Progressive systemic sclerosis: radionuclide esophageal scintigraphy and manometry

Radionuclide esophageal scintigraphy (RES) and manometry were used for prospective evaluation of esophageal involvement and disease severity in 11 patients (nine women and two men; median time since diagnosis, 1 year) with progressive systemic sclerosis (PSS). Quantitation of RES included calculation of the percentage of emptying at 30 seconds, while manometry provided measurements of proximal, distal, and lower esophageal sphincter (LES) pressures. The findings of both RES and manometry were abnormal in all 11 patients. There was a high correlation between the percentage of emptying and either distal esophageal pressure (r = .86, P less than .01) or LES pressure (r = .79, P less than .01). No significant correlation was found between the percentage of emptying and proximal esophageal pressure (r = .28, P = .39). RES is a safe, simple procedure that is readily accepted by patients and can be used in place of manometry for the detection and staging of esophageal involvement in PSS.     

Inhibition of intravascular thrombosis in murine endotoxemia by targeted expression of hirudin and tissue factor pathway inhibitor analogs to activated endothelium

We have generated transgenic mice expressing the leech anticoagulant hirudin and human tissue factor pathway inhibitor tethered to the cell surface by fusion with fragments of human CD4 and P-selectin. Expression of the transgenes is under the control of the CD31 (platelet endothelial cell adhesion molecule [PECAM]) promoter, limiting expression to endothelial cells, monocytes, and platelets. In addition, the P-selectin sequence directs expression to secretory granules. Functional cell surface expression only occurs when the cells are activated. In a mouse model of systemic lipopolysaccharide (LPS)-induced endotoxemia, we show that expression of either anticoagulant on activated endothelium inhibits the widespread intravascular thrombosis, thrombocytopenia, and consumptive coagulopathy associated with endotoxemia. Importantly, non- LPS-treated transgenic mice had normal baseline bleeding times. We speculate that targeted delivery of anticoagulants to the endothelium may be a strategy worth pursuing in clinical sepsis to improve efficacy of systemic anticoagulation while minimizing potential hemorrhagic side effects.     

Short- and long-term cause-specific survival of patients with inflammatory breast cancer

Background  

Inflammatory breast cancer (IBC) had been perceived to have a poor prognosis. Oncologists were not enthusiastic in the past to give aggressive treatment. Single institution studies tend to have small patient numbers and limited years of follow-up. Most studies do not report 10-, 15- or 20-year results.     

An in-service investigation of the additive effect of topical adrenergic agonists and beta-blockers

Background: We assessed the long-term additive effect of topical adrenaline or adrenaline precursor and betablockers because of doubts as to the presence and persistence of such an effect. Methods: In 43 patients (20 males and 23 females; mean (± SD) age 68.4 ± 11.5 years, range 24–84 years) on combined therapy for a mean 4.6 ± 4.4 years (range 3 months to 17 years) for chronic open-angle glaucoma, the adrenaline or adrenaline precursor drop was stopped for 4 weeks in both eyes of 27 patients and in one eye of 16 patients. Results: There was a mean rise in intra-ocular pressure (IOP) for the whole group from 17.5 ± 4.0 to 18.7 ± 4.9 mmHg (range 10–28 and 9–31 mmHg, respectively) on stopping adrenergic agonist drops. Three different responses were identified: (i) a rise in IOP < 2 mmHg (mean 5.8 ± 3.2 mmHg; range 3–14 mmHg) in 20 eyes of 15 patients; (ii) no rise or fall <2 mmHg in 43 eyes of 23 patients, with a mean rise of 0.2 ± 1.1 mmHg; and (iii) a fall in IOP of < 2 mmHg (mean 5.6 ± 3.2 mmHg; range 3-1 1 mmHg) in seven eyes of five patients. Conclusions: The effect of adrenergic agonist and betablocker drops is variable, but an additive effect may be strong and persistent in some eyes, suggesting considerable variation in the distribution and density of adrenoceptors in different eyes. Therefore, there may be some variation in the effect of new α₂-adrenoceptor agonists, but such effects should be additive to those of beta-blockers.     

