Blood pressure response to the first dose of angiotensin-converting enzyme inhibitors in congestive heart failure

Angiotensin-converting enzyme (ACE) inhibitors improve survival in heart failure and delay progression to clinical heart failure in patients with left ventricular dysfunction after myocardial infarction. Increasing numbers of older patients are being considered for such treatment. However, there are reports of excessive and prolonged decreases in blood pressure (BP) after the first dose of some ACE inhibitors. We have studied the hemodynamics, pharmacokinetics, and neurohumoral responses to the first dose of oral captopril 6.25 mg, enalapril 2.5 mg, perindopril 2.0 mg, intravenous enalaprilat 1.5 mg, and perindoprilat 1.0 mg, compared with oral or intravenous placebo in 6 parallel groups of 12 elderly patients each with moderate-to-severe (New York Heart Association classes II-IV) heart failure. Oral dosing with active drugs led to different temporal responses. After captopril, there was an early short-lived decrease in BP. Enalapril led to a later long-lasting decrease, but perindopril was not different from placebo. Intravenous enalaprilat and intravenous perindoprilat each lowered BP to a similar extent. The doses of drugs used appeared to be comparable because plasma ACE inhibition was similar following perindopril or enalapril and also comparing perindoprilat and enalaprilat. These studies indicate that oral ACE inhibitors have different profiles of acute BP changes after the first dose. The explanation is not clear, but could include physicochemical differences in the interaction between prodrug ester and diacid metabolites leading to differences in tissue distribution and local enzyme inhibition.     

Long-term outcomes for Kienböck's disease

Background

The precise etiology of Kienböck's disease is unclear. Controversy exists regarding the appropriate treatment modality. The present study sought to investigate and compare surgical and nonsurgical treatment outcomes of patients suffering from Kienböck's disease in the province of Newfoundland and Labrador (NL), Canada.

Methods

The present study was a retrospective analysis of 66 patients. The primary outcome was the Disabilities of the Arm, Shoulder, and Hand (DASH) score. Student's t test was used to assess differences in outcomes between treatment groups. One-way ANOVA was used to assess differences in primary outcome in time since first assessed in an effort to examine progression over time. Pearson correlation was used to assess for correlation between primary outcome and age at diagnosis.

Results

The average age was 38.6?±?11.4 (18–70) years; Four patients were excluded due to inaccessible imaging. Of the remaining patients, 44 were treated conservatively, while 18 were treated surgically. The DASH scores for the surgical group were 23.7?±?24.5 (0.9–82.8) and nonsurgical group were 20.0?±?20.1 (1.7–81). As expected, the surgical group was mainly comprised of late-stage Kienböck's. When both groups were compared, there was no significant difference in the DASH scores. There were no difference in DASH scores within groups according to time since first diagnosed (<5 years; between 5 and 10 years; and >10 years). A positive correlation was found between age at diagnosis and DASH score (r?=?0.42, p?=?0.007), despite treatment modality. This finding remained significant after accounting for confounding factors (p?=?0.029).

Conclusion

The DASH score for the surgical group was 23.7?±?24.5 (0.9–82.8) and nonsurgical group was 20.0?±?20.1 (1.7–81). No significant difference in DASH scores was found between surgically and nonsurgically treated patients. A positive association was found between the age at diagnosis of Kienböck's and DASH score, which suggests that patients diagnosed and treated later in life tend not to do as well.     

Lack of differential motor outcome with subthalamic nucleus region stimulation in Parkinson’s disease

Deep brain stimulation (DBS) has emerged as a viable therapy for Parkinson’s disease (PD). The impact of subthalamic nucleus (STN) lead placement (lateral versus medial) on motor outcome, however, has not been systematically evaluated. Forty-eight patients with PD underwent STN-DBS surgery and were evaluated postoperatively for 48 weeks for motor improvement as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III (standardized motor examination) and levodopa equivalent daily dose (LEDD). Postoperative MRI was used to identify the location of the active stimulating contact and motor outcome was analyzed. STN-DBS was associated with significant improvement in motor outcome as determined by a reduction in the UPDRS part III subscore from 34.44 ± 1.29 at baseline to 18.76 ± 1.06 at end visit (p < 0.0001) and a reduction in LEDD from 1721 ± 152 mg/day at baseline to 1134 ± 119 mg/day at end visit (p = 0.0024). Patients with stimulating contacts in the medial STN compared to the lateral STN did not demonstrate any significant differences in motor outcome (UPDRS, p = 0.5811; LEDD, p = 0.7341). No significant differences were found in motor outcome between patients with STN stimulation compared to stimulation of surrounding fiber tracts (p = 0.80). No significant difference in stimulation voltage was noted with respect to lead location. Our study did not find a significant effect for the location of active contact and motor outcome neither within the subregions of the STN nor between the STN and surrounding fibers. Further research is needed to better understand the neurophysiological basis for these results.     

