Lung injury mediated by antibodies to endothelium. I. In the rabbit a repeated interaction of heterologous anti-angiotensin-converting enzyme antibodies with alveolar endothelium results in resistance to immune injury through antigenic modulation.

To study the effects of relatively long-term interaction of antibodies with surface antigens of lung endothelium, rabbits were intravenously injected for a maximum of 4 d with goat anti-rabbit lung angiotensin-converting enzyme (Gt anti-RbACE) antibodies. On day 1 69%, on day 2 13%, and on days 3 and 4 of injection none of the rabbits developed lethal pulmonary edema. By immunofluorescence microscopy, deposits of GtIgG, frequently in association with RbC3, were found along the endothelium of alveolar capillary walls in all rabbits studied on day 1, in 57% on day 2, in 33% on day 3, and in none of them on day 4. While in vitro anti-ACE antibodies bound in a linear pattern to the lung endothelium, the binding pattern in vivo was distinctly granular. The in vivo interaction of antibodies with ACE also redistributed ACE in a granular pattern along capillary walls. In contrast to the granular deposition of injected anti-ACE IgG and F(ab')2 fragments of anti-ACE IgG, Fab fragments of anti-ACE IgG localized, without fixing C3, in a linear pattern along the endothelium of lung capillaries and did not modify the normal distribution of ACE. However, when the injection of Fab fragments of Gt anti-RbACE IgG was followed by an injection of Rb anti-GtIgG serum, granular deposits of Gt Fab fragments, RbIgG and RbC3 were seen along alveolar capillary walls. Biochemical measurement of ACE activity in lung homogenates provided data in agreement with those obtained by immunofluorescence microscopy, showing diminished activity to none on day 4, with some return of ACE activity on day 5, 24 h after the last injection of antibody, and normal values on day 21. The results obtained indicate that divalent antibodies to an antigen expressed on the plasma membrane of rabbit lung endothelial cells promotes a rapid redistribution of antigenic receptors, fixation of complement and, in surviving rabbits, disappearance of the antigen from the endothelial cells that are no longer susceptible to immune injury. In vivo "immunologic enzymectomy" induced by a ligand-surface antigen interaction is an example of antigenic modulation. These events may have an important role in the pathogenesis of inflammatory lesions induced by antibodies reacting with antigens expressed on the plasma membrane of cells in the lung and in other organs.

Toward endobronchial Ir-192 high-dose-rate brachytherapy therapeutic optimization.

A number of patients with lung cancer receive either palliative or curative high-dose-rate (HDR) endobronchial brachytherapy. Up to a third of patients treated with endobronchial HDR die from hemoptysis. Rather than accept hemoptysis as an expected potential consequence of HDR, we have calculated the radial dose distribution for an Ir-192 HDR source, rigorously examined the dose and prescription points recommended by the American Brachytherapy Society (ABS), and performed a radiobiological-based analysis. The radial dose rate of a commercially available Ir-192 source was calculated with a Monte Carlo simulation. Based on the linear quadratic model, the estimated palliative, curative and blood vessel rupture radii from the center of an Ir-192 source were obtained for the ABS recommendations and a series of customized HDR prescriptions. The estimated radius at risk for blood vessel perforation for the ABS recommendations ranges from 7 to 9 mm. An optimized prescription may in some situations reduce this radius to 4 mm. The estimated blood perforation radius is generally smaller than the palliative radius. Optimized and individualized endobronchial HDR prescriptions are currently feasible based on our current understanding of tumor and normal tissue radiobiology. Individualized prescriptions could minimize complications such as fatal hemoptysis without sacrificing efficacy. Fiducial stents, HDR catheter centering or spacers and the use of CT imaging to better assess the relationship between the catheter and blood vessels promise to be useful strategies for increasing the therapeutic index of this treatment modality. Prospective trials employing treatment optimization algorithms are needed.

Photodynamic therapy of the intact breast.

As breast cancer is diagnosed in over a million patients a year it is a significant oncological issue. Treatment paradigms have shifted to emphasize breast preservation protocols. However, due to a lack of equipment and facilities this option is only rarely offered to poverty stricken patients and those in the developing world. Photodynamic therapy may play a role in allowing for greater breast conservation based in part on the emerging success of partial breast radiation. This paper will review the rationale behind and technical aspects for intact breast photodynamic therapy.

Clinical photodynamic therapy of head and neck cancers-A review of applications and outcomes.

