Anatomical integration and rich-club connectivity in euthymic bipolar disorder.

BACKGROUND: Although repeatedly associated with white matter microstructural alterations, bipolar disorder (BD) has been relatively unexplored using complex network analysis. This method combines structural and diffusion magnetic resonance imaging (MRI) to model the brain as a network and evaluate its topological properties. A group of highly interconnected high-density structures, termed the 'rich-club', represents an important network for integration of brain functioning. This study aimed to assess structural and rich-club connectivity properties in BD through graph theory analyses. METHOD: We obtained structural and diffusion MRI scans from 42 euthymic patients with BD type I and 43 age- and gender-matched healthy volunteers. Weighted fractional anisotropy connections mapped between cortical and subcortical structures defined the neuroanatomical networks. Next, we examined between-group differences in features of graph properties and sub-networks. RESULTS: Patients exhibited significantly reduced clustering coefficient and global efficiency, compared with controls globally and regionally in frontal and occipital regions. Additionally, patients displayed weaker sub-network connectivity in distributed regions. Rich-club analysis revealed subtly reduced density in patients, which did not withstand multiple comparison correction. However, hub identification in most participants indicated differentially affected rich-club membership in the BD group, with two hubs absent when compared with controls, namely the superior frontal gyrus and thalamus. CONCLUSIONS: This graph theory analysis presents a thorough investigation of topological features of connectivity in euthymic BD. Abnormalities of global and local measures and network components provide further neuroanatomically specific evidence for distributed dysconnectivity as a trait feature of BD.

Neurobiological trait abnormalities in bipolar disorder.

Dissecting trait neurobiological abnormalities in bipolar disorder (BD) from those characterizing episodes of mood disturbance will help elucidate the aetiopathogenesis of the illness. This selective review highlights the immunological, neuroendocrinological, molecular biological and neuroimaging abnormalities characteristic of BD, with a focus on those likely to reflect trait abnormalities by virtue of their presence in euthymic patients or in unaffected relatives of patients at high genetic liability for illness. Trait neurobiological abnormalities of BD include heightened pro-inflammatory function and hypothalamic-pituitary-adrenal axis dysfunction. Dysfunction in the intracellular signal transduction pathway is indicated by elevated protein kinase A activity and altered intracellular calcium signalling. Consistent neuroimaging abnormalities include the presence of ventricular enlargement and white matter abnormalities in patients with BD, which may represent intermediate phenotypes of illness. In addition, spectroscopy studies indicate reduced prefrontal cerebral N-acetylaspartate and phosphomonoester concentrations. Functional neuroimaging studies of euthymic patients implicate inherently impaired neural networks subserving emotional regulation, including anterior limbic, ventral and dorsal prefrontal regions. Despite heterogeneous samples and conflicting findings pervading the literature, there is accumulating evidence for the existence of neurobiological trait abnormalities in BD at various scales of investigation. The aetiopathogenesis of BD will be better elucidated by future clinical research studies, which investigate larger and more homogenous samples and employ a longitudinal design to dissect neurobiological abnormalities that are underlying traits of the illness from those related to episodes of mood exacerbation or pharmacological treatment.

Oral gemifloxacin once daily for 5 days compared with sequential therapy with i.v. ceftriaxone/oral cefuroxime (maximum of 10 days) in the treatment of hospitalized patients with acute exacerbations of chronic bronchitis.

In a randomized, open-label, controlled, multicentre study, the clinical and bacteriological efficacy, safety and tolerability of oral gemifloxacin (320 mg once daily, 5 days) was compared with sequential intravenous (i.v.) ceftriaxone (1 g once daily, maximum 3 days) followed by oral cefuroxime axetil (500 mg twice daily, maximum 7 days) in adult hospitalized patients with acute exacerbations of chronic bronchitis (AECB) (n = 274). The clinical success rates at follow-up (21-28 days post-therapy) in the clinical per-protocol population (the primary endpoint) were 86.8% (105/121) for gemifloxacin vs. 81.3% (91/112) for ceftriaxone/cefuroxime (treatment difference = 5.5,95% CI -3.9,14.9). The corresponding clinical results in the clinical intention-to-treat (ITT) population were 82.6% (114/138) vs. 72.1% (98/136), respectively (treatment difference = 10.5,95% CI 0.7, 20.4).Thus, gemifloxacin had significantly higher clinical success rates than ceftriaxone/cefuroxime. The median time to discharge was 9 days in the gemifloxacin group vs. 11 days in the ceftriaxone/cefuroxime group (P = 0.04, Wilcoxon test). At follow-up, 120/138 (87.0%) gemifloxacin-treated patients had been discharged from hospital, compared with 111/136 (81.6%) ceftriaxone/cefuroxime-treated patients in the clinical ITT population. Both treatments were generally well tolerated and there was no significant difference between the treatment groups in the incidence or type of adverse events reported. A 5-day course of oral gemifloxacin was shown by this study to be at least equivalent to sequential i.v. ceftriaxone/cefuroxime axetil (for up to 10 days) in patients with AECB who require hospital treatment.

