Reducing the dose of smallpox vaccine reduces vaccine-associated morbidity without reducing vaccination success rates or immune responses

BACKGROUND: When the decision was made to prepare for a deliberate release of smallpox, the United States had approximately 15 million doses of Wyeth Dryvax vaccine, which was known to induce significant morbidity when used undiluted; Sanofi Pasteur, Inc., later identified approximately 85 million additional doses in storage. METHODS: Eleven vaccine-dose groups, each with 30 vaccinia-naive subjects, were given diluted Dryvax vaccine or 1 of 2 lots of Sanofi Pasteur smallpox vaccine and were evaluated for vaccination success rates, morbidity, and immune responses. RESULTS: Estimated doses of 10(6.6)-10(8.2) pfu of virus/mL induced major reactions (or "takes") in 93%-100% of subjects in each dose group. No differences in vaccination take rates, lesion size, erythema, and induration or in serum neutralizing-antibody response were detected between the groups. However, systemic reactogenicity and missed activities were significantly lower for the vaccine groups given doses of 10(6.6)-10(7.2) pfu/mL than for those given doses of 10(7.6)-10(8.2) pfu/mL. CONCLUSIONS: These findings support the use of a higher dilution of Wyeth Dryvax vaccine and Sanofi Pasteur smallpox vaccine, given that the resulting morbidity should be significantly lower without loss of vaccine effectiveness. A plan for use of higher dilutions would create an enormous stockpile of vaccine.     

Evolving approach to aortic valve replacement in children and adolescents--a preliminary report

BACKGROUND: Surgical treatment methods are still controversial in children with congenital or acquired aortic valve dysfunction. AIM: To evaluate treatment results in children after mechanical or biological valve implantation. METHODS: We analysed a group of 55 children after mechanical valve implantation (group A) and a group of 8 children after Freestyle biological valve implantation (group B). We evaluated in both groups: patient's age, type of valve dysfunctions, severity of heart failure symptoms, and quality of life. The parameters of physiological left ventricular (LV) remodelling were examined on the basis of echocardiographical signs of LV contractibility (%SF) and anatomical changes: LV diastolic diameter (LVDd), LV posterior wall thickness (LVPW), thickness of intra-ventricle septum (IVS) and pressure gradient between LV and aorta (LV-Ao). RESULTS: There were no hospital deaths in either group. There were two late deaths in children from group A. Thromboembolic (2), nonspecific bleeding complications (2), and infections (2) occurred in group A. There were two re-operations in children after mechanical valve implantation. The early postoperative period was good in groups A and B. Furthermore, late postoperative period was good in group B. Physiological LV remodelling occurred in children in groups A and B. Quality of life was good in both groups. CONCLUSIONS: Good clinical results, simplicity, repeatability and safety of surgical technique mean that mechanical valve implantation in the aortic position is still an attractive option for treatment in children and adults. However, absence of bleeding, thromboembolic and infection complications and improvement of durability mean that the Freestyle biological new generation valve could be a good option for future in children and adolescents who need aortic valve replacement.     

CYP1B1 and predisposition to breast cancer in Poland

Background The CYP1B1 gene is a polymorphic member of the P450 gene family and is considered to be a candidate gene for cancers of various types. Objective We inquired whether four SNPs in the CYP1B1 gene, alone or in combination, might be associated with breast cancer risk in Poland. Methods We genotyped 2017 cases of breast cancer and 876 controls, for four SNPs in the CYP1B1 gene. Genotype and haplotype frequencies were compared in cases and controls. Results In combinations of the R48G, A119S and L432V SNPs, four of the eight CYP1B1 haplotypes were more common in controls than in cases and each of these appeared to have a significant protective effect. A large reduction in risk was observed for women who were homozygous for one of these four haplotypes (OR = 0.2; 95%; CI = 0.05–0.5; P = 0.001) compared to women who were homozygous for the most common haplotype. In contrast, women who were homozygous for the GTC haplotype were at increased risk (OR = 1.5; 95%; CI = 1.0–2.1; P = 0.03) compared to women with the most common haplotype. Conclusions The CYP1B1 gene appears to influence breast cancer susceptibility in Poland.     

Methylenetetrahydrofolate reductase polymorphisms modify <Emphasis Type="Italic">BRCA1</Emphasis>-associated breast and ovarian cancer risks

Methylenetetrahydrofolate reductase (MTHFR), a key regulatory enzyme in the metabolism of folate, is suspected to play a role in the etiology of cancer, via its effects on DNA methylation and nucleotide synthesis. In this study we have investigated the effect of two functional polymorphisms of the MTHFR gene, MTHFR_677_C > T and MTHFR_1298_A > C, on breast and ovarian cancer risk in Polish BRCA1 mutation carriers. The study included 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Odds ratios (OR) were calculated using univariate and multivariate logistic regression taking into account a series of confounding variables that potentially could have biased any association. The results revealed that the MTHFR_677_C > T change was associated with an increased risk of breast and ovarian cancer. The MTHFR_1298_A > C polymorphism was only associated with a decrease in breast cancer risk. Together, it appears that functional polymorphisms in the MTHFR gene modify the risk of breast and may potentially alter the risk of ovarian cancer in women with an inherited predisposition.     

