Outpatient parenteral antibiotic therapy (OPAT) for bone and joint infections: experience from a UK teaching hospital-based service.

OBJECTIVES: We describe failure rates of 198 patients with bone and joint infection (BJI), including prosthetic joint infection and diabetic foot osteomyelitis, managed through the Glasgow centre for outpatient parenteral antibiotic therapy (OPAT) over a period of 4 years. Outcomes following initial intravenous antimicrobial therapy and a median follow-up time of 60 weeks are described. PATIENTS AND METHODS: A prospectively maintained registry of all patients attending OPAT was examined for cases of BJI. Once identified, patient case records were reviewed and data extracted. Diagnosis, demographics, microbiology and treatment were recorded, and case records were examined for evidence of failing initial prescribed OPAT therapy and up to 24 months of follow-up. RESULTS: One hundred and ninety-eight cases of BJI were identified. The overall success rate following initial OPAT was 86.4%, with a range from 71.8% success rate for diabetic foot or stump infection (DFI) to 100% for metalwork-related infection. The failure rate over the follow-up period was 29.8%. Factors associated with poor initial outcome included older age, methicillin-resistant Staphylococcus aureus infection and DFI, factors that continued to explain failure up to 24 months in multivariate survival analysis. CONCLUSIONS: For the majority of conditions, BJI can be successfully managed through OPAT. Identification of those likely to respond less well, including older patients, those with DFI and those with infections by resistant organisms, may encourage enhanced vigilance and consideration of newer or more aggressive treatments in these subgroups of patients.

Outpatient parenteral antimicrobial therapy-treated bone and joint infections in a tropical setting.

BACKGROUND: Osteoarticular infections are a primary indication for outpatient parenteral antimicrobial therapy (OPAT). The climate and geographical diversity of tropical Australia, together with the prevalence of melioidosis, disseminated gonococcal disease and community-acquired methicillin-resistant Staphylococcus aureus renders this a challenging environment in which to manage such infections. We evaluated patients managed by the Royal Darwin Hospital Hospital in the Home service for bone and joint infections. METHODS: A retrospective analysis of the therapeutic outcomes at the end of intravenous therapy was carried out for patients treated between 1 January 2006 and 15 September 2007. RESULTS: Fifty-five patients were treated, including 21 (38%) indigenous Australians and 18 (33%) from remote communities. Baseline characteristics were similar to other published data, but there were two cases each of gonococcal septic arthritis and melioidosis. During treatment, 39 (71%) lived at home, with five (9%) of these receiving treatment at community clinics. Thirteen (24%) resided in self-care units in the hospital grounds. Three (5%) were managed at hostels or in prison. Median duration of parenteral therapy was 42 days, with a median of 22 days outside hospital, providing a total saving of 1307 bed-days. Clinical success at end of therapy was 84%, with no significant difference between indigenous and non-indigenous cohorts. CONCLUSION: OPAT for osteoarticular infections is both feasible and effective in a tropical environment, including for indigenous patients. Extension of treatment to remote-dwelling patients is facilitated by the innovative use of self-care units and administration of treatment at remote clinics.

Estimating risk associated with radiation exposure during follow-up after endovascular aortic repair (EVAR).

Late rupture incidence following endovascular repair (EVAR) of abdominal aortic aneurysm does not appear to decrease with time, mandating life-long surveillance. Popular regimes based on computed tomography (CT) originated in early registry and randomised trial protocols and are not evidence-based. We evaluated the radiation burden (and implications) associated with "conventional" CT surveillance and explored alternative surveillance paradigms. An EVAR program comprising planning CT, EVAR and surveillance CT at 1, 3, 6 and 12 months and yearly thereafter, equates to a total effective radiation dose of around 145-205 mSv over five years. A 70-year-old exposed to 145 mSv has a lifetime attributable cancer risk of 0.42% (i.e., odds of 1 in 240). Similarly, for a total dose of 204 mSv, the risk would be 0.60% (1 in 170). The corresponding data for a 50-year-old would be 0.73% (1 in 140) and 1.03% (1 in 100), respectively. In high throughput units this could mean one cancer per year attributable to the EVAR programme. Of particular concern is the cumulative dose in those most sensitive to it; younger patients, smokers and women. Repeat exposure within short exposure intervals is particularly burdensome (e.g., planning CT followed by EVAR one week later and first surveillance CT at one month). Three alternatives reduce radiation exposure; reduction of the effective dose associated with each CT scan, reduction in the number of CT scans requested (or better temporal spacing of them) or replacement of CT with alternative modes of imaging/assessment.

Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide.

The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 act on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). These hormones (incretins) are rapidly hydrolyzed by the circulating enzyme dipeptidyl peptidase IV (DP IV) into biologically inactive NH2-terminally truncated fragments. This study describes the effect of inhibiting endogenous DP IV with a specific DP IV inhibitor, isoleucine thiazolidide (Ile-thiazolidide), on glucose tolerance and insulin secretion in the obese Zucker rat. In initial studies, the specificity of Ile-thiazolidide as an inhibitor of incretin degradation was determined using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These results showed that inhibiting DP IV activity with Ile-thiazolidide blocked the formation of NH2-terminally truncated GIP and GLP-1. Oral administration of Ile-thiazolidide resulted in rapid inhibition of circulating DP IV levels by 65% in obese and lean Zucker rats. Suppression of DP IV levels enhanced insulin secretion in both phenotypes with the most dramatic effect occurring in obese animals (150% increase in integrated insulin response vs. 27% increase in lean animals). Ile-thiazolidide treatment improved glucose tolerance in both phenotypes and restored glucose tolerance to near-normal levels in obese animals. This was attributed to the glucose-lowering actions of increasing the circulating half-lives of the endogenously released incretins GIP and, particularly, GLP-1. This study suggests that drug manipulation of plasma incretin activity by inhibiting the enzyme DP IV is a valid therapeutic approach for lowering glucose levels in NIDDM and other disorders involving glucose intolerance.

Antenatal hepatitis B in a large teaching NHS Trust - implications for future care.

OBJECTIVES: To establish the workload expected as a result of introducing antenatal antivirals for the prevention of vertical transmission of hepatitis B virus. METHODS: Retrospective review of all HBsAg-positive women and their infants, between 2005 and 2011, in a large (population 1 million) teaching NHS Trust in Leicester, UK, a highly ethnically diverse city. RESULTS: 7% of pregnancies occurred in women who were taking, or would now be recommended to take, antenatal antivirals. 176 infants were born to 140 HBsAg-positive women through 172 pregnancies (mean 29 pregnancies/year). Two (1.1%) were vertically infected, including one born to a mother with HBeAg(-)/HBeAb(+) disease and HBV viral load 2 million IU/ml who would not currently be recommended for antenatal antivirals. 81.1% infants completed all HBV vaccinations; 79.5% completed serology testing. 96.4% women were referred to the hepatitis clinic, but 30% disengaged from clinic follow-up, with no significant difference between ethnic groups in terms of maternal disengagement, or failure to complete infant vaccinations or serology testing. CONCLUSIONS: Only a small percentage of HBsAg-positive women are likely to meet the newly published criteria for antenatal anti-viral treatment. Strengthened community engagement across multiple ethnic groups is of paramount importance to improve maternal and infant outcomes.

Components of the Goeckerman regimen.

Although application of tar products and subsequent exposure to ultraviolet radiation (the Goeckerman regimen) has repeatedly been demonstrated to be effective therapy for psoriasis, the therapeutic role of each component has remained uncertain. Utilizing the bilateral comparison technique in 30 hospitalized patients with chronic stable plaque-type psoriasis vulgaris, we closely monitored the clinical responses to ultraviolet radiation (Westinghouse fluorescent FS40 bulbs, 290--400 nm) and a variety of tar preparations and lubricant vehicles in combination and separately. We found that: 1) 4 weeks of maximally-aggressive exposure to ultraviolet radiation alone will markedly improve, but not completely clear, psoriasis unless combined with a tar preparation or lubricating base; 2) 5% crude coal tar plus ultraviolet radiation offers no clear advantage or benefit over lubricating base plus ultraviolet radiation; and 3) none of the tar preparations tested offered any consistent advantage over any other preparation.

Therapy of psoriasis by tar photosensitization.

For the first time since Goeckerman suggested the therapeutic potential of tar photosensitization of psoriatic skin, this mechanism has been shown to the effective in treating generalized psoriasis vulgaris. Long treatment times, need for special high-intensity sources, the presence of skin pain, and absence of information about long-term effects makes this treatment impractical at present.

