Detection and characterization of a novel functional polymorphism in the GSTT1 gene

A novel functional polymorphism in the GSTT1 gene associated with the non-conjugator phenotype has been identified. Sequencing of GSTT1 cDNA revealed a single nucleotide substitution, 310A>C, that altered the amino acid residue 104 from threonine to proline (T104P). Modelling studies of GSTT1 have suggested that residue 104 is located in the middle of alpha-helix 4. Introduction of an alpha-helix-disrupting proline most likely distorts the conformation of the protein. Individuals that lacked GSTT1 activity and carried the variant allele, tentatively denoted GSTT1*B, had no detectable GSTT1 immunoreactive protein. An allele-specific polymerase chain reaction method was developed to determine the frequency of the GSTT1*B allele. In 497 ethnic Swedes, the frequency of the active GSTT1*A allele was 0.65 [95% confidence interval (CI) 0.62-0.68] whereas the frequencies of the non-functional alleles GSTT1*O and the novel GSTT1*B allele were 0.34 (CI 0.31-0.37) and 0.01 (CI 0.01-0.02), respectively. In 100 Swedish Saamis, the GSTT1*B allele appeared to be slightly more common with a frequency of 0.03 (CI 0.01-0.07). The GSTT1 enzyme activity was measured in erythrocytes using methyl chloride as substrate. Individuals with the GSTT1*A/*A genotype had a two-fold higher GSTT1 activity compared to individuals with the GSTT1*A/*B genotype and subjects with the GSTT1*O/*B genotype totally lacked GSTT1 activity, indicating a strict gene-dose effect. By combining the analyses for the novel single nucleotide polymorphism with analyses for the deletion polymorphism, the accuracy in predicting all three GSTT1 conjugator phenotypes was improved from 96% to 99%.     

Do means matter?: Differences in characteristics of Finnish suicide completers using different methods

It is unclear whether suicides by different methods are distinguishable by their sociodemographic or clinical characteristics. We set out to investigate whether completed suicides by different methods show disparities in their sociodemographic and clinical characteristics. Within the National Suicide Prevention Project in Finland, all 1,397 suicides occurring April 1, 1987, through March 31, 1988, were investigated using the psychological autopsy method. Disparities were found in characteristics of suicide completers using different methods. Intoxication suicides were more often female and had a history of both previous attempts and psychiatric treatment, whereas suicides by shooting were the opposite in character. Victims using vehicle exhaust gas were most frequently younger males who had experienced a recent interpersonal loss or other adverse event and committed suicide while intoxicated with alcohol. Thus, typical characteristics associate with certain suicide methods, probably due to differences in availability and acceptability of the methods. Various restrictions on the availability of suicide methods are likely to exert their possible impact on somewhat different subpopulations at risk. In terms of suicide prevention, it seems reasonable to target availability restrictions for certain identifiable groups of potential suicide attempters. For instance, carefulness in the practice of prescribing of intoxicating substances to particular psychiatric patients seems justified.     

Comorbid substance use reduces the health care contacts of suicide attempters with schizophrenia spectrum or mood disorders

Utilization of health care services has been found to differ between psychiatric disorders. However, the pattern of health care contacts among suicide attempters with mental disorders is not known. This study systematically investigated the pattern of health care contacts among suicide attempters with schizophrenia spectrum versus mood disorders with or without comorbid substance use disorders both before and after attempted suicide. All consecutive medically treated suicide attempters in Helsinki from January 15, 1997, to January 14, 1998, were identified (n = 1,198). Data were gathered on all their health care contacts within the 12 months before and after the index attempt. Whereas the clear majority of all suicide attempters with schizophrenia spectrum or mood disorders had a treatment contact during the 30 days following the attempt, half of those with pure substance use disorders were without any contact with health care. Comorbid substance use made treatment less likely after attempted suicide among both psychiatric disorder groups; those with schizophrenia spectrum and comorbid substance use disorders were seven times more often left without aftercare recommendation than those without substance use comorbidity. Comorbid substance use disorders among suicide attempters with schizophrenia spectrum disorders decrease the likelihood of active aftercare, despite high suicide risk.     