Intraoperative parathyroid hormone assay improves outcomes of minimally invasive parathyroidectomy mainly in patients with a presumed solitary parathyroid adenoma and missing concordance of preoperative imaging

OBJECTIVE: Intraoperative parathyroid hormone assay (IOPTH) is often used during minimally invasive parathyroidectomy (MIP) for primary hyperparathyroidism (pHPT). However, several investigators have reported conflicting outcomes, throwing doubt on the real influence of this adjunct on surgical decision-making. The aim of this study was to determine the impact of routine use of IOPTH on the success rate of MIP as the primary outcome, and whether it value-added to surgical decision-making during the operations at our institution. DESIGN: The results of MIP were determined on postoperative follow-up in 177 consecutive patients with pHPT and compared with the results of preoperative imaging, findings at surgery and the value-added accuracy of IOPTH in surgical decisions. PATIENTS: All 177 patients had biochemically documented pHPT and all were referred for first-time surgery. MEASUREMENTS: Group 1 patients (n = 62) underwent a unilateral neck exploration (UNE) without IOPTH, and group 2 patients (n = 115) underwent MIP (either video-assisted or open) with IOPTH. The primary outcome was the cure rate, whereas the secondary outcome was the value-adding of IOPTH to surgical decision-making during MIP. RESULTS: Of the group 1 vs. 2 patients, 57/62 (91.9%) vs. 114/115 (99.1%) were cured (P = 0.01). Five (8.1%) of the group 1 patients were hypercalcaemic postoperatively, owing to an additional, overlooked, hyperfunctioning parathyroid gland, whereas among the 115 group 2 patients, 104 (90.4%) underwent resection of a single parathyroid adenoma, met the Miami criterion, and were cured. The remaining 11 (9.6%) patients did not have an adequate reduction in parathyroid hormone levels and underwent further neck exploration, with resection of additional hyperfunctioning parathyroids in nine of them. One group 2 patient was not cured. However, a decrease of less than 50% of intraoperative parathyroid hormone (iPTH) assay correctly identified the risk of persistent disease in that patient. Another patient in group 2 had a false-negative IOPTH result. The value-added accuracy of IOPTH (correct assay-based surgeon's decision of further neck exploration) was demonstrated in 3 of 78 group 2 patients with concordant results of both imaging studies vs. 7 of 37 group 2 patients with only one positive imaging study, or 3.8 vs. 18.9% of patients (P = 0.007). CONCLUSIONS: Routine use of IOPTH significantly improves cure rates of MIP in comparison to open image-guided UNE without IOPTH. It is a valuable adjunct in surgical decision-making, allowing for intraoperative recognition and resection of additional hyperfunctioning parathyroid tissue missed by preoperative imaging studies. IOPTH offers substantial value-adding to surgical decision-making, particularly in patients with only one positive imaging study result, and significantly improves the success rate of MIP in these patients. However, in patients with concordant results of two imaging studies, the assay offers significantly lower value-adding to surgical decisions, as a vast majority of patients are cured after removal of a two-image-indexed parathyroid lesion. Despite this, we strongly advocate routine use of IOPTH in all patients undergoing MIP, as this adjunct offers maximum safety for the patient and confidence for the surgeon.     

Technetium-99m-sestamibi subtraction scintigraphy vs. ultrasonography combined with a rapid parathyroid hormone assay in parathyroid aspirates in preoperative localization of parathyroid adenomas and in directing surgical approach

OBJECTIVE: To determine the sensitivity and positive predictive value (PPV) of subtraction scintigraphy (SS) vs. ultrasonography (US) of the neck combined with rapid intact parathyroid hormone (iPTH) assay in US-guided fine-needle parathyroid aspirates in preoperative localization of parathyroid adenomas and in directing surgical approach. DESIGN: The results of SS for localization of parathyroid adenoma were determined in 121 patients with primary hyperparathyroidism (pHPT) and compared with findings at surgery and with the results of US alone (in patients without nodular goitre) and US in combination with the iPTH assay in US-guided fine-needle aspirates (FNAs) of suspicious parathyroid lesions (in patients with concomitant nodular goitre). PATIENTS: All 121 patients had biochemically documented pHPT; all were referred for first-time surgery. MEASUREMENTS: SS was performed with 99mTc-sestamibi and 99mTc-pertechnetate. High-resolution US of the neck was performed by a single endocrine surgeon and combined with US-guided FNAs of suspicious parathyroid lesions in all patients with nodular goitre (n = 43). RESULTS: The sensitivity and PPV of SS were significantly higher in patients without vs. with goitre (89.3% and 95.7%vs. 74.3% and 76.5%, respectively; P < 0.001). The sensitivity and PPV of US were significantly higher in patients without vs. with goitre (96% and 97.3%vs. 67.7% and 71.9%, respectively; P < 0.001). The iPTH assay of US-guided FNAs of suspicious parathyroid lesions in patients with nodular goitre significantly improved both the sensitivity and PPV of US imaging (90.7% and 100%, respectively), allowing for an accurate choice of surgical approach in 118 (97.5%) of 121 patients. SS was more accurate than US alone in detection of ectopic parathyroid adenomas. However, US alone was characterized by a higher sensitivity in detection of small parathyroid adenomas (< 500 mg) at typical sites (P < 0.01). CONCLUSIONS: Both the sensitivity and PPV of SS and US alone are comparable, with significantly less accurate results obtained in patients with goitre. In cases of equivocal results of US and/or in patients with concomitant goitre, an iPTH assay in US-guided FNAs of suspicious parathyroid lesions may be used to establish the nature of the mass, distinguish between parathyroid and nonparathyroid tissue (goitre, lymph nodes) and improve the accuracy of US parathyroid imaging, allowing for successful directing of surgical approach in a majority of patients.