New regimen for eccentric calf-muscle training in patients with chronic insertional achilles tendinopathy : results of a pilot study

Background: Chronic painful insertional Achilles tendinopathy is seen in both physically active and non-active individuals. Painful eccentric training, where the patients load the Achilles tendon into full dorsiflexion, has shown good results in patients with mid-portion Achilles tendinosis. However, only 32% of patients with insertional Achilles tendinopathy had good clinical results with that type of eccentric training regimen.

Aim: To investigate whether a new model of painful eccentric training had an effect on chronic painful insertional Achilles tendinopathy.

Patients and methods: 27 patients (12 men, 15 women, mean age 53 years) with a total of 34 painful Achilles tendons with a long duration of pain (mean 26 months), diagnosed as insertional Achilles tendinopathy, were included. The patients performed a new model of painful eccentric training regimen without loading into dorsiflexion. This was done as 3x15 reps, twice a day, 7 days/week, for 12 weeks. Pain during Achilles-tendon-loading activity (VAS) and patient’s satisfaction (back to previous activity) were evaluated.

Results: At follow-up (mean 4 months) 18 patients (67%, 23/34 tendons) were satisfied and back to their previous tendon-loading activity. Their mean VAS had decreased from 69.9 (SD 18.9) to 21 (SD 20.6) (p<0.001). Nine patients (11 tendons) were not satisfied with the treatment, although their VAS was significantly reduced from 77.5 (8.6) to 58.1 (14.8) (p<0.01).

Conclusion: In this short-term pilot study this new model of painful eccentric calf-muscle training showed promising clinical results in 67% of the patients.

Intensifying insulin regimen after basal insulin optimization in adults with type 2 diabetes: a 24-week, randomized, open-label trial comparing insulin glargine plus insulin glulisine with biphasic insulin aspart (LanScape)

AIM: To test the hypothesis that a 'basal plus' regimenadding once-daily main-meal fast-acting insulin to basal insulin once dailywould be non-inferior to biphasic insulin twice daily as assessed by glycated haemoglobin (HbA1c) concentration (predefined as ≤0.4%), but would provide superior treatment satisfaction. METHODS: This open-label trial enrolled adults to an 8- or 12-week run-in period, during which oral therapies except metformin were stopped and insulin glargine dose was titrated. Those with fasting glucose <7 mmol/l but HbA1c >7% (53 mmol/mol) were randomized to insulin glargine/glulisine once daily (n = 170) or insulin aspart/aspart protamine 30/70 twice daily (n = 165) for 24 weeks, with dose titration to glucose targets using standardized algorithms. RESULTS: For HbA1c, the basal plus regimen was non-inferior to biphasic insulin (least squares mean difference, 0.21%, upper 97.5% confidence limit 0.38%) meeting the predefined non-inferiority margin of 0.4%. Treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version and Insulin Treatment Satisfaction Questionnaire total scores) significantly favoured basal plus. No difference was observed between the basal plus and the biphasic insulin groups in responders (HbA1c <7%, 20.6 vs 27.9%; p = 0.12), weight gain (2.06 vs 2.50 kg; p = 0.2), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life average weighted impact (AWI) score) and generic health status (five-dimension European Quality of Life questionnaire). Overall hypoglycaemia rates were similar between groups (15.3 vs 18.2 events/patient-year; p = 0.22); nocturnal hypoglycaemia was higher with the basal plus regimen (5.7 vs 3.6 events/patient-year; p = 0.02). CONCLUSION: In long-standing type 2 diabetes with suboptimal glycaemia despite oral therapies and basal insulin, the basal plus regimen was non-inferior to biphasic insulin for biomedical outcomes, with a similar overall hypoglycaemia rate but more nocturnal events.

"I will start treatment when I think the time is right":HIV-positive gay men talk about their decision not to access antiretroviral therapy.

