Mechanisms of pulmonary dysfunction after on-pump and off-pump cardiac surgery: a prospective cohort study

Background  

Pulmonary dysfunction following cardiac surgery is believed to be caused, at least in part, by a lung vascular injury and/or atelectasis following cardiopulmonary bypass (CPB) perfusion and collapse of non-ventilated lungs.     

Treatment of myofascial trigger points in common shoulder disorders by physical therapy: A randomized controlled trial [ISRCTN75722066]

Background  

Shoulder disorders are a common health problem in western societies. Several treatment protocols have been developed for the clinical management of persons with shoulder pain. However available evidence does not support any protocol as being superior over others. Systematic reviews provide some evidence that certain physical therapy interventions (i.e. supervised exercises and mobilisation) are effective in particular shoulder disorders (i.e. rotator cuff disorders, mixed shoulder disorders and adhesive capsulitis), but there is an ongoing need for high quality trials of physical therapy interventions. Usually, physical therapy consists of active exercises intended to strengthen the shoulder muscles as stabilizers of the glenohumeral joint or perform mobilisations to improve restricted mobility of the glenohumeral or adjacent joints (shoulder girdle). It is generally accepted that a-traumatic shoulder problems are the result of impingement of the subacromial structures, such as the bursa or rotator cuff tendons. Myofascial trigger points (MTrPs) in shoulder muscles may also lead to a complex of symptoms that are often seen in patients diagnosed with subacromial impingement or rotator cuff tendinopathy. Little is known about the treatment of MTrPs in patients with shoulder disorders.     

S-nitrosoglutathione-containing hydrogel accelerates rat cutaneous wound repair

BACKGROUND: Nitric oxide (NO) plays a key role in wound repair and S-nitrosothiols like S-nitrosoglutathione (GSNO) are well known NO donors. METHODS: Animals were separated in two groups and submitted to excisional wounds on the dorsal surface at the first day. GSNO (100 microm)-containing hydrogels were topically applied on the wound bed in the GSNO group, daily, during the first 4 days. Control group was topically treated with hydrogel without GSNO for the same period. Wound contraction and re-epithelialization were measured. Animals were sacrificed 21 days after wounding. Samples of lesion and normal tissue were formalin-fixed, paraffin embedded for histological analysis. RESULTS: Wound contraction, measured 14 and 21 days after wounding, was greater in the GSNO group than in the control group (P<0.05 for both). The re-epithelialized wound area, measured 14 days after wounding, was higher in the GSNO group than in the control group (P<0.05). A higher amount of inflammatory cells was observed in superficial and deep areas of the granulation tissue of the control group compared to the GSNO group. Twenty-one days after wounding, thin red-yellow collagen fibers arranged perpendicularly to the surface were found in the granulation tissue of the control group, whereas in the GSNO-treated group collagen fibers were thicker and arranged parallel to the surface. Increased number of mast cells was observed in the GSNO group compared with that in the control group. Vascularization and myofibroblast distribution were similar in both groups. CONCLUSION: Topical application of GSNO-containing hydrogel during the early phases of rat cutaneous wound repair accelerates wound closure and re-epithelialization and affects granulation tissue organization.     

