Analyzing atopic and non-atopic asthma

There is a need to better define phenotypes of asthma. However, many studies have data available only on asthma and atopy, so they are often used to define ‘atopic’ and ‘non-atopic’ asthma. We discuss and illustrate the problems of analyzing such outcomes. We used the 31 year follow-up of the Northern Finland Birth Cohort 1966 (n=5,429). ‘Atopic asthma’ and ‘non-atopic asthma’ were defined based on presence or absence of atopy (any skin prick test ≥3 mm) at age 31. Gender and ownership of cat in childhood were used as risk factors. Simple calculations on hypothetical datasets were used to support the conclusions. ‘Atopic asthma’ and ‘non-atopic asthma’, are not well separated disease entities. The association of a risk factor with ‘atopic asthma’ and ‘non-atopic asthma’ is determined both by its association with asthma and with atopy. E.g. if a risk factor is not associated with asthma, but is protective for atopy, this will produce a protective association with ‘atopic asthma’, but an opposite association with ‘non-atopic asthma’. This is the result from the typical analysis, which uses all non-asthmatics as the comparison group. Valid results, unconfounded by atopy, can be gained by comparing asthmatics to nonasthmatics separately among atopics and non-atopics, i.e. by doing the analysis stratified by atopy. If data only on asthma and atopy are available, asthma and atopy should be analyzed at first as separate outcomes. If atopic and nonatopic asthma are used as additional outcomes, valid results can be gained by stratifying the analysis by atopy.     

Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine.

Members of the vascular endothelial growth factor (VEGF) family are among the most powerful modulators of vascular biology. They regulate vasculogenesis, angiogenesis, and vascular maintenance during embryogenesis and in adults. Because of their profound effects on blood vessels, VEGFs have received much attention regarding their potential therapeutic use in cardiovascular medicine, especially for therapeutic vascular growth in myocardial and peripheral ischemia. However, completed randomized controlled VEGF trials have not provided convincing evidence of clinical efficacy. On the other hand, recent preclinical proangiogenic VEGF studies have given insight, and anti-VEGF studies have shown that the disturbance of vascular homeostasis by blocking VEGF-A may lead to endothelial dysfunction and adverse vascular effects. Excess VEGF-A may contribute to neovascularization of atherosclerotic lesions but, currently, there is no evidence that transient overexpression by gene transfer could lead to plaque destabilization. Here, we review the biology and effects of VEGFs as well as the current status of clinical applications and future perspectives of the therapeutic use of VEGFs in cardiovascular medicine.     

Self-reported temporomandibular disorder symptoms and severity of malocclusion in prospective orthognathic-surgical patients

Objective: The objective of this study is to analyze the association between self-reported symptoms of temporomandibular joint disorder (TMD) and the severity of malocclusion in prospective orthognathic-surgical patients.

Material and methods: The subjects consisted of 50 consecutive patients (13 males and 37 females) referred to two university clinics for assessment of orthodontic-surgical treatment need. Data considering self-reported TMD symptoms were gathered using a semi-structured diary. At the first appointment, all patients rated the importance of treatment (on a scale of 1–10) and assessed self-perceived dental appearance using a VAS scale. The scale was anchored with photographs 1 and 10 from the Aesthetic Component (AC) of the Index of Orthodontic Treatment Need (IOTN). Study models were assessed by an experienced orthodontic specialist using the Peer Assessment Rating (PAR) index and the Index of Complexity, Outcome and Need (ICON). Association between the PAR and ICON scores and the number of reported symptoms was analyzed statistically.

Results: Seventy-one percent of patients reported experiencing TMD symptoms. The most prevalent symptoms were pain in the head and/or neck region and fatigue in the TMJ region. The number of symptoms was highest in the morning. Ninety percent of males and 86% of females rated the importance of treatment as high; males experiencing TMD symptoms tended to rate surgery as more important compared with males with no symptoms (p?=?0.056).

Conclusions: In this sample, the results cannot unambiguously confirm an association between self-reported symptoms of TMD and objectively defined severity of malocclusion.     

Impaired negative chronotropic response to adenosine in patients with inappropriate sinus tachycardia

INTRODUCTION: Adenosine is an endogenous nucleoside that has an important role in the diagnosis and treatment of several cardiac arrhythmias. However, its effects on inappropriate sinus tachycardia (IST) are not well established. METHODS AND RESULTS: In this study, the response to intravenous adenosine (0.1 to 0.15 mg/kg) was studied in 18 patients (age 46+/-15 years) with IST. In a subset of patients (n = 5), the direct effects of adenosine were assessed during pharmacologic beta-adrenergic and cholinergic blockade. Atrial cycle length (ACL) was measured before adenosine injection, at the time of the greatest cycle length prolongation, and during the maximum rebound acceleration of heart rate. Eighteen subjects (age 46+/-11 years) with normal sinus rhythm undergoing clinically indicated electrophysiologic study served as controls. Adenosine did not terminate IST in any patient. The maximum dose of adenosine prolonged the sinus interval significantly, from 780+/-128 msec to 985+/-225 msec (P < 0.001) in the control subjects. In contrast, adenosine caused no significant lengthening of atrial cycle length (527+/-69 msec vs 590+/-148 msec; P = NS) in the patients with IST. Similar difference in the response to adenosine was seen during the pharmacologic autonomic blockade. The reflex increase of the sinus rate (rebound effect) was greater in the control subjects than in the patients with IST (21.2%+/-9.7% vs 8.5%+/-8.8%; P < 0.001). CONCLUSION: The usual negative chronotropic effect of adenosine was impaired in the patients with IST. This may have important diagnostic implications and provide new insight into the mechanism(s) of IST.     