As local control is tantamount to cure in head and neck cancer, an aggressive regimen of surgery and radiation remains the standard of care for most patients. Despite significant technical advances, these treatments are highly morbid. Further, patients who fail treatment have limited salvage options. Photodynamic therapy (PDT) and photodiagnosis (PD) of head and neck cancer offer significant potential for improved outcomes in a myriad of clinical indications ranging from in situ to recurrent disease. However, despite promising results, these modalities remain at the fringe of head and neck treatment options. Photofrin(®), Photosan and Foscan(®) are photosensitizers used clinically in head and neck PD/PDT. In addition, aminolevulinic acid (ALA), which gives origin to Protoporphyrin IX, an endogeneous photosensitizer, is also used for PD/PDT. We review the clinical literature on these photosensitizers to assist in the integration of these important modalities into the mainstream of head and neck oncological therapy.

PD/PDT for gynecological disease: A clinical review.

The evolution of diagnostic and interventional procedures for gynecologic disease has led to organ, sexual and reproductive sparing treatments. Photodiagnosis (PD) and photodynamic therapy (PDT) may play a great role for gynecological patients as both offer the potential to achieve these goals. PD/PDT for a wide variety of diagnostic and therapeutic interventions have shown potential for excellent clinical outcomes. However, significant limitations remains, both clinically and dosimetrically, that prevent consistent results. When those limitations are resolved PD/PDT could move to the forefront of gynecological therapy. This clinical review highlights the outcomes and shortcomings of PD/PDT through the peer reviewed literature for gynecological sites.

Cholelithoptysis. A complication following laparoscopic cholecystectomy.

A 59-year-old woman who underwent laparoscopic cholecystectomy for symptomatic cholecystitis presented four months later with fever, malaise, anorexia, hemoptysis and lithoptysis. Chemical analysis of the expectorated lithes revealed them to be gallstones. Ultrasound studies of the right upper quadrant demonstrated both supradiaphragmatic and subdiaphragmatic fluid collections containing echogenic fragments. ERCP failed to demonstrate retained ductal stones or fistula formation. To our knowledge, this is the first reported case of cholelithoptysis and demonstrates an unusual complication of gallstone retention following laparoscopic cholecystectomy.

Photodynamic therapy for chest wall recurrence from breast cancer.

Breast cancer is common with over 230,000 new cases diagnosed each year in North America alone. While great strides have been made to achieve excellent cancer control and survival, a significant minority of patients fail locally. While initial salvage to regain disease control is of the utmost importance, it is not universally successful. This leads to a therapeutic quagmire. Additional surgery, radiation and chemo-hormonal therapy are possible, but they are usually highly morbid with low success rates. Photodynamic therapy appears to be an underutilized salvage modality for this unfortunate patient population. This report analyzes and reviews the role of photodynamic therapy for patients with chest wall re-recurrence from breast cancer.

Limb deficiencies and prosthetic devices.

The child with a congenital limb deficiency is best managed by an interdisciplinary clinic team, which can see him early and work with parents and agencies to provide adequate and early prosthetic prescriptions. Terminal transverse limb deficiencies are generally fitted similarly to the patient with acquired amputation at the same level. Other deficiencies often require nonstandard prosthetic devices in association with corrective or conversion surgery.

A strategy to reduce laxative use among older people.

Institutions can be places of routine and unquestioned practice in the administration of medications. In one mixed ward of psychogeriatric patients constipation was a common problem for which laxatives were routinely given. In this particular ward, many of the patients were receiving up to five different laxatives a day either orally or rectally. Dementia and being bed or chair-bound greatly increased the risk of chronic constipation. Excessive laxative use is another cause of chronic constipation. A review of practice and a decision implement a new approach was prompted by the arrival of new ward managers. The use of laxatives was stopped almost entirely and a new dietary regime was started. This article outlines how the changes were implemented.

Hospital transmission of hepatitis B virus in the absence of exposure prone procedures.

In February and in June 1998, two people developed acute hepatitis B following in-patient care in a district general hospital. Initial enquiries indicated their infections were not attributable to staff undertaking exposure-prone procedures (EPPs). We report the findings and implications of the subsequent investigation: a multi-disciplinary, multi-agency investigation, including molecular epidemiological analysis. Occupational Health records showed that staff involved in EPPs with the patients were HBsAg negative. No contact between the patients was identified nor were there failures in sterilization. The patients' HBV strains were identical, indicating a common source. A total of 231 out of 232 staff who might have treated either patient were tested for HBsAg; the remaining doctor, working abroad, was HBsAg- and HBeAg-positive and had the same HBV strain as the patients. On two occasions the doctor's hand had been cut while breaking glass vials, but there was no documentation linking these events to the two patients. The doctor had been vaccinated in 1993 and tested for anti-HBs prior to commencing work in 1997. The doctor was recalled to Occupational Health but did not attend and was not followed up. In total, 4948 patients potentially treated by the doctor received an explanatory letter and 3150 were tested for HBsAg. Only one was positive, and HBV sequencing showed no link to the doctor. Occasionally transmission of HBV from heath-care workers can occur in a non-EPP setting and the implications of this require examination by those setting national policy. Occupational Health Services should investigate clinical heath-care workers who do not respond to vaccination. They should ensure HBV carriers are identified and offer them appropriate advice to prevent transmission to patients.

