EFFECT OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON NEUTROPHIL CHEMOTAXIS--AN IN VITRO AND IN VIVO STUDY

We have studied the effects of the two non-steroidal anti-inflammatorydrugs (NSAIDs), nabumetone and indomethacin, on neutrophil chemotaxisin vitro and in vivo. When used in therapeutic concentrationsin vitro, neither agent had any effect on the chemotactic responseof neutrophils isolated from healthy volunteers. This was truefor the three chemotactic agents studied: FMLP, zymosan activatedserum and purulent sputum. Nabumetone and indomethacin decreasedneutrophil chemotaxis over a period of 2 weeks in 12 normalsubjects in vivo. The average chemotactic response to 10^–8mol/1 FMLP for all 12 during the control period was 42.1 ±6.1 cells per high power field and this fell to 26.1 ±4.9 (P>0.025) after 7 days and to 15.6 ± 2.5 (P>0.005)after 14 days. The results were similar for both drugs analysedindependently. The results suggest that NSAIDs have no effect on the chemotacticresponse of mature cells in vitro, but suppress chemotaxis progressivelywhen given in vivo. This may be explained by an effect of NSAIDson maturing cells prior to release into the circulation KEY WORDS: Polymorphonuclear cells, Chemotaxis, Nabumetone, Indomethacin     

Subpectoral Implantation of ICD Generators: Long-Term Follow-Up

A nonthoracotomy surgical approach using an endocardial electrode and combined implantation of a subcutaneous patch and the implantable cardioverter defibrillator (ICD) generator in a Subpectoral pocket has been described. We report the long-term follow-up results in patients undergoing implantation using this approach. The patient population consisted of 28 patients (22 men and 6 women) with a mean age of 59 ± 12 years. The underlying heart disease consisted of coronary artery disease in 20 patients and dilated cardiomyopathy in 8 patients. Sustained ventricular tachycardia was the mode of presentation in 16 patients and sudden cardiac death in 12 patients. The mean left ventricular ejection fraction was 31%± 6%. The lead system consisted of an 8 French bipolar passive fixation rate sensing lead positioned at the right ventricular apex, an 11 French spring coil electrode positioned at the superior vena cava-right atrial junction (surface area 700 mm²), and submuscular placement of a large patch (surface area 28 cm²) on the anterolateral chest wall near the cardiac apex via a submammary incision. A defibrillation threshold of ≤ 15 joules (J) was required for implantation. This criterion was not satisfied in five patients; thus, a limited thoracotomy was performed via the submammary incision, and the large patch was placed epicardially. The mean R wave amplitude was 12 ± 3 mV, the mean pacing threshold was 1.0 ± 0.5 V at 0.5 msec, and the mean defibrillation threshold was 12.6 ± 3 J. ICD generators implanted were the Ventak-P in 17, PCD-7217 in 5, and the Cadence V-l00 in 6 patients. These patients have been followed for a mean of 14.6 ± 6 months. There was no perioperative mortality, and none of the patients developed an infection during follow-up. Generator migration or significant discomfort requiring ICD repositioning was not observed, although one patient developed an erosion requiring surgical repair.Conclusions: Subpectoral implantation of the ICD generator is feasible and was well tolerated by all patients with an acceptable complication rate (3.5%). As the size of future generation ICDs is reduced, subpectoral implantation may become the preferred approach.     

Treatment of patients with uric acid stones

Uric acid nephrolithiasis and unduly acidic urinary pH are both considered a renal manifestation of insulin resistance but the underlying mechanisms for the development of low urinary pH and the propensity for uric acid stone formation are not completely elucidated. Nevertheless, excessive dietary acid intake, increased endogenous acid production and/or defective NH4+ excretion play an important role, among other factors. The main principles of therapy for uric acid nephrolithiasis are aimed at urinary alkalinization through diet modification or pharmacologic agents, increase of urinary volume, and less importantly at the reduction of uric acid excretion.     

