Botulinum neurotoxin type A inhibits synaptic vesicle 2 expression in breast cancer cell lines

Aim: It is known that botulinum neurotoxin type A (BoNTA) improves some kinds of cancer (e.g. prostate) and that synaptic vesicle glycoprotein 2 (SV2) is the molecular target of this neurotoxin. Besides having potential therapeutic value, this glycoprotein has recently been proposed as a molecular marker for several types of cancer. Although the mechanisms of cancer development and the improvement found with botulinum treatment are not well understood, the formation of the botulinum-SV2 complex may influence the presence and distribution of SV2 and the function of vesicles. To date, there are no reports on the possible effect of botulinum on breast cancer of unknown causes, which have a great impact on women’s health. Thus we determined the presence of SV2 in three breast cancer cell lines and the alterations found with botulinum application. Materials and methods: With and without adding 10 units of botulinum, SV2 protein expression was determined by optical densitometry in T47D, MDA-MB-231 and MDA-MB-453 cell lines and the distribution of SV2 was observed with immunochemistry (hematoxylin staining). Results: The SV2 protein was abundant in the cancer cells herein tested, and maximally so in T47D. In all three cancer cell lines botulinum diminished SV2 expression, which was found mostly in the cell periphery. Conclusion: SV2 could be a molecular marker in breast cancer. Its expression and distribution is regulated by botulinum, suggesting an interesting control mechanism for SV2 expression and a possible alternative therapy. Further studies are needed in this sense.     

Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability ( approximately 2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species.      

HLA antigens in Omani patients with vitiligo

Fifty native Omanis with vitiligo were studied to compare the incidence of HLA ABC and DR antigens with a control population. HLA Bw6 was found in 82% of patients compared with 49% controls (P_c= 0.0009 RR = 4.56) and HLA DR7 occurred in 40% of patients and 9% in controls (P_c= 0.00075 RR = 6.17). HLA DR7 was significantly increased in those patients with acrofacial, compared to focal disease (57% vs. 24%P= 0.038). Sixty-six per cent of the patients in this study had parents who were consanguineous and a positive family history was only found in this group with an incidence of 32%. HLA Bw4 segregated 100% with patients with a positive family history compared with 48% in consanguineous patients without a positive family history (P_c= 0.011 RR = 23). Vitiligo appears to be associated with different HLA antigens in different ethnic groups.     

Haemodynamic parameters predicting variceal haemorrhage and survival in alcoholic cirrhosis

The relationship between the various haemodynamic abnormalities observed in cirrhosis and their prognostic value remains unclear. We report haemodynamic measurements on 96 patients with alcoholic cirrhosis (mean Childs-Pugh Score, CPS, 9.0 +/- 0.2, mean age 55.6 +/- 1.0 years) and assess their value in predicting variceal bleeding and death during a mean follow-up of 19.3 +/- 1.5 months. Baseline CPS correlated with hepatic venous pressure gradient (HVPG) (p = 0.001), azygos blood flow (p < 0.05), cardiac index (p < 0.05), and inversely with mean arterial pressure (p < 0.01) and systemic vascular resistance index (p < 0.05). Renal blood flow was not related to any haemodynamic parameter or CPS. Thirty-eight patients died during follow-up, and 16 had a variceal bleed. Death (p = 0.001) and variceal bleeding (p < 0.05) were more likely in patients with HVPG > 16 mmHg than in those with HVPG < 16 mmHg, and variceal bleeding was more likely in patients with HVPG > 12 mmHg (vs. HVPG < 12 mmHg, p < 0.05). HVPG also predicted death and variceal haemorrhage on univariate and multivariate analyses. No other haemodynamic parameter predicted death or bleeding. In alcoholic cirrhosis, severity of liver disease is related to HVPG, collateral blood flow and degree of systemic circulatory abnormalities. HVPG is a useful predictor of survival and variceal bleeding in these patients.      

Specific antibodies to Trypanosoma cruzi among blood donors in Los Angeles, California