Autologous stem cell transplantation in patients with mantle cell lymphoma

High-dose therapy followed by autologous stem cell transplantation (ASCT) has been considered a potential treatment approach in order to improve the poor prognosis in mantle cell lymphoma (MCL), but its role has not yet been clearly established. We analyzed retrospectively the outcome and prognostic factors in 48 consecutive patients with MCL scheduled for ASCT in five transplant centers. In 14 patients (29%), a sufficient amount of stem cells could not be collected. Mobilization failure was associated with female sex, blastoid cytology, and low hemoglobin level. Altogether 35 patients underwent ASCT, 24 patients as part of the first-line treatment and 11 patients later. After transplantation 28 patients (80%) remained in or achieved remission. Two patients died of transplant-related complications. During the median follow-up time of 38 months, nine patients have relapsed. The median event-free survival (EFS) was 39 months. Age over 60 years and elevated C-reactive protein level at diagnosis were associated with poorer outcome after transelantation. ASCT is an effective treatment in MCL with a high response rate and a longer survival than seen in conventionally treated patients. However, no plateau was seen in the EFS curve after ASCT. Whether cure Can be achieved in a proportion of patients with ASCT is currently unknown and should be studied in larger patient series with a longer follow-up.     

Specialization of tumour vasculature

Tumour blood vessels express markers that are not present in resting blood vessels of normal tissues, but that can be shared by angiogenic vessels in non-malignant conditions. Many of these proteins are functionally important in the angiogenic process. Some tumours also contain lymphatic vessels, as well as channels that consist of cancer cells and their extracellular matrix. These special features of tumour vessels are good targets for cancer therapies.     

Probiotic effects on faecal inflammatory markers and on faecal IgA in food allergic atopic eczema/dermatitis syndrome infants

Probiotic bacteria are proposed to alleviate intestinal inflammation in infants with atopic eczema/dermatitis syndrome (AEDS) and food allergy. In such infants we investigated effects of probiotic bacteria on faecal IgA, and on the intestinal inflammation markers tumour necrosis factor-alpha (TNF-alpha), alpha1-antitrypsin (AT), and eosinophil cationic protein (ECP). A total of 230 infants with AEDS and suspected cow's milk allergy (CMA) received in a randomized double-blinded manner, concomitant with elimination diet, Lactobacillus GG (LGG), a mixture of four probiotic strains (MIX), or placebo for 4 wk. Four weeks after treatment, CMA was diagnosed with a double-blind placebo-controlled milk challenge. Faecal samples of 102 infants, randomly chosen for analysis, were collected before treatment, after 4-wk treatment, and on the first day of milk challenge. After treatment, IgA levels tended to be higher in probiotic groups than in the placebo group (LGG vs. placebo, p=0.064; MIX vs. placebo, p=0.064), and AT decreased in the LGG group, but not in other treatment groups. After challenge in IgE-associated CMA infants, faecal IgA was higher for LGG than for placebo (p=0.014), and TNF-alpha was lower for LGG than for placebo, but non-significantly (p=0.111). In conclusion, 4-wk treatment with LGG may alleviate intestinal inflammation in infants with AEDS and CMA.     

A similar high level of immunoglobulin A and immunoglobulin G class milk antibodies and increment of local lymphoid tissue on the duodenal mucosa in subjects with cow's milk allergy and recurrent abdominal pains

In previous studies, we have reported endoscopic and histological alterations locally on the gastrointestinal (GI) tract associated with a gastrointestinal type of cow's milk allergy. In this study, we sought to further characterize endoscopic, and immunological findings in these children. We also hypothesized that the same type of immune responses might also be found in children with unexplained and recurrent abdominal pains. We did a gastroduodenoscopy for persistent GI symptoms, examined the mucosal histology of the small intestine and measured the antibodies to whole cow's milk and its fractions with an enzyme‐linked immunosorbent assay (ELISA) in a consecutive series of 22 subjects with untreated and 14 with treated cow's milk allergy (CMA) and 44 with recurrent abdominal pains (RAP). The immunological findings of the study subjects were compared with 54 controls. Lymphonodular hyperplasia (LNH) of the duodenum was the main endoscopic finding in 11 subjects (50%) with untreated and 5 (36%) with treated CMA. It was also found in 6 of 44 subjects with RAP. Compared with the controls, the patients with CMA showed significantly higher levels of IgA class antibodies to whole milk (p = 0.003) and βLG (p < 0.0001). Of the IgG class antibodies to βLG (p = 0.032), BSA (p < 0.0001) and αCAS (p < 0.0001) were significantly higher. The patients with LNH of the duodenal bulb as the main endoscopic finding showed significantly higher values of IgG class antibodies to βLG (p = 0.01) and αCAS (p = 0.005). Interestingly, the patients examined for RAP showed a similar increment in the pattern of whole milk and specific milk protein antibodies as the CMA children. In conclusion this study showed that gastrointestinal CMA beyond infancy is significantly associated with high levels of IgG and IgA class antibodies to milk and its fractions. As high levels of these antibodies and LNH of the duodenal bulb were also found in subjects with RAP, the study further suggests that gastrointestinal CMA might be one major reason for RAP.     

