Ischaemic heart disease in young hypertensive women.

The association between hypertension and ischaemic heart disease was explored in a retrospective analysis of 50 severely hypertensive premenopausal women (presenting diatolic pressure greater than or equal to 120 mmHg) under 45 years of age who were seen over a seven-year period. Twenty-two per cent of these patients had angina pectoris, and 38 per cent had Minnesota code 4-1 or 5-1 changes on the resting electrocardiogram. The contribution of other risk factors, including smoking habits, was assessed: 72 per cent of the patients smoked; significantly less smoking was found among two groups of age-matched women with less severe hypertension [diastolic pressures of 90 to 104 mmHg (n=50) and 105 to 119 mmHg (n=50)]. In these latter groups, only one patient had angina pectoris and none had 4-1 or 5-1 changes on the electrocardiogram.     

Action of intravenously administered aminophylline on normal airways

The changes in airway caliber and plasma cyclic-AMP levels after intravenously administered aminophylline, and the effect of DL- and D-propranolol on these responses have been investigated in a double-blind manner in normal subjects. Aminophylline 5.6 mg/kg was given intravenously over a 10-min period and the airway response was measured as change in specific airway conductance (delta SGaw) in the body plethysmograph. In the initial study in 6 subjects, orally administered placebo or propranolol was followed 2 h later by intravenously administered aminophylline. Neither placebo nor propranolol alone caused any change in SGaw at 2 h. After placebo, intravenously injected aminophylline produced a 30% increase in SGaw, reaching a peak 5 min after injection. This response was equivalent to 77% of the maximal response to 400 micrograms inhaled albuterol in the same subjects. After propranolol, the airway response to aminophylline was attenuated, with a 53% reduction in delta SGaw at the time of peak response. In a further study on 6 subjects, intravenously given aminophylline produced a 25% increase in SGaw and a 51% increase in plasma cyclic-AMP levels after placebo tablets. Pretreatment with 40 and 80 mg DL-propranolol caused a dose-dependent reduction of both the airway and plasma cyclic-AMP response to aminophylline. The airway response to aminophylline was not attenuated by D-propranolol so the effect of DL-propranolol is thought to be due to beta-adrenoceptor blockade. The absence of any detectable change in SGaw after DL-propranolol suggests there is little resting sympathetic tone to the airways in normal subjects. In the absence of sympathetic stimulation, the rapid response to aminophylline is unlikely to be due to phosphodiesterase inhibition. The attenuation of the airway and cyclic-AMP response by propranolol suggests that part of the action of aminophylline may be due to beta-agonist activity.     

Rapid‐onset clinical and mechanistic effects of anti‐C5aR treatment in the mouse collagen‐induced arthritis model

Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti‐C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti‐murine C5aR (anti‐mC5aR) surrogate antibody in mouse collagen‐induced arthritis (CIA). First, efficacy was demonstrated in a multiple‐dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti‐mC5aR‐treated mice. Then, the mechanism of action was examined by looking for early effects of anti‐mC5aR treatment in single‐dose treatment studies. We found that 48 h after single‐dose treatment with anti‐mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and IL‐17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose‐setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti‐C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.     

Comparison of periodontal open flap debridement versus closed debridement with Er,Cr:YSGG laser

Background

Traditional periodontal open flap debridement (OFD) results in reduced pocket depth (PD), clinical attachment loss (CAL), gingival recession (GR) and postoperative pain and discomfort. The quest to overcome these shortcomings has led to research into Er,Cr:YSGG laser assisted pocket therapy (ELAPT). This study was designed to compare the clinical outcomes of ELAPT versus OFD.

Methods

Fifteen patients with a PD of ≥5 mm and ≤8 mm at two sites were selected. Test sites (Group 1) were treated by ELAPT and the control (Group 2) by OFD. Clinical parameters were recorded at baseline, 3 and 6 months and included Plaque Index (PI), Gingival Index (GI), modified Sulcular Bleeding Index (mSBI), PD, CAL and GR.

Results

Both treatments produced a reduction in PI, GI, mSBI and PD, an increase in GR, and a gain in CAL at 3 and 6 months. The mean gain of CAL in Group 1 at 3 and 6 months (1.60 ± 0.78 and 1.80 ± 0.63) was similar (p > 0.05) to the value of Group 2 (1.93 ± 0.88 and 2.00 ± 0.54). GR increased significantly (p < 0.05) only in Group 2 at 3 and 6 months (1.80 ± 0.56 and 1.87 ± 0.64) compared to Group 1 (0.50 ± 0.68 and 0.60 ± 0.74).