Preservation of urine samples for metabolic evaluation of stone-forming patients

Metabolic evaluation of stone-forming (SF) patients is based on the determination of calcium, oxalate, citrate, uric acid and other parameters in 24-h urine samples under a random diet. A reliable measurement of urinary oxalate requires the collection of urine in a receptacle containing acid preservative. However, urinary uric acid cannot be determined in the same sample under this condition. Therefore, we tested the hypothesis that the addition of preservatives (acid or alkali) after urine collection would not modify the results of those lithogenic parameters. Thirty-four healthy subjects (HS) were submitted to two non-consecutive collections of 24-h urine. The first sample was collected in a receptacle containing hydrochloric acid (HCl 6 N) and the second in a dry plastic container, with HCl being added as soon as the urine sample was received at the laboratory. Additionally, 34 HS and 34 SF patients collected a spot urine sample that was divided into four aliquots, one containing HCl, another containing sodium bicarbonate (NaHCO₃ 5 g/l), and two others in which these two preservative agents were added 24 h later. Urinary oxalate, calcium, magnesium, citrate, creatinine and uric acid were determined. Urinary parameters were also evaluated in the presence of calcium oxalate or uric acid crystals. Mean values of all urinary parameters obtained from previously acidified 24-h urine samples did not differ from those where acid was added after urine collection. The same was true for spot urine samples, with the exception of urinary citrate that presented a slight albeit significant change of 5.9% between samples in HS and 3.1% in SF. Uric acid was also not different between pre- and post-alkalinized spot urine samples. The presence of crystals did not alter these results. We concluded that post-delivery acidification or alkalinization of urine samples does not modify the measured levels of urinary oxalate, calcium, magnesium, creatinine and uric acid, and that the change on citrate was not relevant, hence allowing all parameters to be determined in a single urine sample, thus avoiding the inconvenience and cost of multiple 24-h urine sample collections.     

Linkage analysis of candidate regions for coeliac disease genes

A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.      

HPLC-MS analysis of Schisandra lignans and their metabolites in Caco-2 cell monolayer and rat everted gut sac models and in rat plasma

The absorption profiles of Schisandra chinensis were evaluated using the human Caco-2 cell monolayer and rat everted gut sac models, as well as in rat plasma. By analyzing the chromatographic and MSⁿ characteristics of individual peak acquired by HPLC-DAD-APCI-MSⁿ determination, thirteen lignans were identified as the major in vitro absorbable components of the Schisandra extract. Most of these compounds were also detected and identified in rat plasma after an oral administration of the Schisandra extract, except for angeloyl(tigloyl)gomisin H and angeloyl(tigloyl)gomisin Q, whose structures possess an ester group at the cyclooctadiene ring. In addition, four metabolites, corresponding to the hydroxylation and demethylation products of schisandrin and the hydrolysis derivative of angeloyl(tigloyl)gomisin Q, were tentatively identified. The results demonstrate that Schisandra lignans are the major absorbable components of this crude drug, and hydroxylation, demethylation and hydrolysis are important metabolic transformations of the absorbable lignans.     

Programming Antitachycardia Pacing for Primary Prevention in Patients With Implantable Cardioverter Defibrillators: Results From the PROVE Trial

Programming ATP for ICD Patients. Objectives: The PROVE trial was designed to determine if antitachycardia pacing (ATP) is clinically beneficial for primary prevention in patients who have implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT‐Ds). Background: Use of ICDs and CRT‐Ds reduces mortality in patients with ventricular dysfunction and mild to moderate heart failure. However, in studies of the primary prevention population, shock‐only ICDs are predominantly used, without ATP programming for less painful termination of ventricular tachycardia (VT). Methods: We conducted a prospective, nonrandomized, multicenter study using market‐released ICDs and CRT‐Ds. Patients received devices programmed to deliver ATP for VT cycle lengths of 270–330 ms. Follow‐up evaluation was performed at 3, 6, and 12 months. The incidence of VT and the rate of successful termination by ATP were analyzed. Results: Of 830 patients in the study population (men, 73%; mean age, 67.3 ± 12 years), 32% received single‐chamber ICDs, 44% dual‐chamber ICDs, and 24% CRT‐Ds. ATP was attempted for 112 VT episodes in 71 patients, and 103 (92%) of the VT episodes were successfully terminated. Three VT episodes were accelerated by ATP and required termination by ICD shock; 6 episodes terminated spontaneously or by ICD shock. Conclusions: VT is common in patients without a history of this arrhythmia who have received ICDs or CRT‐Ds for primary prevention indications. Programming ICDs for ATP therapy at the time of implantation could potentially terminate most VT episodes and reduce the number of painful shocks for these patients. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1349‐1354, December 2010)     

Relationship between Thrombophilic Disorders and Type of Severe Early-Onset Hypertensive Disorder of Pregnancy