Pulmonary arteriovenous malformation.

Pulmonary arteriovenous malformations (PAVM) are rare pulmonary vascular anomalies. Although most patients are asymptomatic, PAVMs can cause dyspnoea from right-to-left shunt. Because of paradoxical emboli, various central nervous system complications have been described including stroke and brain abscess. There is a strong association between PAVM and hereditary haemorrhagic telangiectasia. Chest radiography and contrast enhanced computed tomography are essential initial diagnostic tools but pulmonary angiography is the gold standard. Contrast echocardiography is useful for diagnosis and monitoring after treatment. Most patients should be treated. Therapeutic options include angiographic embolisation with metal coil or balloon occlusion and surgical excision.

Adherence to the Grampian joint drug formulary in general practice.

A joint drug formulary covering both hospital and general practice prescribing has been in existence in Grampian since 1990. The aims of this study were to measure adherence to this formulary in general practice and to identify who had initiated non-formulary drugs. The drug therapy of elderly patients on presentation to hospital was compared to the formulary. Of the 449 drugs prescribed 377 (84%) were recommended in the formulary. The main areas of non-formulary prescribing were antidepressants, hypnotics, nitrates and diuretics, with some non-formulary drugs being initiated by hospital prescribers. The method described was found to be extremely simple and had the advantage that it reflected actual prescribing at the time of the study.

Chronic low back pain: results of treatment at the Pain Therapy Center.

We evaluated the outcome of 100 consecutive patients with chronic benign low back pain admitted for comprehensive interdisciplinary rehabilitation at the Pain Therapy Center. The average patient had been disabled for nearly two years and had had two unsuccessful operations for pain relief. Seventy-two percent of the patients treated had open claims against their workmen's compensation carriers. Significant improvements were demonstrated in physical strength, stamina, endurance and overall level of physical activity, drug reduction, subjective pain intensity, and return to employment.

An assessment of antibiotic therapy of urinary tract infection in elderly, hospitalised patients.

The aim of the study was to compare the antibiotic treatment actually received by elderly, hospitalised patients with urinary tract infection (UTI) with 'optimal' therapy (as gauged by compliance with antibiotic policy, infecting organism, sensitivity data, patient renal function and cost). UTI was more common in females and in catheterised patients and E.Coli was the commonest pathogen. Trimethoprim and co-amoxiclav were the drugs used most frequently for either empirical or sensitivity data-based treatment. In 96% of infections a drug with appropriate action was administered. Often, however, treatment could have been optimised by substituting a cheaper suitable antibiotic, by standardising duration of therapy and ensuring that doses were adjusted for renal impairment. Savings from the use of 'optimal' therapy were estimated at 17%. There is clearly considerable scope for positive input from the clinical pharmacist in this area.

Interleukin-2 directly increases albumin permeability of bovine and human vascular endothelium in vitro.

The direct effects of interleukin-2 (IL-2) on albumin permeability of cultured bovine pulmonary artery endothelial cell (BPAEC) and human arterial endothelial cell (HAEC) monolayers were studied. BPAEC were exposed to IL-2 (500 to 25,000 U/ml) for 4 h. The steady-state transfer rate of [125I]albumin across the BPAEC monolayer was 3.3 +/- 0.4%/h (n = 10) in control BPAEC (diluent alone), was significantly increased in BPAEC exposed to 500 U/ml of IL-2 (72 +/- 3% above control values, n = 6, P less than 0.02), and further increased in BPAEC exposed to 5,000 U/ml (60 +/- 2% increase above 500 U/ml values, n = 5, P less than 0.02). No further increase was noted after exposure to 25,000 U/ml of IL-2. Additionally, no further increase in [125I]albumin transfer rates was noted in BPAEC exposed to 5,000 U/ml of IL-2 for 24 versus 4 h. Similar changes were found using HAEC. Preincubation of HAEC with an anti-IL-2 low-affinity receptor antibody (anti-IL-2R alpha) inhibited the IL-2-induced permeability increase. Expression of IL-2R alpha receptors in HAEC incubated with 5,000 U/ml of IL-2 for 4 h was also found. Thus, IL-2 appears to have a direct effect on cultural arterial endothelial monolayers not requiring the presence of other cell types or serum proteins. IL-2-induced increases in endothelial macromolecular permeability may play an important role in the pathogenesis of the IL-2-induced vascular leak syndrome seen in vivo.