The comparative pharmacokinetics of carboplatin and cisplatin in mice and rats

The plasma, urinary and biliary clearances of cisplatin and its non-nephrotoxic analogue, Carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II, CBDCA, JM8) have been determined in mice and rats following intravenous administration of the compounds. The plasma concentration-time curves were biphasic during the time period studied (0-60 min), with t1/2 alpha of 2-3 min for both platinum complexes and t1/2 beta of 10-15 min for cisplatin and 25-26 min for Carboplatin. The kinetic rate constants, k12 and k21, were similar for both Carboplatin and cisplatin, indicating that there was no appreciable net accumulation of the compounds in the peripheral tissues. Immediately after administration, Carboplatin became reversibly bound to plasma proteins in vivo to the extent of about 20%. Appreciable irreversible binding appeared after the first 60 min and increased steadily, so that by 4 hr only 34% of the compound was present in the plasma as the free drug. In comparison, binding of cisplatin to plasma was exclusively irreversible and, after the first 10 min, free drug disappeared rapidly, such that by 60 min free platinum was not detectable. The plasma clearance of free cisplatin (26.1 ml/min/kg) was significantly greater than that of either Carboplatin (10.3 ml/min/kg) or insulin (10.1 ml/min/kg). The main route of excretion of the two platinum complexes was via the urine, with 80-90% of Carboplatin and 43-48% of cisplatin being excreted within 4 hr. In the rat, the Carboplatin excreted in the urine was predominantly as the unchanged compound. The renal clearance of cisplatin (12.3 ml/min/kg) was significantly greater than that of either Carboplatin (9.3 ml/min/kg) or insulin (9.6 ml/min/kg), suggesting that cisplatin was excreted by an active renal secretory mechanism whilst Carboplatin was eliminated by glomerular filtration alone. Biliary excretion of the two compounds was only 0.4-1.2% of the administered dose in 6 hr, with biliary clearance of cisplatin (0.27 ml/min/kg) being fivefold greater than that of Carboplatin (0.053 ml/min/kg). The results indicate that the major pharmacokinetic differences between Carboplatin and cisplatin relate to their renal handling and their reactivity with macromolecules. These differences may well underline the substantial lack of Carboplatin nephrotoxicity in comparison with cisplatin.     

Long-Term Depression in Rat Cerebellum Requires both NO Synthase and NO-sensitive Guanylyl Cyclase

Long-term depression (LTD) of synaptic transmission between parallel fibres and Purkinje cells is a well-known example of synaptic plasticity taking place in the cerebellum. Nitric oxide (NO) has been implicated in synaptic plasticity in other brain areas, but its function in cerebellar LTD is controversial. Even when an involvement is suggested, the NO signal transduction pathway is unclear. One candidate is the cyclic GMP-synthesizing enzyme, soluble guanylyl cyclase, whose activity in the brain and elsewhere is powerfully stimulated by NO. By recording intracellularly from Purkinje cells in cerebellar slices, we demonstrate that blockade of NO synthase completely inhibits LTD induced by pairing parallel fibre stimulation with postsynaptic Ca²⁺ spike firing. LTD was also blocked by intracellular application of 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one, a recently identified potent and selective inhibitor of soluble guanylyl cyclase. These findings indicate that soluble guanylyl cyclase is required for cerebellar LTD and suggest that this enzyme, located within Purkinje cells, transduces the NO signal in this form of synaptic plasticity.     

Comparative distribution and excretion of carboplatin and cisplatin in mice

Summary The comparative distribution and excretion of Carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II, CBDCA, JM8) and cisplatin have been investigated in Balb C^- mice following i.v. administration of the maximally tolerated doses (MTDs) of the compounds. Although the concentrations of platinum in the plasma and tissues during the -phase were much higher for Carboplatin than for cisplatin, reflecting the difference in the doses used (4 vs 80 mg/kg), the tissue-to-plasma ratios were similar. During the -phase (1–10 days), however, both the platinum concentrations and the ratios were found to be similar for most tissues when cisplatin and Carboplatin were compared. The platinum concentrations and the tissue-to-plasma ratios of the spleen, brain, muscle, testes, ovary and bile, on the other hand, were consistently higher (two- to sixfold) after Carboplatin than after cisplatin. The highest ratios (>20) were found in the kidney, liver, spleen (after Carboplatin only) and skin at 6 days after treatment. Comparison of the two compounds showed that the half-lives of platinum in the plasma and tissues during both the - and -phases were similar, except for the spleen, in which a nine-fold greater t 1/2 was recorded for Carboplatin than for cisplatin. The main route of excretion for the two complexes is via the kidneys, with 52% of cisplatin and 93% of Carboplatin being excreted during the first 3 days. The major part of this, however, is excreted within the 1st day. These results indicate that, although there are quantitative differences, the distribution and excretion profiles are similar for Carboplatin and cisplatin.     