Resistance to 6-thioguanine in mismatch repair-deficient human cancer cell lines correlates with an increase in induced mutations at the HPRT locus

Although the resistance to the cytotoxic response of certain DNA damaging agents has been well characterized in cells deficient in mismatch repair, little is known about how such resistance affects mutagenesis. Using human cancer cell lines defective in mismatch repair (MMR) and complementary cell lines in which the MMR defects were corrected by chromosome transfer, we present the cytotoxic effect and the mutagenic response at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus following exposure to the chemotherapeutic agent, 6-thioguanine (6-TG). Upon exposure to 6-TG, there was a differential cytotoxic response. The MMR-deficient cells were resistant to 6-TG exposure up to 5 microM, whereas the MMR-proficient cell lines were significantly more sensitive at the same levels of exposure. Furthermore, the mutagenic response at HPRT induced by 6-TG was substantially increased in the MMR-deficient lines relative to the MMR- proficient cell lines. These findings support the notion that cytotoxicity to 6-TG is mediated through functional MMR and that resistance to the cytotoxic effects of 6-TG is directly associated with an increase in induced mutations in MMR-defective cells. These data suggest that the use of 6-TG as a chemotherapeutic agent may result in the selection of MMR-defective cells, thereby predisposing the patient to an increased risk for developing secondary tumors.      

Salter-Harris II fracture of the proximal humerus in a preterm infant

A premature twin infant presented with clinical signs of shoulder injury shortly after birth. He had been delivered by cesarean section due to malpresentation. Bony abnormality was not initially recognized on plain radiographs, but ultrasound revealed a Salter-Harris II fracture of the proximal humerus. Plain radiographs are limited in the premature newborn because of lack of calcification of the epiphysis. Ultrasound examination in these infants can be helpful in determining the true extent of skeletal injury. Immobilization and pain control are then indicated to optimize the outcome.     

A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats

BACKGROUND: C5a has been implicated in numerous pathophysiological conditions, including ischemia/reperfusion (I/R) injury of the kidney. We examined whether a novel and specific C5a receptor antagonist, the cyclic compound AcF-[OPdChaWR] could moderate I/R-induced renal injury in rats. METHODS: Female Wistar rats were subjected to renal ischemia (60 min) and reperfusion (5 h). Rats were treated with either 1 mg/kg IV in 5% ethanol/saline or 10 mg/kg PO in 25% ethanol/saline prior to ischemia. I/R injury was characterized by significant tissue hemorrhage with increased microvascular permeability, elevated renal tissue levels of tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO), increased serum levels of creatinine and aspartate aminotransferase (AST) and hematuria. RESULTS: Pre-ischemic treatment with the C5a receptor (C5aR) antagonist (1 mg/kg IV or 10 mg/kg PO) substantially inhibited or prevented I/R-induced hematuria, vascular leakage, tissue levels of TNF-alpha and MPO, and serum levels of AST and creatinine. Histological examination of kidneys from antagonist pretreated I/R animals showed a marked reduction in tissue damage compared to drug-free I/R rats. This antagonist, however, did not inhibit complement-mediated lysis of red blood cells, suggesting unimpaired formation of the membrane attack complex (MAC). CONCLUSIONS: The results demonstrate for the first time that a selective antagonist of both human and rat C5a receptors, given either intravenously or orally, significantly protects the kidney from I/R injury in the rat. We conclude that C5a is an important pathogenic agent in renal I/R injury, and that C5a receptor antagonists may be useful therapeutic agents for the pretreatment of anticipated renal reperfusion injury in humans.     

The influence of GP and patient gender interaction on the duration of certified sickness absence

BACKGROUND: Little research has focused upon how GP and patient gender interact to influence the outcome of consultation. In particular, no UK studies have investigated the effect of gender interaction on the duration of patients' certified sickness. OBJECTIVE: To investigate associations between the four GP-patient gender interaction categories and patient risk of intermediate or long-term work incapacity. METHODS: Design: Use of carbonized sickness certificates to collect routine sick note data over a 12-month collection period. Setting: Nine general practices in the Mersey Primary Care R&D Consortium. Subjects: A total of 3906 patients, certified sick by 67 GPs (including 45 GP principals). Main outcome measures: The effect of gender interaction was measured against two outcomes: intermediate (6-28 week) and long-term (28 weeks or over) periods of certified sickness. RESULTS: After univariate and multivariate analyses, it was discovered that certification of male patients by male GPs was significantly associated with increased prevalence of intermediate (6-28 week) certified sickness outcomes, compared with females certified by females (OR=1.38 P=0.009). This result was replicated in the subgroup of patients with mild mental disorder-related sickness absence. However, no association was demonstrated between gender interaction and long-term (>or=28 week) outcome, in the total patient group or within diagnostic subcategories. CONCLUSION: GP and patient gender appear to have most impact upon sickness certification in the intermediate period. This period is already recognized as the optimum time for interventions to prevent onset of long-term incapacity, particularly in cases where the cause of sickness absence is reversible (as in psychological-related certified sickness absence). Further research is needed (particularly focusing upon attitudes and content of consultations) in order to shed more light on the gender differences found in this study.