Influenza and pneumococcal vaccination: patient perceptions.

The efficacy of the influenza vaccine in reducing mortality and hospital admissions is established, particularly in the elderly. However, up to 50% of those at risk do not receive the vaccine. These patients are also at risk from pneumococcal infection and there is considerable overlap between the target group for each vaccine. This study sought to identify at risk individuals from consecutive admissions to an acute geriatric unit and to gain an insight into their perceptions with regard to vaccination. The awareness of each vaccine was recorded, together with the vaccination history. Seventy four per cent of the final cohort had heard of the influenza vaccine, while only 13% had heard of the pneumococcal vaccine. Fifty per cent perceived themselves to be at risk from influenza and its complications and 87% of the cohort believed it to be a serious infection. Influenza vaccine was judged to confer good protection by 72% of the sample and yet up to 50% believed that the vaccine can make the recipient ill. Influenza is perceived as a serious infection by patients and yet many do not believe themselves to be at particular risk. Although influenza vaccination is believed to confer protection, the decision whether, or not, to accept the vaccine is coloured by many factors, including popular myths and anecdotal information from friends and relatives. The uptake of influenza vaccine is suboptimal and the awareness of the pneumococcal vaccine certainly in the elderly is poor. The need for a comprehensive nationwide education campaign promoting both influenza and pneumococcal vaccine is highlighted.

Pharmacist-led medication review in patients over 65: a randomized, controlled trial in primary care.

BACKGROUND: regular medication review has been recommended for those over 75 and those on multiple drug therapy. Pharmacists are a potential source of assistance in reviewing medication. Evidence of the benefits of this process is needed. OBJECTIVE: to study the effect of medication review led by a pharmacist on resolution of pharmaceutical care issues, medicine costs, use of health and social services and health-related quality of life. DESIGN: randomized, controlled trial. SETTING: general medical practices in the Grampian region of Scotland. SUBJECTS: patients aged at least 65 years, with at least two chronic disease states who were taking at least four prescribed medicines regularly. METHODS: pharmacists reviewed the drug therapy of 332 patients, using information obtained from the practice computer, medical records and patient interviews. In 168 patients, a pharmaceutical care plan was then drawn up and implemented. The 164 control patients continued to receive normal care. All outcome measures were assessed at baseline and after 3 months. RESULTS: all patients had at least two pharmaceutical care issues at baseline. Half of these were identified from the prescription record, the rest from notes and patient interview. Of all the issues, 21% were resolved by information found in notes and 8.5% by patient interview. General practitioners agreed with 96% of all care issues documented on the care plans in the intervention group. At the time of follow-up, 70% of the remaining care issues had been resolved in the intervention group, while only 14% had been resolved in the control group. There were no changes in medicine costs or health-related quality of life in either group. There were small increases in contacts with health-care professionals and slightly fewer hospital admissions among the intervention group than the control group. CONCLUSIONS: pharmacist-led medication review has the capacity to identify and resolve pharmaceutical care issues and may have some impact on the use of other health services.

Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis.

Alveolar proteinosis (AP) is characterized by excessive surfactant accumulation, and most cases are of unknown etiology. Standard therapy for AP is whole-lung lavage, which may not correct the underlying defect. Because the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for normal surfactant homeostasis, we evaluated the therapeutic activity of GM-CSF in patients with idiopathic AP. Fourteen patients received 5 microg/kg/d GM-CSF for 6 to 12 wk with serial monitoring of the alveolar-arterial oxygen gradient ([A-a]DO2), diffusing capacity of carbon monoxide, computed tomographic scans, and exercise testing. Patients not responding to 5 microg/kg/d GM-CSF underwent stepwise dose escalation, and responding patients were retreated at disease recurrence. Stored pretreatment sera were assayed for GM-CSF-neutralizing autoantibodies. According to prospective criteria, five of 14 patients responded to 5 microg/kg/d GM- CSF, and one of four patients responded after dose escalation (20 microg/kg/d). The overall response rate was 43% (mean improvement in [A-a]DO2 = 23.2 mm Hg). Responses lasted a median of 39 wk, and were reproducible with retreatment. GM-CSF was well-tolerated, with no late toxicity seen. The only treatment-related factor predictive of response was GM-CSF-induced eosinophilia (p = 0.01). Each of 12 patients tested had GM-CSF-neutralizing autoantibodies present in pretreatment serum. We conclude that GM- CSF has therapeutic activity in idiopathic AP, providing a potential alternative to whole-lung lavage.