Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine.

BACKGROUND: Intranasal dexmedetomidine produces safe, effective sedation in children and adults. It may be administered by drops from a syringe or by nasal mucosal atomisation (MAD NasalTM). METHODS: This prospective, three-period, crossover, double-blind study compared the pharmacokinetic (PK) and pharmacodynamic (PD) profile of i.v. administration with these two different modes of administration. In each session each subject received 1 µg kg-1 dexmedetomidine, either i.v., intranasal with the atomiser or intranasal by drops. Dexmedetomidine plasma concentration and Ramsay sedation score were used for PK/PD modelling by NONMEM. RESULTS: The i.v. route had a significantly faster onset (15 min, 95% CI 15-20 min) compared to intranasal routes by atomiser (47.5 min, 95% CI 25-135 min), and by drops (60 min, 95%CI 30-75 min), (P<0.001). There was no significant difference in sedation duration across the three treatment groups (P=0.88) nor in the median onset time between the two modes of intranasal administration (P=0.94). A 2-compartment disposition model, with transit intranasal absorption and clearance driven by cardiac output using the well-stirred liver model, was the final PK model. Intranasal bioavailability was estimated to be 40.6% (95% CI 34.7-54.4%) and 40.7% (95% CI 36.5-53.2%) for atomisation and drops respectively. Sedation score was modelled via a sigmoidal Emax model driven by an effect compartment. The effect compartment had an equilibration half time 3.3 (95% CI 1.8-4.7) min-1, and the EC50 was estimated to be 903 (95% CI 450-2344) pg ml-1. CONCLUSIONS: There is no difference in bioavailability with atomisation or nasal drops. A similar degree of sedation can be achieved by either method. CLINICAL TRIAL REGISTRATION: HKUCTR-1617.

Effects of bone density alterations on strain patterns in the pelvis: application of a finite element model.

Insufficiency fractures occur when physiological loads are applied to bone deficient in mechanical resistance. A better understanding of pelvic mechanics and the effect of bone density alterations could lead to improved diagnosis and treatment of insufficiency fractures. This study aimed to develop and validate a subject-specific three-dimensional (3D) finite element (FE) model of a pelvis, to analyse pelvic strains as a function of interior and cortical surface bone density, and to compare high strain regions with common insufficiency fracture sites. The FE model yielded strong agreement between experimental and model strains. By means of the response surface method, changes to cortical surface bone density using the FE model were found to have a 60 per cent greater influence compared with changes in interior bone density. A small interaction was also found to exist between surface and interior bone densities (< 3 per cent), and a non-linear effect of surface bone density on strain was observed. Areas with greater increases in average principal strains with reductions in density in the FE model corresponded to areas prone to insufficiency fracture. Owing to the influence of cortical surface bone density on strain, it may be considered a strong global (non-linear) indicator for insufficiency fracture risk.

Psychometric properties of a generic health measure in Chinese patients with low back pain in Hong Kong.

In Hong Kong, the measurement of perceived health status in patients with low back pain (LBP) can be facilitated by the availability of a health profile specifically designed for the Chinese culture. This prospective observational study investigated the psychometric properties of the generic Current Perceived Health 42 (CPH42) Profile in four separate samples (totalling 473) of Chinese patients with LBP in Hong Kong. The patients completed the CPH42 Profile and the Roland LBP Disability Scale at various points in the course of physiotherapy. Their pain intensity was measured using the 11-point pain numerical rating scale (NRS). The test-retest reliability and internal consistency of the CPH42 Profile demonstrated high intra-class correlation coefficient of 0.92 and Cronbach's alpha of 0.90. Validity was confirmed by a moderate correlation with the Chinese adaptations of the Roland LBP Disability Scale and the NRS at the commencement of physiotherapy (Spearman's correlation coefficients were 0.48 and 0.42, respectively). The responsiveness, measured from the commencement of physiotherapy to weeks 3 and 6 (standard response means of 0.33 and 0.58, respectively), were commensurate with the respective changes in pain intensity. The psychometric properties of the CPH42 Profile suggest its suitability for use as an outcome instrument in future efficacy studies on LBP intervention.

Characterization of AFMP1: a novel target for serodiagnosis of aspergillosis.

We cloned the AFMP1 gene, which encodes the first antigenic cell wall galactomannoprotein in Aspergillus fumigatus. AFMP1 codes for a protein, Afmp1p, of 284 amino acid residues, with a few sequence features that are present in Mp1p, the antigenic cell wall mannoprotein in Penicillium marneffei that we described previously, as well as several other cell wall proteins of Saccharomyces cerevisiae and Candida albicans. It contains a serine- and threonine-rich region for O glycosylation, a signal peptide, and a putative glycosylphosphatidyl inositol attachment signal sequence. Specific anti-Afmp1p antibody was generated with recombinant Afmp1p protein purified from Escherichia coli to allow further characterization of Afmp1p. Afmp1p has a high affinity for Galanthus nivalis agglutinin, a characteristic indicative of a mannoprotein. Furthermore, it was recognized by a rat monoclonal antibody against the galactofuran side chain of galactomannan, indicating that it is a galactomannoprotein. Ultrastructural analysis by immunogold staining indicated that Afmp1p is present in the cell walls of the hyphae and conidia of A. fumigatus. Finally, it was observed that patients with aspergilloma and invasive aspergillosis due to A. fumigatus develop a specific antibody response against Afmp1p. This suggested that the recombinant protein and its antibody may be useful for serodiagnosis in patients with aspergilloma or invasive aspergillosis, and the protein may represent a good cell surface target for host humoral immunity.

