Macromolecular Prodrugs. XVI. Colon-Targeted Delivery—Comparison of the Rate of Release of Naproxen from Dextran Ester Prodrugs in Homogenates of Various Segments of the Pig Gastrointestinal (GI) Tract

We have determined initial rates of naproxen formation from dextran-naproxen ester prodrugs incubated in homogenates of various segments of the pig GI tract. Drug liberation proceeded 15–17 times faster in cecum and colon homogenates than in aqueous pH 7.4 buffer or homogenates of the small intestine. The degree of conjugate substitution did not affect the liberation rates, whereas enhanced drug activation was observed with decreasing molecular size of the carrier dextran. During incubation in colon homogenates the average molecular weight of the dextran prodrugs decreased. The mechanism of drug activation from the prodrugs may therefore involve an initial depolymerization step of the dextran chains by dextranases secreted from bacteria in the pig colon. The generated small fragments then serve as substrates for esterases and other hydrolases.     

Normative values for musculoskeletal- and neuromotor fitness in apparently healthy Norwegian adults and the association with obesity: a cross-sectional study

Background

Up-to-date research on musculoskeletal- and neuromotor fitness (MSMF) is lacking. The aims of the present paper were to a) establish normative values of MSMF by gender and age, and b) to assess how much of the variance in MSMF can be explained by obesity in adults.

Methods

A random selection of 726 Norwegians (20–65 years) participated in a national cross-sectional study. Muscular endurance, muscular strength, explosive power, flexibility and balance were assessed in addition to waist circumference (WC).

Results

Females displayed significantly higher scores compared to males on muscular endurance of the back extensors and on the flexibility tests (p?<?0.001). Males displayed significantly higher scores than females (p?<?0.001) on handgrip strength, modified push-ups, and explosive power. An inverse association was found between age and all MSMF scores for females (Beta:?0.06–(?0.92), p?≤?0.044) and males (Beta:?0.15–(0.91), p?≤?0.006), where younger participants displayed higher test scores on all MSMF tests, compared to older participants. Furthermore, participants showing higher scores on WC displayed lower scores on the following MSMF tests for both females and males: muscular endurance of the back extensors, balance, flexibility of the shoulder, and explosive power (p?<?0.001). Additionally, male participants with higher WC scores showed lower scores on muscular endurance of the upper body and flexibility of the hamstrings compared to males with lower WC scores (p?<?0.001).

Conclusions

The data provide normative values of MSMF for adults based on age and gender, and support an inverse relationship of MSMF to age and WC.

     

Effect of calibration material lot changes on results for the "SMAC"

The effect of two changes of calibration material (separated by five months) for the SMAC continuous-flow analyzer was followed by means of five quality-control indices: three normal and abnormal control sera, the mean of the central 50th percentile of patients' results, and the mean value for normal individuals. After the first and second changes of calibration materials, eight and six, respectively, of the 20 different tests exhibited statistically significant changes as shown by the indices. The cumulative shift for two of the 20 tests was considered medically significant. Prospective studies on split samples of patients' sera before the change in calibration material only predicted half the significant changes in test results later evidenced by the above-mentioned indices.     

N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin

Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.     

Principles of cancer treatment by radiotherapy

Radiotherapy plays an integral role in the management of more than 50% of cancer cases and 40% of patients cured of their cancer have radiotherapy as a part of their management. For some patients, it can be used definitively in place of surgery, offering the advantage of organ preservation. It is sometimes used before surgery to improve resection rates or after surgery to reduce recurrence rates. Outcomes may be improved if radiotherapy is combined with systemic therapies such as chemotherapy. The process of delivering radiotherapy is multi-level, involving clinical oncologists, medical physicists and therapeutic radiographers. Each step takes advantage of new technology that allows more accurate definition of the tumour and delivery of radiation, with the aim of improving treatment outcomes and reducing normal tissue toxicity. There have been significant advances in defining the target and delivering the radiation in the last few years, discussed further in this article.     