BACKGROUND: Trypanosoma cruzi, the cause of Chagas' disease, is often transmitted by transfusion in Latin America. Previous studies showed that at least 1 in 1000 eligible blood donors at the Los Angeles County+University of Southern California (LAC+USC) Medical Center Blood Bank had specific antibodies to T. cruzi. In June 1993, serologic screening of prospective allogeneic donors at epidemiologic risk for T. cruzi infection was begun voluntarily. STUDY DESIGN AND METHODS: The risk of T. cruzi infection in all eligible donors was assessed by questionnaire. At-risk donors were screened serologically for antibodies to T. cruzi with an enzyme immunoassay, and confirmatory testing was done with a radioimmunoprecipitation assay. RESULTS: During the 29-month study period 1311 (39.5%) of 3320 donors were judged to be at risk for T. cruzi infection. Seven donors (1/475) were reactive by an enzyme immunoassay, and six of these seven (1/ 553) were positive in a radioimmunoprecipitation assay. All radioimmunoprecipitation assay- positive donors had been born in countries in which Chagas' disease is endemic. One person in this group had received a transfusion in his homeland. CONCLUSION: These results demonstrate that a substantive proportion of eligible blood donors at our institution have antibodies specific for T. cruzi and that a commercially available assay can be used to detect these antibodies. Our data suggest that the risk of transmission of T. cruzi by transfusion could be eliminated by serologic testing limited to persons born in or transfused in countries in which Chagas' disease is endemic.     

Human T-lymphotropic virus type I and type II infections and correlation with risk factors in blood donors from Sao Paulo, Brazil

BACKGROUND: Little is known about the prevalence of and risk factors for human T-lymphotropic virus type I and type II (HTLV-I, HTLV-II) infections in Brazil. STUDY DESIGN AND METHODS: Sera from 17,063 healthy Brazilian donors were screened by enzyme-linked immunosorbent assay for antibody to HTLV-I/II between August 1991 and July 1993. Repeatedly reactive samples were confirmed by Western blot, and discrimination between HTLV-I and HTLV-II was made by polymerase chain reaction or synthetic peptide enzyme-linked immunosorbent assay. A univariate analysis was performed on demographic and serologic data. RESULTS: HTLV-I infection was demonstrated in 83 percent of the 30 donors with reactive serologic tests (0.15% of the total tested [17,063]; 95% CI, 0.09-0.20) and HTLV-II infection in 17 percent (0.03% of the total tested [17,063]; 95% CI, 0.01-0.05). HTLV-I-positive donors were more likely than reference groups to be of Asian ethnicity (odds ratio [OR] 15.1; reference group: whites), more than 50 years old (OR 4.2; reference group: 20–29 years old), and positive for antibody to hepatitis C virus (anti-HCV) (OR 21.8) or to hepatitis B core (antigen) (anti-HBc) (OR 5.7). HTLV-II showed a significant association with anti-HCV (OR 75.2) and anti-HBc (OR 21.8). Eleven of the 25 HTLV-I- positive donors were counseled. Family origin in endemic areas of Japan (n = 4), prior blood transfusion (n = 3), or sexual contact with prostitutes (n = 1) were the risk factors reported by 8 donors. In 3 white men, no risk factors could be identified. CONCLUSION: Both HTLV-I and HTLV-II occur among Brazilian blood donors. HTLV-I is associated with Asian ethnicity, greater age, and the presence of anti-HCV and anti-HBc. Three HTLV-I-positive donors had a history of blood transfusion, which emphasizes the need for HTLV-I/II screening in Brazil.     

Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients

Introduction

The aim of this study was to investigate whether in-hospital mortality was associated with the administered fraction of oxygen in inspired air (FiO₂) and achieved arterial partial pressure of oxygen (PaO₂).

Methods

This was a retrospective, observational study on data from the first 24 h after admission from 36,307 consecutive patients admitted to 50 Dutch intensive care units (ICUs) and treated with mechanical ventilation. Oxygenation data from all admission days were analysed in a subset of 3,322 patients in 5 ICUs.

Results

Mean PaO₂ and FiO₂ in the first 24 h after ICU admission were 13.2 kPa (standard deviation (SD) 6.5) and 50% (SD 20%) respectively. Mean PaO₂ and FiO₂ from all admission days were 12.4 kPa (SD 5.5) and 53% (SD 18). Focusing on oxygenation in the first 24 h of admission, in-hospital mortality was shown to be linearly related to FiO₂ value and had a U-shaped relationship with PaO₂ (both lower and higher PaO₂ values were associated with a higher mortality), independent of each other and of Simplified Acute Physiology Score (SAPS) II, age, admission type, reduced Glasgow Coma Scale (GCS) score, and individual ICU. Focusing on the entire ICU stay, in-hospital mortality was independently associated with mean FiO₂ during ICU stay and with the lower two quintiles of mean PaO₂ value during ICU stay.

Conclusions

Actually achieved PaO₂ values in ICU patients in The Netherlands are higher than generally recommended in the literature. High FiO₂, and both low PaO₂ and high PaO₂ in the first 24 h after admission are independently associated with in-hospital mortality in ICU patients. Future research should study whether this association is causal or merely a reflection of differences in severity of illness insufficiently corrected for in the multivariate analysis.     

