A screening programme for the prospective prevention of Mediterranean anaemia in Latium: results of seven years'' work.

Since 1975 the Rome Microcythaemia Centre has carried out every year, under the auspices of the health authorities of the Latium region, a screening of thalassaemics among intermediate schoolchildren of Latium. From these campaigns, knowledge about thalassaemias among the young adult population has grown which, in its turn, has resulted in screening of these young adults. Through screening in schools between 1975 and 1982, of 289 763 students examined, 6838 thalassaemics were identified, 6045 of whom were beta- or delta beta-thalassaemics. The total number of young thalassaemics who are identified at present in the Centre through screenings of schoolchildren and young adults is about 3300 per year. Furthermore, from January 1980 to April 1983, 110 prospective couples of child-bearing age at risk (94 of whom originated from Latium) were identified at the Centre, and five homozygous fetuses (three of which originated from Latium) were diagnosed. These data derive from an area in which the frequency of thalassaemia is only 2.4%, and they show that the programme in Latium for the prevention of Mediterranean anaemia has been successful.     

Appearance of esophageal peristalsis in treated idiopathic achalasia

The authors studied 22 patients with severe dysphagia, and follow-up studies showed the appearance of some esophageal peristalsis for the first time in three of these patients after Heller myotomy. Comparison of pre- and postoperative clinical, radiological, and manometric data of these three subjects and the data of the other 19 patients showed no statistically significant differences between the two groups of patients either before or after cardiomyotomy except for the unusual appearance of esophageal peristalsis after surgery. According to these results it is not possible to predict which patients will develop peristalsis after cardiomyotomy. The different motor pattern observed after surgery might suggest the existence of a different pathogenesis underlying the esophageal motor disorders in these two groups of patients.     

The ATAC ('Arimidex', Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: baseline endometrial sub-protocol data on the effectiveness of transvaginal ultrasonography and diagnostic hysteroscopy

BACKGROUND: The 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial is a randomized, double-blind trial comparing anastrozole ('Arimidex'), alone or in combination with tamoxifen, relative to tamoxifen alone as 5 year adjuvant treatment for post-menopausal women with early breast cancer. Since tamoxifen is associated with endometrial pathology, the ATAC endometrial sub-protocol was initiated to establish the background prevalence of intrauterine pathology, and to assess prospectively the incidence and nature of intrauterine changes following endocrine therapy. Another aim was to provide data from which advice could be generated on the best endometrium screening method for patients receiving tamoxifen. METHODS: Patients underwent endometrial assessments at entry to the sub-protocol. The baseline investigations comprised transvaginal ultrasound scanning (TVUS), a hysteroscopy and an endometrial biopsy. RESULTS: A total of 285 gynaecologically asymptomatic women from 31 centres in 10 countries entered the endometrial sub-protocol. The mean uterine volume was 47.7 cm3. The median endometrial thickness overall was 3 mm. Twenty-four histologically confirmed, pathological changes were observed. Twenty-three pathologies were confirmed by TVUS, and 21 were identified by hysteroscopy and confirmed by histopathology. Women with or without intrauterine pathology had median endometrial thickness of 5 and 3 mm respectively. CONCLUSIONS: The presence of pathology was associated with increased endometrial thickness. The relative sensitivity and specificity of hysteroscopy and endometrial thickness for the diagnosis of endometrial pathology was comparable to other studies. If screening of the endometrium prior to treatment is appropriate, this study supports the use of an endometrial thickness of 3 mm, as assessed by TVUS, as a threshold for needing further investigation. This study demonstrates that if the endometrial thickness is >3 mm, hysteroscopy and biopsy is the optimal method of detecting intrauterine pathology in women with breast cancer who are about to commence endocrine treatment.     

The Secreted Larval Acidic Proteins (SLAPs) of Onchocerca spp. are encoded by orthologues of the alt gene family of Brugia malayi and have host protective potential

Onchocerca volvulus is a tissue-dwelling, vector-borne nematode parasite of humans and the causative agent of onchocerciasis, or 'River Blindness'. Resistance to infection is associated with immune responses to the infective, third-stage (L3) larvae. The antigens of greatest interest for their vaccine potential are surface and secreted molecules. We have previously identified a family of Secreted Larval Acidic Proteins (SLAPs) from the L3 larvae of O. volvulus by biosynthetic labelling. Here, we provide further characterisation of these molecules following cloning and expression of the corresponding cDNAs. Using protein sequencing, we show that SLAPs are members of the alt gene family, first described in the lymphatic filarial parasite, Brugia malayi. Ov-ALT-1 and Ov-ALT-2 correspond with 20 and 18kDa SLAPs. Both proteins are highly acidic and related by sequence, differing chiefly in an 8-amino acid deletion from Ov-ALT-2. By immunochemistry, we confirm that Ov-ALTs are highly stage-specific, being expressed exclusively in late L2 and L3 larvae during growth in the vector. They are synthesised and stored in the glandular oesophagus. Secretion is triggered by the resumption of development in the definitive host and occurs via the pseudocoelom and cuticle. Serological responses in humans to recombinant Ov-ALT-1 indicate that the level of IgG production may be governed by the force of transmission but does not overtly reflect infection status. Immunisation of mice with recombinant Ov-ALT-1 resulted in a modest level of protection against challenge with O. volvulus L3 larvae (P = 0.036). We conclude that Ov-ALT genes, like those of other filariae, are of interest from the standpoint of parasite transmission and infectivity. They may also offer promise as components of a future sub-unit vaccine should the means to enhance protection be achieved.     