Identification of slide coagulase positive, tube coagulase negative Staphylococcus aureus by 16S ribosomal RNA gene sequencing.

AIMS: To ascertain the clinical importance of a strain of slide coagulase positive but tube coagulase negative Staphylococcus species isolated from the blood culture of a 43 year old patient with refractory anaemia with excessive blasts in transformation who had neutropenic fever. METHODS: The isolate was investigated phenotypically by standard biochemical methods using conventional biochemical tests and two commercially available systems, the Vitek (GPI) and API (Staph) systems. Genotypically, the 16S ribosomal RNA (rRNA) gene of the bacteria was amplified by the polymerase chain reaction (PCR) and sequenced. The sequence of the PCR product was compared with known 16S rRNA gene sequences in the GenBank by multiple sequence alignment. RESULTS: Conventional biochemical tests did not reveal a pattern resembling a known Staphylococcus species. The Vitek system (GPI) showed that it was 94% S. simulans and 3% S. haemolyticus, whereas the API system (Staph) showed that it was 86.8% S. aureus and 5.1% S. warneri. 16S rRNA gene sequencing showed that there was a 0 base difference between the isolate and S. aureus, 28 base difference between the isolate and S. lugdunensis, 39 base difference between the isolate and S. schleiferi, 21 base difference between the isolate and S. haemolyticus, 41 base difference between the isolate and S. simulans, and 23 base difference between the isolate and S. warneri, indicating that the isolate was a strain of S. aureus. Vancomycin was subsequently prescribed and blood cultures taken four days after the start of treatment were negative. CONCLUSIONS: 16S rRNA gene sequencing was useful in ascertaining the clinical importance of the strain of slide coagulase positive but tube coagulase negative Staphylococcus species isolated from blood culture and allowing appropriate management.

Identification of Mycobacterium neoaurum isolated from a neutropenic patient with catheter-related bacteremia by 16S rRNA sequencing.

A rapidly growing pigmented mycobacterial strain with an ambiguous biochemical profile was isolated from the blood culture taken through the Hickman catheter of a 9-year-old girl with acute lymphoblastic leukemia. Whole-cell fatty acid analysis showed that the best match profile was that of Mycobacterium aurum, but the similarity index was only 0.217, meaning that there were no good matches between the isolate and the organisms in the database of the Microbial Identification System. The 16S rRNA gene of the mycobacterial strain was amplified, agarose gel purified, and sequenced. There were 44 base differences between the gene sequence of the isolate and that of M. aurum but only one base difference between the sequence of the isolate and that of Mycobacterium neoaurum, showing that the isolate was indeed a strain of M. neoaurum by using this "gold standard." This represents the first case of M. neoaurum infection documented by 16S rRNA sequencing.

Use of a subjective health measure on Chinese low back pain patients in Hong Kong.

STUDY DESIGN: A prospective observational study on the use of the Aberdeen Low Back Pain Disability Scale. OBJECTIVE: To evaluate the reliability, validity, and responsiveness of the Chinese adaptation of the Aberdeen Low Back Pain Scale in Chinese patients in Hong Kong who have back pain. SUMMARY OF BACKGROUND DATA: Frontline clinicians, researchers, and health care managers in Hong Kong are urgently in need of a Chinese adaptation of a low back pain outcome measure that has been subjected to a rigorous process of psychometric and clinical testing. METHODS: Four samples with 473 consecutive adult patients with low back pain from six physiotherapy outpatient departments in Hong Kong who completed the Aberdeen Low Back Pain Scale were observed and measured at time points including the beginning physiotherapy; 10 days, 3 weeks, and 6 weeks after physiotherapy; and when discharged from treatment. RESULTS: The test-retest reliability coefficient was 0.94 (0.94 in the original English version; figures from the English version are reported in parentheses). The Cronbach alpha coefficient was 0.85 (0.80). The Spearman correlation coefficient, when the Aberdeen score was correlated with that of a generic current 42-item questionnaire regarding the patient's perceived health to establish cross-sectional construct validity, was 0.59 (0.36-0.66, with the Short Form 36 scale). The effect sizes (responsiveness) at weeks 3 and 6 after treatment began were 0.59 and 0.81, respectively (a high of 0.62 reported in the English version). CONCLUSIONS: The Chinese version of the Aberdeen Low Back Pain Disability Scale retained the high levels of reliability, validity, and responsiveness of the original English version when tested in Hong Kong in four samples of Chinese patients with low back pain.

Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism.

OBJECTIVE: To determine whether control of hyperthyroidism during pregnancy reduces the risk of low birth weight infants and severe preeclampsia. METHODS: Labor, delivery, and postpartum records of 181 hyperthyroid women were reviewed for maternal and fetal outcomes. Subjects were separated into three groups based on their thyroid status: controlled (n = 34), including women who were euthyroid at presentation and delivery; controlled during pregnancy (n = 90), including women who were hyperthyroid at presentation and euthyroid at delivery; and uncontrolled (n = 57), including women who were hyperthyroid at presentation and delivery. RESULTS: The risk of low birth weight infants was 0.74 (95% confidence interval [CI] 0.18-3.08) among controlled women, 2.36 (95% CI 1.36-4.12) among women who were controlled during pregnancy, and 9.24 (95% CI 5.47-15.6) among women who were uncontrolled during pregnancy compared to the incidence among nonhyperthyroid mothers. The risk of severe preeclampsia was significantly higher (odds ratio 4.74, 95% CI 1.14-19.7) among uncontrolled women compared with those who were controlled during their pregnancies. Elevated TSH-receptor antibody levels were not related to preeclampsia. Maternal thioamide therapy did not adversely affect neonatal outcomes. CONCLUSION: Lack of control of hyperthyroidism significantly increases the risk of low birth weight infants and severe preeclampsia.

Uterine rupture after previous cesarean delivery: maternal and fetal consequences.

OBJECTIVE: The purpose of this study was to identify the risk factors associated with overt, catastrophic uterine rupture and to report maternal and neonatal outcomes. The associated elapsed time window for delivery of an uncompromised neonate was also investigated. STUDY DESIGN: A retrospective study with review of charts and monitor strips was performed. RESULTS: Between Jan. 1, 1983, and June 30, 1992, there were 106 cases of uterine rupture at our institution. Of these, seven charts were incomplete and excluded; of the remainder, 28 patients had complete, 13 patients had partial, and 58 patients had no fetal extrusion into the maternal abdomen. Maternal characteristics or intrapartum events were not predictive of the catastrophic extent of uterine rupture. There was one maternal death. Complete fetal extrusion was associated with a higher incidence of perinatal mortality and morbidity. Significant neonatal morbidity occurred when > or = 18 minutes elapsed between the onset of prolonged deceleration and delivery. CONCLUSION: Neonatal and maternal complications in uterine rupture with complete fetal extrusion were low with prompt intervention.

Risk factors associated with uterine rupture during trial of labor after cesarean delivery: a case-control study.

OBJECTIVE: The purpose of our study was to thoroughly investigate the risk factors of uterine rupture in patients undergoing trial of labor after cesarean section. STUDY DESIGN: We conducted a case-control study of 70 patients with prior cesarean delivery with uterine rupture during trial of labor between January 1983 and June 1990. The risk factors of uterine rupture were identified, and the estimates of the relative risks were reported. RESULTS: The risk of uterine rupture was increased in patients who had an excessive amount of oxytocin, who had experienced dysfunctional labor, and who had a history of two or more cesarean deliveries. Epidural anesthesia, macrosomia, history of successful vaginal delivery after cesarean section, unknown uterine scar, and history of cesarean delivery because of cephalopelvic disproportion were not associated with uterine rupture. CONCLUSIONS: We recommend that all patients with a history of cesarean delivery be observed closely for progression of labor. Recognition of an active-phase arrest disorder, despite adequate augmentation with oxytocin, requires operative delivery.

Perinatal outcome in hypothyroid pregnancies.

OBJECTIVE: To relate hypothyroidism to perinatal outcome. METHODS: A cohort of 68 hypothyroid patients with no other medical illnesses was divided into two groups according to the initial thyroid function tests. The first group had 23 women with overt hypothyroidism, and the second had 45 subjects with subclinical hypothyroidism. We sought to identify the pregnancy outcomes of gestational hypertension, low birth weight, fetal death, congenital anomalies, maternal anemia, and postpartum hemorrhage. RESULTS: Gestational hypertension--namely, eclampsia, preeclampsia, and pregnancy-induced hypertension--was significantly more common in the overt and subclinical hypothyroid patients than in the general population, with rates of 22, 15, and 7.6%, respectively. In addition, 36% of the overt and 25% of the subclinical hypothyroid subjects who remained hypothyroid at delivery developed gestational hypertension. Low birth weight in both overt and subclinical hypothyroid patients was secondary to premature delivery for gestational hypertension. Except for one stillbirth and one case of clubfeet, hypothyroidism was not associated with adverse fetal and neonatal outcomes. CONCLUSION: Normalization of thyroid function tests may prevent gestational hypertension and its attendant complications in hypothyroid patients.