In a qualitative study, 20 HIV-infected Australian gay men were interviewed about their decision not to access antiretroviral drug therapy. The main reasons given for the decision were fear of side effects; fear of long-term damage to body organs; the inconvenience of the treatment regimens; belief that the regimen's demands would be a threat to morale; and belief that there was no reason to start therapy in the absence of AIDS-related symptoms. Actions taken by the men to monitor and maintain their health included seeing a doctor regularly; having regular T-cell and viral load tests; and trying to maintain a positive outlook by not letting HIV/AIDS 'take over' their lives. Almost half the men considered they had been subjected to unreasonable pressure to access therapy and there was considerable pride at having resisted this pressure. The findings suggest that the men disagreed with the biomedical model for managing HIV/AIDS only on the question of if and when to access therapy. They also suggest that underlying the men's dissent from the biomedical model was a different mode of thinking than is required by the model: while the model demands thinking that is abstract, the men focused strongly on factors close to the 'here and now' of immediate experience. The practical implications of the findings are explored.

Applying a quality use of medicines framework to using essential oils in nursing practice

Nurses are increasingly incorporating complementary therapies into their practices. Aromatherapy is one of the most popular therapies. The basis of aromatherapy is essential oils, which are chemically active substances with a long history of safe traditional use and a growing evidence base to support their use in nursing care. In Australia, essential oils are classified and regulated under the same policies as conventional medicines such as the National Medicines Policy and the Quality Use of Medicines (QUM) framework applies. QUM is a framework for selecting and using medicines safely and effectively if medicines are indicated. The key elements of QUM are a systems-based approach to using medicines based on relevant evidence, partnerships, and informed client consent. Clients are placed at the centre of a QUM medication management process, which is consistent with holistic care. Applying a QUM approach to essential oil use, Quality Use of Essential Oils (QUEO), involves developing effective systems for managing essential oils from an holistic perspective that includes structured assessment and diagnostic processes to enable effective essential oil prescribing and outcome monitoring. In a QUEO approach, essential oils are integrated into the client's overall medication regimen and care plan rather than being used as ‘add-ons’. Adopting QUEO is consistent with the current national focus on the quality use of therapeutic substances, increases the profile of aromatherapy in nursing care and provides important information to guide future aromatherapy practices.

Effects of purified herbal extract of Saliva miltiorrhiza on ischemic rat myocardium after acute myocardial infarction

In the current study, we compared purified Salvia miltiorrhiza extract (PSME) with Angiotensin-converting enzyme inhibitor, Ramipril, in in vitro experiments and also in vivo using animal model of myocardial infarction. PSME was found to have a significantly higher trolox equivalent antioxidant capacity which indicated a great capacity for scavenging free radicals. PSME could also prevent pyrogallo red bleaching and DNA damage.

After 2 weeks treatment with PSME or Ramipril, survival rates of rats with experimental myocardial infarction were marginally increased (68.2% and 71.4%) compared with saline (61.5%). The ratios of infarct size to left ventricular size in both PSME-and Ramipril-treated rats were significantly less than that in the saline-treated group. Activity of cardiac antioxidant enzyme superoxide dismutase (SOD) was significant higher while level of Thiobarbituric acid-reactive substances (TBARs) was lower in the PSME treated group. Purified and standardized Chinese herb could provide an alternative regimen for the prevention of ischemic heart disease.

Relationship of glutathione S-transferase genotypes with side-effects of pulsed cyclophsphamide therapy in patients with systemic lupus erythematosus