Conclusions

ELAPT compared with OFD results in similar CAL gains with less GR and significant reductions in PD, GI and mSBI, and may be considered as an alternative to surgical therapy.     

A look at the thoracic surgery workforce in Canada: how demographics and scope of practice may impact future workforce needs

Background

The purpose of this study is to describe the demographics, training and practice characteristics of physicians performing thoracic surgery across Canada to better assess workforce needs.

Methods

We developed a questionnaire using a modified Delphi process to generate questionnaire items. The questionnaire was administered to all Canadian thoracic surgeons via email (n = 102) or mail (n = 35).

Results

In all, 97 surgeons completed the survey (71% response rate). The mean age of respondents was 47.7 (standard deviation 9.1) years; 10.3% were older than 60. Ninety respondents (88.7%) were men, 95 (81.1%) practised in English and 93 (76%) were born in Canada. Most (90.4%) had a medical school affiliation, with an equal proportion practising in community or university teaching hospitals. Only 18% of respondents reported working fewer than 60 hours per week, and 34% were on call more than 1 in 3. Three-quarters of work hours were devoted to clinical care, with the remaining time split among research, administration and teaching. Malignant lung disease accounted for 61.2% of practice time, with the remaining time equally split between benign and malignant thoracic diseases. Preoperative testing (49.4%) and insufficient operating time (49.5%) were the most common factors delaying delivery of care. More than 80% of respondents reported being satisfied with their careers, with 62.1% planning on retiring after age 60.

Conclusion

This survey characterizes Canadian thoracic surgeons by providing specific demographic, satisfaction and scope of practice information. Despite challenges in obtaining adequate resources for providing timely care, job satisfaction remains high, with a balanced workforce supply and demand anticipated for the foreseeable future.     

Brain attacks and stroke in children

Emergency physicians are often the first point of contact in children presenting with acute neurological disorders. Differentiating serious disorders, such as stroke, from benign disorders, such as migraine, can be challenging. Clinical assessment influences decision‐making, in particular the need for emergent neuroimaging to confirm diagnosis. This review describes the spectrum of disorders causing ‘brain attack’ symptoms, or acute onset focal neurological dysfunction, with particular emphasis on childhood stroke, because early recognition is essential to improve access to thrombolytic treatments, which have improved outcomes in adults. Clues to diagnosis of specific conditions are discussed. Symptoms and signs, which discriminate stroke from mimics, are described, highlighting differences to adults. Haemorrhagic and ischaemic stroke have different presenting features, which influence choice of the most appropriate imaging modality to maximise diagnostic accuracy. Improvements in the care of children with brain attacks require coordinated approaches and system improvements similar to those developed in adults.     

An erythroid chaperone that facilitates folding of alpha-globin subunits for hemoglobin synthesis

Erythrocyte precursors produce abundant alpha- and beta-globin proteins, which assemble with each other to form hemoglobin A (HbA), the major blood oxygen carrier. alphaHb-stabilizing protein (AHSP) binds free alpha subunits reversibly to maintain their structure and limit their ability to generate reactive oxygen species. Accordingly, loss of AHSP aggravates the toxicity of excessive free alpha-globin caused by beta-globin gene disruption in mice. Surprisingly, we found that AHSP also has important functions when free alpha-globin is limited. Thus, compound mutants lacking both Ahsp and 1 of 4 alpha-globin genes (genotype Ahsp(-/-)alpha-globin*(alpha/alphaalpha)) exhibited more severe anemia and Hb instability than mice with either mutation alone. In vitro, recombinant AHSP promoted folding of newly translated alpha-globin, enhanced its refolding after denaturation, and facilitated its incorporation into HbA. Moreover, in erythroid precursors, newly formed free alpha-globin was destabilized by loss of AHSP. Therefore, in addition to its previously defined role in detoxification of excess alpha-globin, AHSP also acts as a molecular chaperone to stabilize nascent alpha-globin for HbA assembly. Our findings illustrate what we believe to be a novel adaptive mechanism by which a specialized cell coordinates high-level production of a multisubunit protein and protects against various synthetic imbalances.