Characterization of trisomy 8 in pediatric undifferentiated sarcomas using advanced molecular cytogenetic techniques

Pediatric undifferentiated soft tissue sarcomas (USTS) are a rare group of neoplasms that are unclassifiable despite the application of immunohistochemical, cytogenetic, and molecular techniques. To date, there is a dearth of studies looking at the cytogenetic and molecular genetic alterations in such tumors. Trisomy 8, a frequent molecular alteration in neoplasia, is seen in several soft tissue sarcomas, including Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), synovial sarcoma, and leiomyosarcoma. Because USTS share several clinicobiological features with the aforementioned tumors, the occurrence of alterations in chromosome 8 was studied in 11 pediatric USTS using a combination of interphase fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), and genomic profiling with oligonucleotide array comparative genomic hybridization (aCGH). The copy number status of MYC was also assessed on the same tumors using dual-color FISH, with the aim of delineating the degree and intratumoral distribution of MYC amplification in this tumor. A near-uniform presence of an increase in MYC copy number was observed, along with an increase in chromosome 8 copy number in all the tumors. SKY and aCGH analysis of tumors exhibiting trisomy 8 confirmed the numerical imbalances. The occurrence of trisomy 8 in a subset of pediatric USTS confirms a shared genomic alteration with several other soft tissue sarcomas. Further studies are required to determine the clinical implications of such a finding.     

Liposomal delivery of methylphosphonate antisense oligodeoxynucleotides in chronic myelogenous leukemia [see comments]

Chronic myelogenous leukemia (CML) is a hematologic malignancy characterized by the presence of the Philadelphia (Ph) chromosome. Bcr- abl, the fusion gene associated with the Ph chromosome, expresses a p210bcr-abl protein that promotes a selective expansion of mature myeloid progenitor cells. Methylphosphonate (MP) oligodeoxynucleotides complementary to specific regions of the bcr-abl mRNA were incorporated in liposomes. We studied the effects of liposomal MP (L-MP) on the growth inhibition of CML-like cell lines. L-MP targeted to the breakpoint junctions of the bcr-abl mRNA inhibited the growth of CML cells. Fifty percent inhibition was achieved at approximately 1 mumol/L of L-MP oligonucleotide concentrations. The inhibitory effect was selective because growth inhibition was observed only with CML but not with control cell lines. Moreover, CML cell growth inhibition was dependent on the sequence of the MP oligodeoxynucleotides incorporated in the liposomes. The growth inhibition of CML cells by L-MP resulted from selective inhibition of the expression of the p210bcr-abl protein.     

Plasma N terminal pro-brain natriuretic peptide and cardiotrophin 1 are raised in unstable angina

OBJECTIVE—To compare circulating concentrations of N terminal pro-brain natriuretic peptide (N-BNP) and cardiotrophin 1 in stable and unstable angina.
DESIGN AND SETTING—Observational study in a teaching hospital.
PATIENTS—15 patients with unstable angina, 10 patients with stable angina, and 15 controls.
MAIN OUTCOME MEASURES—Resting plasma N-BNP and cardiotrophin 1 concentrations.
RESULTS—N-BNP concentration (median (range)) was 714 fmol/ml (177-3217 fmol/ml) in unstable angina, 169.5 fmol/ml (105.7-399.5 fmol/ml) in stable angina (p = 0.005 v unstable angina), and 150.5 fmol/ml (104.7-236.9 fmol/ml) in controls (p < 0.0001 v unstable angina; NS v stable angina). Cardiotrophin 1 concentration was 142.5 fmol/ml (42.2-527.4 fmol/ml) in unstable angina, 73.2 fmol/ml (41.5-102.1 fmol/ml) in stable angina (p < 0.05 v unstable angina), and 27 fmol/ml (6.9-54.1 fmol/ml) in controls (p < 0.0005 v stable angina; p < 0.0001 v unstable angina). Log cardiotrophin 1 correlated with log N-BNP in unstable angina (r = 0.93, p < 0.0001).
CONCLUSIONS—Both circulating N-BNP and cardiotrophin 1 are raised in unstable angina, while cardiotrophin 1 alone is raised in stable angina. The role of cardiotrophin 1 and the relation between cardiotrophin 1 and N-BNP in myocardial ischaemia remain to be defined.


Keywords: cardiotrophin 1; brain natriuretic peptide; angina pectoris