International study comparing cefdinir and cefuroxime axetil in the treatment of patients with acute exacerbation of chronic bronchitis.

OBJECTIVES: To assess the efficacy and tolerability of three antibiotic regimens in patients with acute exacerbation of chronic bronchitis. METHODS: In this double-blind, randomized, multicentered, parallel-group study, patients received once-daily cefdinir 600 mg, twice-daily cefdinir 300 mg, or twice-daily cefuroxime axetil 250 mg for 10 days. Primary efficacy measures were microbiologic eradication rate, by pathogen and by patient, and clinical response rate, by patient. RESULTS: Of 1045 patients, 589 were evaluable for efficacy. At baseline, most patients had moderate or severe cough and sputum production as well as rhonchi, wheezing, and dyspnea. The microbiologic eradication rates by pathogen were 90% with once-daily cefdinir, 85% with twice-daily cefdinir, and 88% with twice-daily cefuroxime. The corresponding values for microbiologic eradication rate by patient were 90% (once-daily cefdinir), 85% (twice-daily cefdinir), and 86% (twice-daily cefuroxime). The respective clinical response rates by patient were 81%, 74%, and 80%. There were no significant differences in the incidence of drug-related adverse events or discontinuations due to adverse events. Diarrhea was the most frequent complaint. CONCLUSIONS: The results indicate that the efficacy and tolerability of cefdinir, once or twice daily, and cefuroxime were comparable with no significant differences between the regimens used.

Assessing patient outcomes in acute exacerbations of chronic bronchitis: the measure your medical outcome profile (MYMOP), medical outcomes study 6-item general health survey (MOS-6A) and EuroQol (EQ-5D).

There is little published information on the measurement of health status or quality of life in acute exacerbations of chronic bronchitis. The measure yourself medical outcome profile (MYMOP), the medical outcomes study 6-item general health survey (MOS-6A), and EuroQoL (EQ-5D) were evaluated in 81 patients with acute exacerbations of Type-1 chronic bronchitis presenting at a single general practice centre in Glasgow. The questionnaires were administered at the first clinic visit and at a second visit within 1 week of treatment completion. Item scores for MYMOP were generally more responsive than those for the other instruments, as assessed by standardised response means and an index of responsiveness for those patients reporting minimal change between visits. Construct validity was demonstrated for the MYMOP by the gradient in score change with the patient's perceived change in clinical condition and by the relationship between score change and the physician's assessment of clinical outcome. This study demonstrated that the MYMOP is a valid and potentially useful instrument for the assessment of patient outcomes in acute exacerbations of chronic bronchitis and is more responsive than the MOS-6A or EQ-5D in this setting. The choice of instrument will vary according to the objective of the study.

Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis.

The efficacy and safety of grepafloxacin were compared with clarithromycin in a randomized, double-blind, multicentre clinical trial of 805 patients with acute bacterial exacerbations of chronic bronchitis (ABECB). Patients were randomized to receive grepafloxacin 400 mg od for either 5 (n = 273) or 10 days (n = 268) or clarithromycin 250 mg bd for 10 days (n = 261). Patients were assessed pre-treatment, 3-5 days during treatment, 1-3 days post-treatment and at follow-up (21-28 days post-treatment). The clinical success rates for the evaluable patients were 91% in the 5 day grepafloxacin group, 95% in the 10 day grepafloxacin group and 86% in the clarithromycin group. At follow-up, respective rates were 72%, 81% and 73%. A total of 513 pathogens were isolated from the pre-treatment sputum specimens of 400 (49%) patients. The primary pathogens were Haemophilus influenzae (36% of isolates), Haemophilus parainfluenzae (27%), Moraxella catarrhalis (12%), Streptococcus pneumoniae (11%) and Staphylococcus aureus (3%). Pathogens were eradicated or presumed eradicated at post-treatment in 85%, 91% and 58% of evaluable patients treated with grepafloxacin for 5 days, grepafloxacin 10 days and clarithromycin 10 days, respectively. The eradication rates in both grepafloxacin groups were significantly greater than the clarithromycin group (P<0.001). All treatments were well tolerated and incidence of drug-related adverse events in each group was comparable. This study demonstrates that both a 5 and a 10 day regimen of grepafloxacin 400 mg od are as clinically and bacteriologically effective as in the treatment of ABECB clarithromycin 250 mg bd. for 10 days.