Disease associations and altered immune function in CD45 138G variant carriers

The CD45 antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor mediated signalling in lymphocytes. Expression of different patterns of alternatively spliced CD45 isoforms is associated with distinct functions. We recently identified a polymorphism in exon 6 (A138G) of the gene encoding CD45 (PTPRC) that results in altered CD45 splicing. The 138G allele is present at a high frequency among Japanese (23.7%), with 5.1% individuals homozygous for the G allele. In this study we show that the A138G polymorphism is the cause of altered CD45 isoform expression, promoting splicing towards low molecular weight CD45 isoforms. We further report that the frequency of A138G heterozygotes is significantly reduced in number in cohorts of patients with autoimmune Graves' disease or hepatitis B infection, whereas G138G homozygotes are absent from a cohort of Hashimoto's thyroiditis patients. We also show that 138G individuals exhibit altered cytokine production in vitro and an increased proportion of memory T cells. These data suggest that the 138G variant allele strongly influences these diseases by modulation of immune mechanisms and may have achieved its high frequency as a result of a natural selection probably related to pathogen resistance.     

Routine antenatal screening for hepatitis B using pooled sera: validation and review of 10 years experience.

AIMS: To validate the sensitivity of universal antenatal screening for hepatitis B surface antigen (HBsAg) by testing pools of 10 sera, and to review 10 years' experience using this method. METHODS: 66,945 antenatal patients were tested between 1986 and 1996 using the pooled method. All sera from 1996 (n = 6050) were retrieved and retrospectively tested individually. An in vitro determination of the effect of pooling on sensitivity was performed by checkerboard neutralisation assay. RESULTS: 26 HBsAg positive women were detected by universal screening over 10 years; 12 had non-European surnames and five had known risk factors for hepatitis B infection. High titre anti-HBs sera in the pool reduced the sensitivity of the HBsAg assay, though the effect was only significant at low levels of HBsAg carriage. CONCLUSIONS: The prevalence of hepatitis B is extremely low in the antenatal population served by Plymouth PHL. Pooling is unlikely to reduce sensitivity enough to lead to significant preventable vertical transmission, and is a cost-effective and valid strategy in areas of low seroprevalence.     

Epidemiology of precore mutants of hepatitis B in the United Kingdom

A point mutation assay was used to study the codon 28 and codon 1 precore mutant status of 310 chronic hepatitis B carriers (82 HBeAg positive and 228 HBeAg negative). Fourteen of 228 (6%) of HBeAg negative carriers had high levels of serum HBV DNA. Nine of these were explained by precore variants, three by core promoter variants, and two were not explained by recognised precore changes. Nested PCR detected serum HBV DNA in 36% (82/228) of HBeAg negative carriers and 63% (52/82) of these had precore variants. Four of 82 (4%) of the HBeAg positive carriers had precore variants, all as mixed mutant/wild type populations and evidence indicated that these carriers were seroconverting. Overall 23% (52/228) of HBeAg negative carriers had both serum HBV DNA and codon 1 or 28 precore mutations. A sexual transmission event from an HBeAg negative carrier with a relatively low serum HBV DNA level (10(4)-10(6) genome copies/ml) and only core promoter mutations was observed. Despite high rates of variant carriage in the antenatal sub-group perinatal transmission was not observed. The results of direct sequencing on 45 carriers validated the point mutation assay and also showed that codon 28 mutations were only seen in carriers with the genotype CCT at codon 15. For the Caucasian population a higher prevalence of codon 28 mutations (13/25 or 52%) than expected was seen. Liver biopsy data indicated that there was no link between the presence or absence of precore mutants and the severity of liver disease.