Aims
Cyclophosphamide (CTX) is an established treatment of severe systemic lupus erythematosus (SLE). Cytotoxic CTX metabolites are mainly detoxified by multiple glutathione S-transferases (GSTs). However, data are lacking on the relationship between the short-term side-effects of CTX therapy and GST genotypes. In the present study, the effects of common GSTM1, GSTT1, and GSTP1 genetic mutations on the severity of myelosuppression, gastrointestinal (GI) toxicity, and infection incidences induced by pulsed CTX therapy were evaluated in patients SLE.
Methods
DNA was extracted from peripheral leucocytes in patients with confirmed SLE diagnosis (n = 102). GSTM1 and GSTT1 null mutations were analyzed by a polymerase chain reaction (PCR)-multiplex procedure, whereas the GSTP1 codon 105 polymorphism (Ile→Val) was analyzed by a PCR-restriction fragment length polymorphism (RFLP) assay.
Results
Our study demonstrated that SLE patients carrying the genotypes with GSTP1 codon 105 mutation [GSTP1*-105I/V (heterozygote) and GSTP1*-105 V/V (homozygote)] had an increased risk of myelotoxicity when treated with pulsed high-dose CTX therapy (Odds ratio (OR) 5.00, 95% confidence interval (CI) 1.96, 12.76); especially in patients younger than 30 years (OR 7.50, 95% CI 2.14, 26.24), or in patients treated with a total CTX dose greater than 1.0 g (OR 12.88, 95% CI 3.16, 52.57). Similarly, patients with these genotypes (GSTP1*I/V and GSTP1*V/V) also had an increased risk of GI toxicity when treated with an initial pulsed high-dose CTX regimen (OR 3.33, 95% CI 1.03, 10.79). However, GSTM1 and GSTT1 null mutations did not significantly alter the risks of these short-term side-effects of pulsed high-dose CTX therapy in SLE patients.
Conclusions
The GSTP1 codon 105 polymorphism, but not GSTM1 or GSTT1 null mutations, significantly increased the risks of short-term side-effects of pulsed high-dose CTX therapy in SLE patients. Because of the lack of selective substrates for a GST enzyme phenotyping study, timely detection of this mutation on codon 105 may assist in optimizing pulsed high-dose CTX therapy in SLE patients.

Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin

Purpose Combination of COL-3, a matrix metalloproteinase inhibitor, and doxorubicin (DOX) might be a promising anticancer regimen. The present study was to examine the potential pharmacokinetic interactions and toxicity profile following their coadministration in rats.
Methods Normal rats were treated with single agent or different combinations with oral or intravenous COL-3 and DOX, and the bile-duct cannulated (BDC) rats received oral COL-3 plus DOX. In a separate disposition study, the effects of DOX on the biliary, urinary, and fecal excretion of COL-3 were examined. In addition, the effects of DOX on in vitro protein binding, metabolism, and transport of COL-3 across Caco-2 monolayers were investigated.
Results COL-3 did not affect the pharmacokinetics of DOX in rats. However, treatment with DOX significantly decreased the oral absorption, and prolonged the elimination, of COL-3 in the normal rats, but not in the BDC rats. DOX did not alter the biliary and urinary excretion of COL-3, but significantly decreased the fecal excretion of COL-3. DOX significantly enhanced the basolateral to apical flux of COL-3 across Caco-2 monolayers, but had no apparent effects on the protein binding and metabolism of COL-3. The combination of DOX with oral COL-3 did not significantly (p > 0.05) increase the acute diarrhea score and intestinal damage compared to rats receiving DOX alone.
Conclusions These results indicated that DOX altered the oral absorption and elimination of COL-3, largely resulting from gastrointestinal toxicity caused by biliary excretion of DOX. Further studies are required to explore the efficacy and optimized dosage regimen of this promising combination.

Effect of feeding systems on omega-3 fatty acids, conjugated linoleic acid and trans fatty acids in Australian beef cuts: potential impact on humnan health

The influence of feeding systems on the levels of functional lipids and other fatty acid concentrations in Australian beef was examined. Rump, strip loin and blade cuts obtained from grass feeding, short-term grain feeding (80 days; STGF) and long-term grain feedlot rations (150-200 days; LTFL) were used in the present study. The typical Australian feedlot ration contains more than 50% barley and/or sorghum and balanced with whole cottonseed and protein meals were used as feed for STGF and LTFL regimens. Meat cuts from 18 cattle for each feeding regimen were trimmed of visible fat and  connective tissue and then minced (300 g lean beef); replicate samples of 7g were used for fatty acid (FA) analysis. There was a significantly higher level of total omega-3 (n-3) and long chain n-3 FA in grass-fed beef (P <0.0001) than the grain-fed groups regardless of cut types. Cuts from STGF beef had significantly reduced levels of n-3 FA and conjugated linoleic acid (CLA) and similar levels of saturated, monounsaturated and n-6 FA compared with grass feeding (P <0.001). Cuts from LTFL beef had higher levels of saturated, monounsaturated, n-6 FA and trans 18:1 than similar  cuts from the other two groups (P <0.01), indicating that increased length of grain feeding was associated with more fat deposited in the carcass. There was a step-wise increase in trans 18:1 content from grass to STGF to LTGF, suggesting grain feeding elevates trans FA in beef, probably because of increased intake of 18:2n-6. Only grass-fed beef reached the target of more than 30mg of long chain n-3 FA/100 g muscle as recommended by Food Standard Australia and New Zealand for a food to be considered a source of omega- 3 fatty acids. The proportions of trans 18:1 and n-6 FA were higher (P<0.001) for both grain-fed beef groups than grass-fed beef. Data from the present study show that grain feeding decreases functional lipid  components (long chain n-3 FA and CLA) in Australian beef regardless of meat cuts, while increasing total trans 18:1 and saturated FA levels.