Objective: To determine whether specific subtypes of early-onset hypertensive disorders of pregnancy (haemolysis, elevated liver enzymes, low platelets [HELLP] syndrome; severe preeclampsia; eclampsia; and fetal growth restriction) differ in increased prevalences of thrombophilic disorders. Design: Cohort study. Setting: Two university hospitals in Amsterdam, the Netherlands. Population: 216 patients participating in a randomized clinical trial with severe and early-onset hypertensive disorders of pregnancy. Methods: More than 3 months after delivery, all patients were invited for a thrombophilia screening protocol, including hereditary thrombophilic disorders (Factor II or V-Leiden mutation, APC-resistance, protein S deficiency), antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant activity), and hyperhomocysteinemia (before and after methionin challenge). Disease expression was classified by HELLP syndrome, severe preeclampsia, or neonatal birth weight ratio below the median (0.65). Univariate and multinomial regression analyses examined the association of disease expression with thrombophilic disorders, and other associated factors (chronic hypertension, smoking, body mass index, positive family history of cardiovascular morbidity, and demographic parameters). Main outcome measures: incidence of thrombophilic disorders in different subtypes of disease. Results: Overall prevalence of thrombophilic disorders in 206 (95%) screened women was 36%. Chronic hypertension was present in 32%, and 34% had a positive family history of cardiovascular morbidity. Multinomial regression analysis showed that hereditary thrombophilia was more frequent among women with infants with a birth weight ratio <0.65 than in women with HELLP syndrome or severe preeclampsia (p = 0.01, OR 5.1 (1.5 to 7.3) and OR 3.4 (1.1 to 10.6), respectively). High body mass index was less frequent in women with HELLP syndrome than in those with severe preeclampsia or fetal growth restriction (p = 0.06, OR 0.5 (0.3 to 0.9) and OR 0.4 (0.2 to 1.0), respectively). Conclusion: In this population, the high prevalence of thrombophilic factors and chronic hypertension was confirmed. There were small differences between groups. Hereditary thrombophilic disorders were associated with fetal growth restriction but not with type of maternal disease, suggesting an effect on placental function. Maternal body mass index was lower in women with HELLP syndrome.     

Interventions for replacing missing teeth: dental implants in fresh extraction sockets (immediate,immediate‐delayed and delayed implants)

Background:  ‘Immediate’ implants are placed in dental sockets just after tooth extraction. ‘Immediate‐delayed’ implants are those implants inserted after weeks up to about a couple of months to allow for soft tissue healing. ‘Delayed’ implants are those placed thereafter in partially or completely healed bone. The potential advantages of immediate implants are that treatment time can be shortened and that bone volumes might be partially maintained thus possibly providing good aesthetic results. The potential disadvantages are an increased risk of infection and failures. After implant placement in postextractive sites, gaps can be present between the implant and the bony walls. It is possible to fill these gaps and to augment bone simultaneously to implant placement. There are many techniques to achieve this but it is unclear when augmentation is needed and which could be the best augmentation technique. Objectives:  To evaluate success, complications, aesthetics and patient satisfaction between ‘immediate’, ‘immediate‐delayed’ and ‘delayed’ implants. To evaluate whether and when augmentation procedures are necessary and which is the most effective technique. Search strategy:  The Cochrane Oral Health Group’s Trials Register (to 2 June 2010), CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE via OVID (1950 – 2 June 2010) and EMBASE via OVID (1980 – 2 June 2010) were searched. Several dental journals were handsearched. Selection criteria:  Randomized controlled trials (RCTs) comparing immediate, immediate‐delayed and delayed implants, or comparing various bone augmentation procedures around the inserted implants, reporting the outcome of the interventions to at least 1 year after functional loading. Data collection and analysis:  Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted independently and in duplicate. Trial authors were contacted for any missing information. Results were expressed as random‐effects models using mean differences for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CIs). The statistical unit of the analysis was the patient. Main results:  Fourteen eligible RCTs were identified but only 7 trials could be included. Four RCTs evaluated implant placement timing. Two RCTs compared immediate versus delayed implants in 126 patients and found no statistically significant differences. One RCT compared immediate‐delayed versus delayed implants in 46 patients. After 2 years patients in the immediate‐delayed group perceived the time to functional loading significantly shorter, were more satisfied and an independent blinded assessor judged the level of the peri‐implant marginal mucosa in relation to that of the adjacent teeth as more appropriate (RR = 1.68; 95% CI 1.04 to 2.72). These differences disappeared 5 years after loading but significantly more complications occurred in the immediate‐delayed group (RR = 4.20; 95% CI 1.01 to 17.43). One RCT compared immediate with immediately delayed implants in 16 patients for 2 years and found no differences. Three RCTs evaluated different techniques of bone grafting for implants immediately placed in extraction sockets. No statistically significant difference was observed when evaluating whether autogenous bone is needed in postextractive sites (1 trial with 26 patients) or which was the most effective augmentation technique (2 trials with 56 patients). Authors’ conclusions:  There is insufficient evidence to determine possible advantages or disadvantages of immediate, immediate‐delayed or delayed implants, therefore these preliminary conclusions are based on a few underpowered trials often judged to be at high risk of bias. There is a suggestion that immediate and immediate‐delayed implants may be at higher risks of implant failures and complications than delayed implants. On the other hand the aesthetic outcome might be better when placing implants just after teeth extraction. There is not enough reliable evidence supporting or refuting the need for augmentation procedures at immediate implants placed in fresh extraction sockets or whether any of the augmentation techniques are superior to the others.