Arterial responses in vitro and plasma digoxin immunoreactivity after losartan and enalapril treatments in experimental hypertension

Treatment with the angiotensin-converting enzyme inhibitor, quinapril, has been shown to normalize increased dihydropyridine sensitivity and impaired potassium relaxation, characteristic features of arterial smooth muscle in spontaneously hypertensive rats, and also reduce the concentration of plasma digoxin-like immunoreactivity in these animals. However, whether angiotensin II receptor blocker therapy can beneficially influence these variables is not known. Therefore, we compared the effects of 10-week losartan and enalapril treatments (15 and 4 mg/kg/day, respectively) on functional responses of mesenteric arterial rings in spontaneously hypertensive rats and Wistar-Kyoto rats. Both losartan and enalapril normalized blood pressure, cardiac mass, and media to lumen ratio without significantly changing the media cross-sectional area in the mesenteric artery of spontaneously hypertensive rats (i.e. induced outward remodelling). The inhibitory effect of the calcium entry blocker nifedipine on calcium-evoked contractions was similar and less marked in arterial preparations from Wistar-Kyoto rats and losartan- and enalapril-treated spontaneously hypertensive rats than in those from untreated spontaneously hypertensive rats. Furthermore, the relaxations of arterial rings induced by the return of potassium to the organ bath (upon precontractions elicited by potassium-free solution) were used to evaluate the function of vascular Na+,K+-ATPase. The rate of potassium relaxation was faster in losartan- and enalapril-treated spontaneously hypertensive rats and all Wistar-Kyoto groups than in untreated spontaneously hypertensive rats, and the response was effectively inhibited by the sodium pump inhibitor ouabain. Both treatments especially augmented the ouabain-sensitive part of the potassium-relaxation in spontaneously hypertensive rats, indicating the involvement of the sodium pump in this response. However, no significant changes in plasma digoxin-like immunoreactivity were observed. In conclusion, the outward remodelling following long-term AT1-receptor blockade and angiotensin-converting enzyme inhibition in spontaneously hypertensive rats was associated with normalization of the increased dihydropyridine sensitivity of arteries. Both losartan and enalapril treatments also augmented arterial potassium relaxation in spontaneously hypertensive rats, suggesting enhanced function of Na+,K+-ATPase, but this effect could not be attributed to changes in circulating sodium pump inhibitor concentration.     

Intraoperative changes in coronary resistance during aortic valve replacement

Coronary vascular resistance was investigated in 10 patients undergoing aortic valve replacement using continuous constant-pressure coronary perfusion at 32 degrees C. After coronary flow was initiated, resistance was low but increased steadily until it reached a certain resting level. The plateau was attained faster after a short period of anoxia than after a longer period. The initial postischemic resistance was dependent on the duration preceding anoxia, being of the same magnitude after short and moderate periods of anoxia but significantly higher after a long period. This resistance difference between the groups lasted for the whole perfusion. The total coronary resistance and flow reached a plateau in 30 minutes, while resistance increased threefold but flow decreased to half of the initial postanoxia flow. Our results indicate the importance of initiating coronary perfusion soon after aortic cross-clamping to avoid increase in the initial vascular resistance and subsequent inadequate myocardial flow.     

Sentinel node metastasectomy in thin ≤1-mm melanoma

Background and aims Sentinel lymph node biopsy (SLNB) has been widely accepted as a precise tool to stage melanoma. In thin T1 melanomas (1 mm), the indication of SLNB is controversial since the risk of nodal metastasis is low. The aim of this study was to assess if SLNB detects occult nodal metastases among patients with thin melanomas.Patients and methods SLNB was performed prospectively in 135 patients with invasive melanoma in any depth category, including 56 T1 melanomas.Results Nodal metastases were detected in 18% by SLNB, and there were three sentinel-positive thin melanomas, constituting 5% of the T1 cases. Histopathologically, there were no factors of the primary tumors that would have predicted these metastases.Conclusion SLNB is a precise method to detect clinically silent nodal metastases in thin invasive melanoma. Certain histopathologic features of a thin primary lesion may correlate with the predictive probability of the sentinel node status. We were unable to identify these predictors, but the conclusions from this study are limited by the small sample size. Advanced melanoma is a lethal disease, and accurate staging is essential also in the T1 group. For stage III patients with occult nodal metastases, metastasectomy is a better option for cure than observation.