Aerobic exercise and resistance training for the management of type 2 diabetes mellitus

BACKGROUND
Implementation of a structured physical exercise program can improve glycemic control in patients with type 2 diabetes mellitus.

OBJECTIVE
To evaluate the efficacy of aerobic exercise and resistance training (either alone or in combination) in the management of type 2 diabetes mellitus.

DESIGN AND INTERVENTION
DARE (Diabetes Aerobic and Resistance Exercise) was a 26-week, single-center, parallel-group, randomized, controlled trial of patients with type 2 diabetes mellitus of >6 months' duration. Participants were aged 39-70 years with a baseline [HbA.sub.1c] level 6.6-9.9%. Exclusion criteria included current insulin therapy, regular exercise regime and blood pressure >160/95 mmHg. All participants underwent a 4-week run-in period that comprised 12 sessions of combined aerobic exercise and resistance training; participants who attended [greater than or equal to] 10 sessions were eligible to enter the study. Eligible participants were randomly allocated to one of four groups: aerobic exercise alone; resistance training alone; combined aerobic exercise and resistance training; and no intervention (control group). Exercise was performed three times weekly. The aerobic exercise group progressed from 15-20 min on a treadmill or bicycle ergometer per session at 60% of the maximum heart rate to 45 min per session at 75% of the maximum heart rate. The resistance training group performed 7 different exercises on weight machines per 45 min session, and progressed to 2-3 sets of each exercise at the maximum weight that could be lifted 7-9 times. The combined exercise group performed the full aerobic exercise program plus the full resistance training program. Participants in the control group reverted to their pre-study exercise levels.

OUTCOME MEASURES
The primary outcome measure was the change in [HbA.sub.1c] from baseline. Secondary outcome measures included changes in blood pressure, lipid profile, and body composition.

RESULTS
A total of 251 participants were eligible for intervention. The median session attendance was 80% (aerobic exercise), 85% (resistance training) and 86% (combined exercise). When compared with the control group, the HbA1c levels were reduced by 0.50% in the aerobic exercise group (P = 0.007) and by 0.38% in the resistance training group (P = 0.038). The combined exercise group had an additional reduction of 0.46% when compared with the aerobic exercise group (P = 0.014) and of 0.59% when compared with the resistance training group (P = 0.001). Decreases in [HbA.sub.1c] levels were greatest for participants with a baseline [HbA.sub.1c] level = 7.5% (P <0.001). For participants with a baseline level [HbA.sub.1c] <7.5%, significant improvements in glycemic control were observed in the combined exercise group only (P = 0.002). Changes in blood pressure and lipid profiles did not differ between the groups. By contrast, participation in a structured exercise program improved body composition.

CONCLUSION
Although aerobic exercise or resistance training alone improved glycemic control, additional improvements were observed with the combined exercise regimen.

Alterations in renal and myocardial adrenoceptors associated with ethynyloestradiol- and levonorgestrel-induced hypertension in the rat