Short-course cefuroxime axetil therapy in the treatment of acute exacerbations of chronic bronchitis.

The efficacy and safety of a five-day course of cefuroxime axetil (250 mg b.d.) and a seven-day course of clarithromycin (250 mg b.d.) were compared in a large double-blind, randomised, multinational study involving 684 patients with acute exacerbations of chronic bronchitis. In an intent-to-treat analysis, the post-treatment clinical responses to each treatment were comparable (82%) and rates at follow-up were similar: 64% on cefuroxime axetil and 61% on clarithromycin. Pre-treatment pathogens were isolated from a total of 192 patients, Haemophilus influenzae being the most common. Overall pathogen eradication rates were similar for both treatments. Both treatments were well tolerated. In conclusion, a five-day course of cefuroxime axetil is clinically equivalent to a seven-day course of clarithromycin in the treatment of acute exacerbations of chronic bronchitis, and may have potential socioeconomic benefits.

Comparison of the efficacy and safety of a short course of ceftibuten with that of amoxycillin/clavulanate in the treatment of acute exacerbations of chronic bronchitis.

The efficay and safety of short course ceftibuten (400 mg od for 5 days; n = 163) were compared with that of amoxycillin/clavulanate (AMX/CA) (250/125 mg tds for 10 days; n = 172) in a multicentre, single-blind, parallel-group trial in 335 adults with acute exacerbations of chronic bronchitis (AECB). Clinical response was equivalent, with cure or improvement in 134/145 (92.4%) ceftibuten-treated patients and 139/150 (92.7%) AMX/CA-treated patients (95% CI: -7.00%, +6.50%). The overall eradication rates were similar (ceftibuten 88.3%; AMX/CA 87.5%) and also the incidence of adverse events which occurred in 24/163 (14.7%) ceftibuten-treated and 27/172 (15.5%) AMX/CA-treated patients. Ceftibuten 400 mg od for 5 days is as effective and well tolerated as AMX/CA 250 mg tds for 10 days in the treatment of AECB.

Stability of spatial working memory across the estrous cycle of Long-Evans rats.

In the adult rat, hippocampal dendritic synaptic connectivity in region CA1 fluctuates across the estrous cycle. This study examined the potential functional impact of such fluctuations on spatial working memory in regularly cycling Long-Evans rats. Rats were trained in a delayed non-match-to-sample radial-arm maze task and performance was monitored across the estrous cycle. There were no significant alterations in the acquisition or performance of the working memory task across the estrous cycle, with 1- or 4-h delays imposed between training and testing sessions. However, rats performed the task significantly more slowly on proestrus than on any other estrous cycle day under both delay conditions. These results indicate that while working memory remains stable, sensorimotor or motivational aspects of the performance of this radial-arm maze task may vary across the estrous cycle.

The effects of 17 alpha-methyltestosterone, methandrostenolone, and nandrolone decanoate on the rat estrous cycle.

In a series of four separate experiments, the effects of anabolic-androgenic steroid (AAS) compounds on the estrous cycle of adult Long-Evans rats were examined. Sexual receptivity, vaginal cytology, and body weight were monitored throughout a 2-week baseline, AAS treatment, and recovery periods. In Experiments 1-3, subjects were administered 17 alpha-methyltestosterone, methandrostenolone, or nandrolone decanoate at doses selected to mimic the human abuse levels of each compound. In these studies, the highest doses of 17 alpha-methyltestosterone (7.5 mg/kg) and nandrolone decanoate (5.6 mg/kg) disrupted behavioral and vaginal cyclicity, whereas the highest dose of methandrostenolone (3.75 mg/kg) appeared to have slightly less robust effects. To compare effects on estrous cyclicity across AAS compounds, subjects in Experiment 4 received a single high dose (7.5 mg/kg) of each compound for 2 weeks. At this dose, all AAS compounds interfered with vaginal cyclicity, although effects on behavioral cyclicity and uterine weight were not uniform. Across all 4 experiments, AAS effects on body weight were minimal. The short-term administration of AAS compounds at levels commonly used by humans disrupts female neuroendocrine function in a dose-dependent manner.

Randomized, double-blind study of grepafloxacin versus amoxycillin in patients with acute bacterial exacerbations of chronic bronchitis.

