hypertensives (HT), relatives of patients with previous stroke (Fam), university students (US) and factory workers (FW), in the context of their usual dietary habits. RESULTS: We evaluated a total of 426 subjects, mean age 50 +/- 22 years, 56% female, BMI 27.9+/-5.1, BP 159/92 mmHg, PWV 10.4+/-2.2 m/s, who showed mean 24h UNa+ of 202 +/- 64 mmol/d, corresponding to a daily salt intake of 12.3 g (ranging from 5.2 to 24.8). The four groups were: HT: n = 245, 49 +/- 18 years, 92% of those selected, 69% treated, BP 163/94 mmHg, PWV 11.9 m/s, 24 h UNa+ 212 mmol/d, i.e. 12.4 g/d of salt); Fam: n = 38, 64 +/- 20 years, 57 % of those selected, BP 144/88 mmHg, PWV 10.5 m/s, 24 h UNa+ 194 mmol/d, i.e. 11.1 g/d of salt; US: n = 82, 22 +/- 3 years, 57% of those selected, BP 124/77 mmHg, PWV 8.7 m/s, 24h UNa+ 199 mmol/d, i.e. 11.3 g/d of salt; FW: n = 61, 39 9 years, 47% of those selected, BP 129/79 mmHg, PWV 9.5 m/s, 24 h UNa+ 221 mmol/d, i.e. 12.9 g/d of salt. The ratio of urinary sodium/potassium excretion (1.9 (0.4) was significantly higher in HT than the other three groups. In the 426 subjects, 24h UNa+ correlated significantly (p < 0.01) with systolic BP (r = 0.209) and with PWV (r=0.256) after adjustment for age and BP. Multivariate analysis showed that BP, age and 24h UNa+ correlated independently with PWV taken as a dependent variable. CONCLUSIONS: Four different Portuguese populations showed similarly high mean daily salt intake levels, almost double those recommended by the WHO. Overall, high urinary sodium excretion correlated consistently with high BP levels and appeared to be an independent determining factor of arterial stiffness. These findings suggest that Portugal in general has a high salt intake diet, and urgent measures are required to restrict salt consumption in order to prevent and treat hypertensive disease and to reduce overall cardiovascular risk and events.     

Hepatic UDP-glucose 13C isotopomers from [U-13C]glucose: a simple analysis by 13C NMR of urinary menthol glucuronide.

Menthol glucuronide was isolated from the urine of a healthy 70-kg female subject following ingestion of 400 mg of peppermint oil and 6 g of 99% [U-(13)C]glucose. Glucuronide (13)C-excess enrichment levels were 4-6% and thus provided high signal-to-noise ratios (SNRs) for confident assignment of (13)C-(13)C spin-coupled multiplet components within each (13)C resonance by (13)C NMR. The [U-(13)C]glucuronide isotopomer derived via direct pathway conversion of [U-(13)C]glucose to [U-(13)C]UDP-glucose was resolved from [1,2,3-(13)C(3)]- and [1,2-(13)C(2)]glucuronide isotopomers derived via Cori cycle or indirect pathway metabolism of [U-(13)C]glucose. In a second study, a group of four overnight-fasted patients (63 +/- 10 kg) with severe heart failure were given peppermint oil and infused with [U-(13)C]glucose for 4 hr (14 mg/kg prime, 0.12 mg/kg/min constant infusion) resulting in a steady-state plasma [U-(13)C]glucose enrichment of 4.6% +/- 0.6%. Menthol glucuronide was harvested and glucuronide (13)C-isotopomers were analyzed by (13)C NMR. [U-(13)C]glucuronide enrichment was 0.6% +/- 0.1%, and the sum of [1,2,3-(13)C(3)] and [1,2-(13)C(2)]glucuronide enrichments was 0.9% +/- 0.2%. From these data, flux of plasma glucose to hepatic UDPG was estimated to be 15% +/- 4% that of endogenous glucose production (EGP), and the Cori cycle accounted for at least 32% +/- 10% of GP.     

Significance of cyclin D1 expression in meningiomas: a preliminary study.

Forty-four evaluable patients with intracranial meningiomas were assessed for the expression of the cell-cycle regulator cyclin D1 and of proteins involved in proliferation and apoptosis such as PCNA, MIB-1, p53 and bcl-2. Analyses were carried out by western blot and immunohistochemistry after immediate processing of fresh tumor specimens. By western blot, expression of cyclin D1 significantly correlated with p53 (p=0.02) and with proliferative activity, as assessed by PCNA expression (p=0.0009). By immunohistochemistry, a significant relationship between cyclin D1 and the proliferation marker MIB-1 was confirmed (p=0.05), whereas significance with bcl-2 expression was not found (p=0.01). Moreover, although the association with tumor grade appeared of borderline statistical significance (p=0.07), all the grade II/III meningiomas showed increased expression of cyclin D1 and high proliferative activity. In conclusion, data from this preliminary study seem to suggest a potential value of the combined expression of cyclin D1 and proliferation indicators in defining subgroups of meningiomas with a more aggressive biological behavior.     

Right upper lobe 'window' in right main bronchus stenting.

Stent insertion for bronchial stenosis has become common practice in lung transplantation and advanced lung malignancy, and for external compression of the airways for other reasons. Right main bronchus stenting may require blocking the right upper lobe by the stent, placing the patient at risk of recurrent pneumonia and atelectasis. In this study, three patients after insertion of a metal stent to the right main bronchus are described. In all cases, the right upper lobe was covered by the stent, and a laser (Nd:YAG) procedure was used to open a 'window' in the stent toward the right upper lobe with a follow-up of 1 year. We conclude that stent insertion to the right main bronchus may be followed by a laser therapy to open a 'window' toward the right upper lobe.