Hypertension is one of many side effects of oral contraceptive use in a small percentage of women. Although the underlying pathology has yet to be fully resolved, alterations in the renin-angiotensin-aldosterone axis, sympathetic nervous system/ renal and cardiac function have been implicated. In the thesis to be presented, the possible involvement of alterations in renal and myocardial adrenoceptor characteristics in the pathogenesis of steroid contraceptive-induced hypertension in rats was examined by radioligand binding techniques. In Chapter 2, a rat model of OC hypertension is described. Chronic low-dose administration of ethynyloestradiol (EE2), levonorgestrel (NG) or a combination of both steroids (EE2/NG) to female Sprague-Dawley rats was shown to significantly increase systolic blood pressure (SBP). Renal and cardiac hypertrophy developed in association with EE2-, EE2/NG- but not NG-induced hypertension. Moreover, whereas administration of NG alone attenuated body weight gain, combined EE2/NG administration increased body weight gain from the second week of treatment onwards. Based on the above observations, it is proposed that EE2 and NG induce hypertension in rats via different mechanisms. Although SBP was elevated to a similar maximum in all steroid-treated groups (+ 20 mmHg compared to controls), only with EE2 administration did SBP remain elevated for the duration of the 17 week treatment regimen. NG may therefore have a protective effect on blood pressure with long-term combined steroid contraceptive treatment. In Chapter 4, renal adrenoceptors were characterized using radioactively labelled adrenocephor antagonists. Under appropriate conditions, binding of [3H]-prazosin and [3H]-rauwolscine to membrane preparations of whole rat kidney displayed the kinetics, saturability and specificity of α1- and α2 -adrenoceptors respectively, which were present in a ratio 3:1. In contrast, [3H]-dihydroergocryptine ([3H]-DHE) apparently bound to both α1 and α2-adrenoceptors. Binding sites identified by [125I] –iodocyanopindolol (ICYP) had the recognition characteristics of β-adrenoceptors. In drug competition studies using the subtype-selective antagonists practolol (β1) and ICI 118,551 (β2)/ the ratio of β1- to β2 -adrenoceptors was found to be approximately 2:1. Subsequently, renal adrenoceptors were investigated at various stages during the development of hypertension with the different steroid contraceptive treatments (Chapters 5 and 6). Preliminary binding studies with [3H]-DHE and [3H]-prazosin suggested that the number of renal α2 - but not α1-adrenoceptors was reduced in rats with established EE2-induced hypertension (17 weeks treatment). This was subsequently confirmed using [3H]-rauwolscine, which in addition showed that the reduction in renal α2 -adrenoceptor number occurred during the developmental stage of EE2/NG~induced hypertension (6 weeks treatment) and established EE2-induced hypertension (12 weeks treatment). NG induced hypertension was unassociated with changes in renal α1- and α2-adrenoceptor characteristics. Renal β-adrenoceptor affinity was reduced in established EE2-, but not NG- or EE2/NG- induced hypertension. Moreover, the β-adrenoceptor agonist (-)-isoprenaline bound to renal β-adrenoceptors with reduced affinity following EE2 administration. Several endogenous and synthetic steroids were found to be ineffective inhibitors of [3H] –prazosin, [3H] –rauwolscine and ICYP binding excluding a direct interaction of these steroids with renal α1-, α2- and β -adrenoceptors. In Chapter 7, myocardial adrenoceptors were characterized and investigated in steroid-treated rats. In membrane preparations of whole myocardium, [3H]-prazosin binding was characteristically to α1- adrenoceptors, whereas there was a notable absence of [3H]-rauwolscine binding. Using ICYP, β-adrenoceptors were also detected, the ratio of β1- to β2~adrenoceptors being 3:1. Steroid contraceptive-induced hypertension was not associated with myocardial α1-adrenoceptor changes. Similarly, myocardial β-adrenoceptors were unchanged in established EE2-, NG- and EE2/NG-induced hypertension (12 weeks treatment). The affinity of (-)-isoprenaline for myocardial β-adrenoceptors was unaffected by EE2 aditiinistration. These studies suggest that established EE2- but not NG-induced hypertension in rats is associated with selective alterations in renal α2- and (β-adrenoceptors. These adrenoceptor changes may help to maintain elevated blood pressure by affecting the control of renal function by the sympathetic nervous system, catecholamines and several hormones which affect renin release and the transport of fluid and electrolytes in the nephron.