N-acetyl-l-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway

First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy.     

Evolution of gastritis in patients with gastric erosions

Objective. Gastric erosions are mainly associated with Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs), but there has been no information available on the long-term evolution of gastritis in subjects with erosions. Material and methods. A series of 117 patients with gastric erosions without peptic ulcer disease and matched controls without erosions or ulcers were studied. Available subjects underwent endoscopy and biopsy 17 years later. Parietal cell antibodies were analysed at the first visit. Results. Fifty-two patients and 67 controls were available for follow-up. Since H. pylori was a major determinant of gastritis, only subjects with unchanged H. pylori status were included in the evaluation of gastritis progression. At the follow-up visit, gastric erosions were present in 38% (16/42) of the patients and 11% (5/46) of the controls (p=0.005). In H. pylori-negative subjects, no evolution of histological changes was seen. In H. pylori-positive subjects, body gastritis was initially less active in the erosion group. With time, antral gastritis worsened only in the erosion group. Parietal cell antibodies were more common in the control group (23%; erosion patients 0%; p=0.01), which also showed worsening of gastritis (p=0.003) and aggravation of atrophy (p=0.002) in the body mucosa. Conclusions. Gastritis in H. pylori-positive subjects with gastric erosions shows evolution of antral predominance, body predominance including development of atrophic changes being rare. Accordingly, patients with erosions share the characteristics of gastritis of the duodenal ulcer phenotype. These findings support the importance of H. pylori and acid in the pathogenesis of gastric erosions in H. pylori-positive patients.     

Two common mutations in the CLN2 gene underlie late infantile neuronal ceroid lipoluscinosis

Zhong N, Wisniewski KE, Hartikainen J, Ju W, Moroziewicz DN, McLendon L, Sklower Brooks S, Brown WT. Two common mutations in the CLN2 gene underlie late infantile neuronal ceroid lipofuscinosis
Late infantile neuronal ceroid lipofuscinosis (LINCL) is one of the most common pediatric neuronal degenerative disorders. A candidate gene underlying this disease, designated CLN2, was recently cloned and the gene product was characterized as a lysosomal pepstatin-insensitive carboxypeptidase (LPIC). Four mutations were identified in CLN2 from three unrelated LINCL individuals. To investigate further the mutation frequency in LINCL, we screened 16 LINCL probands for these four mutations. The previously reported intronic mutation, T523–1 G°C, was found in 56% (9/16) of the cases, of which two were homozygous and accounted for 34% (11/32) of LINCL chromosomes. The previously reported nonsense mutation, 636 C→T leading to R208stop, was found in 31% (5/16) of the cases, including one ho-mozygote and accounted for 19% (6/32) of LINCL chromosomes. Two previously described missense mutations, 1107 T°C and 1108 G→A, were not detected in any of these 16 probands. In total, the two observed mutations, T523–1 G°C and 636 C→T, accounted for 53% (17/32) of LINCL alleles. Thus, one or both mutations were seen in 11 (69%) cases and no mutation has yet been identified in five. Our finding that these two mutations are common in LINCL cases adds further evidence in support of the idea that dysfunction of LPIC underlies LINCL. Positive molecular testing can now complement clinical diagnosis of LPIC and will allow for pre-natal diagnosis for subsequent pregnancies.     

Mitral valve replacement with ball and tilting disc valve prosthesis. A clinical and haemodynamic study.

A survey is presented on the results of 100 consecutive patients who underwent mitral valve (78 patients) or mitral and aortic and/or tricuspid valve replacement (22 patients) with ball or disc valve prosthesis. The patients were followed-up from 6 to 54 months postoperatively. The mortality for mitral valve replacement was 13 (17%) early deaths (up to one month from operation) and 5 (6%) late deaths. The corresponding figures for multiple valve replacements were 9 (41%) and 3 (14%). A direct correlation was found between early mortality and preoperative functional class IV of the New York Heart Association (30% dead). Pulmonary hypertension combined with multiple valve disease resulted in an early mortality of 42%. No significant differences in early mortality figures after MVR were found between ball and disc valve prostheses. Predominant complications were respiratory infection and atelectasis (13%), acute myocardial infarction (11%) and haemorrhage (9%). Haemolysis was found in 9 patients and three other patients had haemolytic anaemia attributable to paravalvular leak which in two indicated the reapplication of the prosthesis. The main causes of death were heart failure, 8 early and 4 late deaths, and myocardial infarction, 5 and 4 respectively.