Dietary restriction slows age pigment accumulation in the retinal pigment epithelium.

PURPOSE: The accumulation of age pigment, or lipofuscin, in postmitotic cells appears to be a universal feature of the aging process in animals. In mammals, the lipofuscin content of the retinal pigment epithelium (RPE) increases progressively during senescence. Dietary restriction has been shown to slow the rate at which many biologic parameters change during aging. Experiments were conducted to determine if dietary restriction alters the rate of age pigment accumulation in the RPE. METHODS: Male Wistar rats were placed on one of three dietary regimens starting at weaning. One group was fed a nutritionally complete diet ad libitum. Another group was fed the same diet but was only allowed to consume 60% as much food daily as the ad libitum group ate. The final group was fed ad libitum a nutritionally complete diet that had a lower caloric density per gram than the diets fed to the other animals primarily because of the replacement of carbohydrate with oat fiber. Ultrastructural morphometric analysis was used to determine the RPE age pigment content in the first group at 6 months of age, and in all of the groups at 18 months of age. RESULTS: Dietary restriction, achieved either by reducing total food intake or by reducing the caloric content of the diet, resulted in significant decreases in RPE lipofuscin accumulation. CONCLUSIONS: Dietary restriction provides a relatively simple means by which RPE age pigment content can be modulated. This should prove useful in assessing the role of RPE lipofuscin accumulation in age-related retinal disorders. That the oat fiber diet fed ad libitum was almost as effective as restriction of total food intake in slowing RPE age pigment accumulation indicates that the effect of restricted caloric intake is not mediated by almost constant hunger.

Improved glucose tolerance in rats treated with the dipeptidyl peptidase IV (CD26) inhibitor Ile-thiazolidide.

The incretins glucose-dependent insulinotropic polypeptide (GIP1-42) and truncated forms of glucagon-like peptide-1 (GLP-1) are hormones released from the gut in response to ingested nutrients, which act on the pancreas to potentiate glucose-induced insulin secretion. These hormones are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV ([DPIV] CD26). This study describes the effect on glucose tolerance and insulin secretion of inhibiting endogenous DPIV in the rat using Ile-thiazolidide, a specific DPIV inhibitor. High-performance liquid chromatography (HPLC) analysis of plasma following in vivo administration of 125I-labeled peptides showed that inhibition of DPIV by about 70% prevented the degradation of 90.0% of injected 125I-GLP-17-36 after 5 minutes, while only 13.4% remained unhydrolyzed in rats not treated with the DPIV-inhibiting agent after only 2 minutes. Ile-thiazolidide treatment also increased the circulating half-life of intact GLP-17-36 released in response to intraduodenal (ID) glucose (as measured by N-terminal specific radioimmunoassay [RIA]). In addition, inhibition of DPIV in vivo resulted in an earlier increase and peak of plasma insulin and a more rapid clearance of blood glucose in response to ID glucose challenge. When considered with the HPLC data, these results suggest that the altered insulin profile is an incretin-mediated response. DPIV inhibition resulting in improved glucose tolerance may have therapeutic potential for the management of type 2 diabetes mellitus.

Manual oligonucleotide synthesis using the phosphoramidite method.

Oligodeoxyribonucleotides may be synthesized on a solid support, which allows for the elongation of the chain without intermediate purifications. The exocyclic amino groups on cytosine and the purines are protected as the alkali-labile benzoyl or iso-butyryl amides. The 3'-OH group of the first nucleoside is attached to the solid support by a spacer chain, and the synthesis procedes by coupling the 5'-OH group of the growing chain to the 3'-phosphorus of the monomer being added, which has its 5'-OH group protected by an acid-labile group. The phosphorus must also be protected to avoid side reactions. When the synthesis is completed, the chain must be cleaved from the support and the base, phosphorus, and terminal 5'-OH-protecting groups removed. The desired oligonucleotide is then separated from the mixture of shorter chains and modified chains (1).

A series of four fractured Exeter™ stems in hip arthroplasty.

We describe the cases of four patients who presented with painful hips and were found to have fractured cemented Exeter™ V40™ stems. Failure was multifactorial. Fractured Exeter™ stems are rarely reported and this series raises a concern that a population of patients may be at risk of such morbidity.