Perceptions and experiences of taking oral hypoglycaemic agents among people of Pakistani and Indian origin : qualitative study

Objective:  To explore British Pakistani and British Indian patients’ perceptions and experiences of taking oral hypoglycaemic agents (OHAs).
Design : Observational cross sectional study using in-depth interviews in English or Punjabi.
Setting and participants : 32 patients of Pakistani and Indian origin with type 2 diabetes, recruited from primary care and community sources in Edinburgh, Scotland.
Results : Respondents reported complex and ambivalent views about OHAs, which reflected their ambivalent attitudes towards Western drugs in general. Respondents considered OHAs to be an important part of the diabetic regimen because they perceived British healthcare professionals to be competent and trustworthy prescribers, and they considered the medicines available in Britain to be superior to those on the Indian subcontinent. Despite this, some respondents made deliberate efforts to reduce their tablet intake without being advised to do so. Reasons for this included perceptions that drugs worked by providing relief of symptoms and concerns that OHAs could be detrimental to health if taken for long periods, in conjunction with other drugs, or without traditional foods.
Conclusions : British Pakistani and Indian patients’ perceptions of their OHAs may partly derive from popular ideas about drugs on the Indian subcontinent. Cultural factors need to be understood and taken into consideration to ensure that these patients are given appropriate advice and to avoid unnecessary changes to prescriptions.

Goblet cell carcinoid tumors (adenocarcinoid) of the appendix

Purpose: Goblet cell appendiceal carcinoids represent rare tumors that exhibit histologic features of both adenocarcinomas and neuroendocrine tumors. We present the long-term results of a series of 15 patients, focusing on clinical manifestations, diagnosis, and management.

Methods: Eight male and seven female patients (median age, 52.8 years) were included. Final diagnosis was confirmed by histology. Patients were evaluated clinically, biochemically, and radiologically every four months. Median follow-up was 30 months.

Results: The majority of patients (7/15) presented with symptoms compatible with acute appendicitis. Right hemicolectomy was performed in all except one, who subsequently developed metastases. Three patients had metastases at previous diagnosis. Plasma chromogranin-A was slightly elevated in two of them, while urinary 5-hydroxy-indol-acetic acid was normal. 111Indium-labeled octreotide scintigraphy was positive only in two of the four patients with metastases. Ki67 index was greater than 20 percent in all of them, while in only one with local tumor. Combination chemotherapy with either cisplatin plus etoposide or with 5-fluorouracil, cisplatin, and streptozotocin was administered to all patients with metastases resulting in temporary stabilization of disease. Twelve patients are alive, while three died of their disease 9, 13, and 14 months after diagnosis.

Conclusions: The diagnostic value of chromogranin-A, urinary 5-hydroxy-indol-acetic acid, and 111Indium-labeled octreotide scintigraphy seems to be limited in these tumors. Ki67 index appears to predict tumor behavior. Right hemicolectomy may reduce the risk of developing metastases. Chemotherapy may have efficacy in metastatic disease, however, more data are required to determine this and the optimal regimen.

Long lived multi-isotype anti-HIV antibody responses following a prime-double boost immunization strategy

Despite decades of work, an effective HIV vaccine remains elusive. In an effort to elicit protective immunity, investigators have sought to define vaccines able to elicit durable HIV-specific B-cell and T-cell activities. Additionally, vaccines are sought which can induce antibodies of a variety of isotypes, as each isotype possesses unique attributes in terms of opsonization, Fc receptor binding capacity, complement fixation and location. One prominent new vaccine strategy, applied to numerous distinct antigenic systems is the prime boost-regimen, with DNA, vaccinia virus (VV), and/or purified recombinant protein. To examine the durability, location and isotype distribution of responses induced by prime-boost regimens, we tested successive immunizations with DNA, VV and protein (D-V-P), comparing three forms of protein inoculations: (i) purified protein administered intramuscularly with complete Freunds adjuvant, (ii) purified protein administered intranasally, and (iii) purified protein conjugated to oxidized mannan, administered intranasally. We found that all three protocols elicited serum antibodies of multiple isotypes, with serum IgA being most prominent among mice immunized with mannan-conjugated protein. All D-V-P protocols, regardless of protein form or route, also elicited antibody responses at mucosal surfaces. In bronchoalveolar lavage, a tendency toward IgA production was again most prominent in mice boosted with the protein–mannan conjugate. Both B-cell and T-cell responses were sustained for more than 1 year post-immunization following each form of vaccination. Contemporaneous with long-lasting serum and mucosal antibodies were antibody forming cells in the bone marrow of primed animals. Results highlight the D-V-P vaccination strategy as a promising approach for attaining durable, multi-isotype B-cell and T-cell activities toward HIV.