This randomized, multicentre, double-blind, double-dummy study compared the efficacy and safety of grepafloxacin and amoxycillin in acute bacterial exacerbations of chronic bronchitis (ABECB). Patients were randomized to receive grepafloxacin 400 mg or 600 mg od, or amoxycillin 500 mg tds, for 7 or 10 days. The trial recruited 656 patients, of whom 566 (86%) completed the study. Clinical success rates at the 2 week follow-up visit for the population evaluable for clinical efficacy were 82% (165/202 patients) in the grepafloxacin 400 mg group, 85% (175/206) in the grepafloxacin 600 mg group and 85% (172/203 patients) in the amoxycillin group. The 95% confidence interval confirmed the equivalence of the two grepafloxacin doses and amoxycillin, with no significant difference between the grepafloxacin groups. The microbiological success rates at follow-up showed equivalence between the grepafloxacin 400 mg and amoxycillin groups: 86% (144/168 isolates) and 83% (162/195), respectively. The grepafloxacin 600 mg group achieved a statistically significantly higher eradication rate (92%, 150/164; 95% CI 2.0%, 16.1%) than the amoxycillin group in the follow-up assessment for microbiological and clinical efficacy (evaluable population). There was no significant difference between the two grepafloxacin treatment groups (95% CI -13.3%, 0.9%; P= 0.087). All three treatment regimens successfully eradicated the pathogens most commonly isolated during the study, including Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae. Grepafloxacin had a good safety profile, comparable to that of amoxycillin, although grepafloxacin 600 mg was associated with a higher incidence of nausea, dyspepsia and taste perversion than amoxycillin. It can be concluded that grepafloxacin 400 mg or 600 mg od is as effective as amoxycillin 500 mg tds in the treatment of ABECB.

A barium enema training programme for radiographers: a pilot study.

We describe a training programme designed to instruct radiographers how to perform the double contrast barium enema (DCBE). The programme was assessed by comparing the first 50 unsupervised examinations with studies performed by senior registrars in radiology. Comparison was made by marking each study blind in terms of barium coating, colonic distension and visualisation of the colon in double contrast. A note was also made of the number of exposures, screening time, examination time and complications. No difference was found in any of these parameters when comparing the two groups. A further 50 patients were assessed at one year and this showed that standards had been maintained in terms of the above criteria. Follow-up at 3 years in the initial group has shown no missed pathology. We believe that delegation of the performance of the DCBE to radiographers is both acceptable to the patient and safe.

Assessment of theophylline compliance in general practice using a 'compliance index' based on apparent drug clearance.

The monitoring of compliance in outpatients using serum drug levels suffers from the difficulty of relating concentrations to changes in dosage. Clearance is independent of dose for most drugs, and may be predicted using a Bayesian based forecasting program. This paper describes how the apparent clearance obtained following a single drug analysis can be compared with the Bayesian population value to derive a Compliance Index. In compliant individuals with stable hepatic and renal function this index should remain constant. We evaluated the usefulness of the Compliance Index in general practice with patients prescribed theophylline. Of 54 patients examined on up to five occasions, only 12% were deemed to be fully compliant at all times. Compliance improved during the study, but worsened again once regular consultation ceased. The results indicate that such a Compliance Index is a viable method of assessing compliance with the aid of concentration measurements.

The isolation of thymidine-requiring Haemophilus influenzae from the sputum of chronic bronchitic patients receiving trimethoprim.

Two different strains of thymidine-requiring Haemophilus influenzae (thy-) were isolated from the sputum of two patients with chronic obstructive airways disease, during therapy with oral trimethoprim for the treatment of an acute exacerbation of chronic bronchitis. Both patients responded clinically. Since trimethoprim levels in sputum and serum were very low the patients were probably non-compliant. Isolates of H. influenzae prototrophic for thymidine (thy+) were isolated from both patients in remission before, at the onset of exacerbation and also within two weeks of stopping therapy. Thy- and thy+ isolates from the same patient were of identical biotype but isolates from the two patients were of different biotypes. The minimum inhibitory concentration (MIC) of trimethoprim for the thy+ isolates obtained after therapy was significantly higher than the MIC for the isolates obtained at the onset of exacerbation. Thy- isolates were further investigated and a novel mechanism of low-level trimethoprim resistance is proposed.

A study of difficult respiratory infections in general practice.

Augmentin was used to treat 40 patients in general practice with exacerbations of bronchiectasis or chronic obstructive airways disease who had not responded clinically to treatment with antimicrobial agents. After ten days treatment 15 patients (38%) were clinically free from infection, 21 (52%) had improved but their sputum still contained pus. Four patients (10%) did not respond to treatment. Pathogens were isolated from 63 per cent of the patients; Haemophilus influenzae was the most common. The clinical response was significantly better in patients from whom recognised pathogens were not isolated.