Targeted inhibition of the serotonin 5HT2A receptor improves coronary patency in an in vivo model of recurrent thrombosis

Summary. Background: Release of serotonin and activation of serotonin 5HT_2A receptors on platelet surfaces is a potent augmentative stimulus for platelet aggregation. However, earlier‐generation serotonin receptor antagonists were not successfully exploited as antiplatelet agents, possibly owing to their lack of specificity for the 5HT_2A receptor subtype. Objective: To assess whether targeted inhibition of the serotonin 5HT_2A receptor attenuates recurrent thrombosis and improves coronary patency in an in vivo canine model mimicking unstable angina. Methods: In protocol 1, anesthetized dogs were pretreated with a novel, selective inverse agonist of the 5HT_2A receptor (APD791) or saline. Recurrent coronary thrombosis was then initiated by coronary artery injury + stenosis, and coronary patency was monitored for 3 h. Protocol 2 was similar, except that: (i) treatment with APD791 or saline was begun 1 h after the onset of recurrent thrombosis; (ii) template bleeding time was measured; and (iii) blood samples were obtained for in vitro flow cytometric assessment of platelet responsiveness to serotonin. Results: APD791 attenuated recurrent thrombosis, irrespective of the time of treatment: in both protocols, flow–time area (index of coronary patency; normalized to baseline coronary flow) averaged 58–59% (P < 0.01) following administration of APD791 vs. 21–28% in saline controls. Moreover, the in vivo antithrombotic effect of APD791 was not accompanied by increased bleeding, but was associated with significant and selective inhibition of serotonin‐mediated platelet activation. Conclusion: 5HT_2A receptor inhibition with APD791, even when initiated after the onset of recurrent thrombosis, improves coronary patency in the in vivo canine model.     

Effect of climate therapy at Gran Canaria on vitamin D production, blood glucose and lipids in patients with psoriasis

Background Climate therapy (heliotherapy) of psoriasis is an effective and natural treatment. Ultraviolet radiation (UVB) from the sun improves psoriasis and induces vitamin D₃ synthesis. Objective The aim of the study was to investigate the effect of climate therapy on vitamin D₃ synthesis, blood glucose, lipids and vitamin B12 in psoriasis patients. Methods Twenty Caucasian patients (6 women and 14 men; mean age, 47.2 years; range, 24–65) with moderate to severe psoriasis [mean Psoriasis Area and Severity Index (PASI) score 9.8; range, 3.8–18.8] received climate therapy at the Gran Canarias for 3 weeks. Blood samples were drawn before and after 15 days of sun exposure. In addition, the patients’ individual skin UV doses based on UV measurements were estimated. Results Sun exposure for 15 days lead to a 72.8% (± 18.0 SD) reduction in the PASI score in psoriasis patients. Although no direct correlation was observed between PASI score improvement and UVB dose, the sun exposure improved the vitamin D, lipid and carbohydrate status of the patients. The serum concentrations of 25‐hydroxyvitamin D [25(OH)D] increased from 57.2 ± 14.9 nmol/L before therapy to 104.5 ± 15.8 nmol/L (P < 0.0001) after 15 days of sun exposure; the serum levels of 1,25‐dihydroxyvitamin D [1,25(OH)₂D] increased from 146.5 ± 42.0 to 182.7 ± 59.1 pmol/L (P = 0.01); the ratio of low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol decreased from 2.4 to 1.9 (P < 0.001); and the haemoglobin A₁c (HbA₁c) levels decreased from 5.6 ± 1.7% to 5.1 ± 0.3% (P < 0.0001). Conclusion Climate therapy with sun exposure had a positive effect on psoriasis, vitamin D production, lipid and carbohydrate status.     

Effects of Tobacco Smoking on the Dorsum of the Tongue and Buccal Epithelium

Objective: The aim of this study was to assess the effects of tobacco smoking on the dorsum of the tongue and buccal epithelium. Methodology: This case control cross-sectional study was conducted with 174 smoking and non-smoking volunteers living in the city of Hail, Northern KSA. Cytological Materials were obtained from buccal mucosa and dorsum of the tongue, and assessed using cytopathological methods. Results: In buccal smears, cytological atypia was observed in 17 out of 101 (16.8%) smoker cases but only 3/73(4.1%) of the controls. For cytological atypia in buccal and tongue smears, the adjusted odd ratio (OR) and the 95% confidence interval (CI) were found to be 4.7 (1.3-16.8), P < 0.016)) and 4.3 (0.93- 20.2), P <0.06)), respectively, in the two sites. Conclusion: Tobacco smoking is a major risk factor for occurrence of cytological atypia, which might subsequently develop into oral precancerous and cancerous lesions. Oral exfoliative cytology is an easy and cheap non-invasive procedure which appears highly suitable for screening populations at risk of developing oral cancer.