Three turbidimetric methods for determining total protein compared

We used human serum protein fractions to evaluate the sensitivity and bias of three turbidimetric methods for determining concentrations of proteins. Each fraction (Cohn Fractions II, III, IV, and V) was assigned a protein concentration value that was determined by the biuret method, which we calibrated with purified monomer of human serum albumin. All three turbidimetric methods (those involving sulfosalicylic acid/sodium sulfate, trichloroacetic acid, and alkaline benzethonium chloride) gave acceptable results for Fraction V with crystallized human serum albumin as the reference material, but there was bias by each of the three methods for the three globulin fractions. The method involving alkaline benzethonium chloride with measurement at 450 nm had the best sensitivity within the range of linearity and the most consistent bias among the three globulin fractions. These results define the dilemma for valid calibration of these methods for total serum protein in cerebrospinal fluid and urine.     

General practitioners’ views on leadership roles and challenges in primary health care: a qualitative study

Objective: To explore general practitioners’ (GPs) views on leadership roles and leadership challenges in general practice and primary health care.

Design: We conducted focus groups (FGs) with 17 GPs.

Setting: Norwegian primary health care.

Subjects: 17 GPs who attended a 5 d course on leadership in primary health care.

Results: Our study suggests that the GPs experience a need for more preparation and formal training for the leadership role, and that they experienced tensions between the clinical and leadership role. GPs recognized the need to take on leadership roles in primary care, but their lack of leadership training and credentials, and the way in which their practices were organized and financed were barriers towards their involvement.

Conclusions: GPs experience tensions between the clinical and leadership role and note a lack of leadership training and awareness. There is a need for a more structured educational and career path for GPs, in which doctors are offered training and preparation in advance.

• KEY POINTS

• Little is known about doctors’ experiences and views about leadership in general practice and primary health care. Our study suggests that:

• There is a lack of preparation and formal training for the leadership role.

• GPs experience tensions between the clinical and leadership role.

• GPs recognize leadership challenges at a system level and that doctors should take on leadership roles in primary health care.

     

<Emphasis Type="Italic">Helicobacter pylori</Emphasis>in apparently healthy children aged 0-12 years in urban Kampala,Uganda: a community-based cross sectional survey

Background

Helicobacter pylori is one of the most common causes of bacterial infection in human beings. Studies have showed a high prevalence of Helicobacter pylori among people in low-income countries and colonization early in life. A monoclonal antigen test, performed on faeces, HpSA^®ImmunoCardSTAT, has a high sensitivity, specificity and accuracy and the faecal test can be performed in all ages, also in resource-limited settings. The main objective of this study was to determine the prevalence and factors associated with Helicobacter pylori colonization in apparently healthy children aged 0-12 years in urban Kampala, Uganda.

Method

We tested 427 apparently healthy children, age 0-12 years (211 males, 216 females), in a cross sectional survey for Helicobacter pylori colonization using HpSA ^®ImmunoCardSTAT. A short standardized interview with socio-demographic information and medical history was used to assess risk factors.

Results

The overall prevalence of Helicobacter pylori in the 427 children was 44.3% (189 out of 427). Early colonization was common, 28.7%, in children younger than 1 year of age. The age specific rates were 46.0% in children age 1- < 3 years, 51.7% in children age 3- < 6 years, 54.8% in children age 6- < 9 years and 40.0% in children age 9- < 12 years. There was a significant difference in prevalence by gender; female 38.5% versus male 49.8% and by type of housing; permanent house 38.5% versus semi-permanent house 48.6%. Congestive living and education level of the female caretaker showed a clear trend for a difference in prevalence. Factors independently associated with Helicobacter pylori colonization included: drugs taken last three months, using a pit latrine, sources of drinking water and wealth index.

Conclusion

The prevalence of Helicobacter pylori colonization among urban Ugandan children is high at an early age and increases with age. The impact of Helicobacter pylori colonization on children's health in Uganda needs to be further clarified.