The progins progesterone receptor gene polymorphism is not related to endometriosis-associated infertility or to idiopathic infertility

OBJECTIVE:

This study aimed to determine the frequency of the PROGINS polymorphism in women with endometriosis‐associated infertility, in infertile women without endometriosis and in controls.

INTRODUCTION:

The human progesterone receptor gene has two isoforms that modulate the biological action of progesterone: isoform A, which is capable of inhibiting the activation of the estrogen receptors, and isoform B, which has the capacity to activate the estrogen receptors. Several polymorphisms have been described for this gene, among which one stands out: a polymorphism named PROGINS, which has been speculated to be related to the genesis of endometriosis by several studies with conflicting results.

METHODS:

This was a prospective study that included 148 patients with endometriosis‐associated infertility, 50 idiopathic infertile patients and 179 fertile women as controls. The PROGINS polymorphism was studied by PCR.

RESULTS:

Genotypes P1P1, P1P2 and P2P2 (P2 representing the PROGINS polymorphism) of the progesterone receptor gene presented frequencies of 93.9%, 5.4% and 0.7%, respectively, in the women with endometriosis‐associated infertility (p = 0.2101, OR = 0.51, 95% CI = 0.24‐1.09); 94.4%, 4.2% and 1.4%, respectively, in the patients with minimal/mild endometriosis (p = 0.2725, OR = 0.53, 95% CI = 0.20‐1.43); 93.5%, 6.5% and 0%, respectively, among the patients with moderate/severe endometriosis (p = 0.3679, OR = 0.49, 95% CI = 0.18‐1.31); 86.0%, 14.0% and 0%, respectively, in idiopathic infertile women (p = 0.8146, OR = 1.10, 95% CI = 0.46‐2.63); and 88.3%, 10.6% and 1.1%, respectively, in the control group.

CONCLUSION:

The data suggest that PROGINS is not related either to endometriosis‐associated infertility or to idiopathic infertility in the population studied.     

Enhancement of anti-inflammatory drug activity by multivalent adamantane-based dendrons

We have developed a straightforward method to prepare 1(st) and 2(nd) generation adamantane-based dendrons, previously called HYDRAmers, bearing at the periphery the anti-inflammatory drug, ibuprofen. The multivalency effect on the drug activity was studied, demonstrating that our multivalent ibuprofen-dendron conjugates exert an enhanced anti-inflammatory activity compared to free ibuprofen, in?vitro. These results provide insights into the effect of HYDRAmer multivalency on biological interactions for therapeutic applications.     

The maturation potential of NK cell clones toward autologous dendritic cells correlates with HMGB1 secretion

Interaction of NK cells with autologous immature dendritic cells (iDCs) results in reciprocal activation. We have previously reported that NK cells trigger iDC to polarize and secrete IL-18; in turn, DC-activated NK cells secrete the nuclear protein/proinflammatory cytokine high mobility group box protein 1 (HMGB1), which induces DC maturation and prevents DC from lysis. However, activated NK cells can also kill iDC. To investigate whether effector and maturative properties may coexist or segregate in different NK subsets, human NK cell clones were generated and analyzed for their effects on iDC. We found that the ability of different NK cell clones to induce iDC maturation is unlinked to their phenotypic and cytolytic features but correlates with the relocation of HMGB1 from nucleus to cytoplasm. "Maturative" NK cell clones secrete HMGB1 spontaneously. It is interesting that secretion is strongly enhanced by engagement of the surface molecule NKp30 but only slightly induced by triggering of the activating NK receptor CD16. However, culturing freshly isolated NK cells for 1 week with low doses of anti-CD16 triggers the relocation of HMGB1 from nucleus to cytoplasm and its spontaneous secretion, resulting in a stronger maturation potential of the NK cells. Together, our data indicate that NK cells comprise functionally different subsets, endowed with different capacities to secrete HMGB1 and to induce maturation of autologous iDC. Nonetheless, maturation properties can be modulated by different stimuli. This suggests that depending on the environmental stimuli, NK/iDC interaction can lead to different outcomes, thus influencing immune response.     

The immunogenicity and safety of an investigational meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine (ACWY-TT) compared with a licensed meningococcal tetravalent polysaccharide vaccine: A randomized, controlled non-inferiority study

Immunogenicity and safety of ACWY-TT compared with licensed ACWY polysaccharide vaccine (MenPS) in healthy adults, and lot-to-lot consistency of three ACWY-TT lots were evaluated in a phase 3, open, controlled study. Adults aged 18-55 y were randomized to receive ACWY-TT (one of three lots) or MenPS. Serum bactericidal antibodies (rSBA) were measured pre- and 1 mo post-vaccination. Adverse events (AEs) were assessed 4 d (solicited symptoms) and 31 d (unsolicited symptoms) post-vaccination. Serious AEs were reported up to 6 mo after vaccination. The number of vaccinated subjects was 1247 (ACWY-TT, n = 935; MenPS, n = 312). ACWY-TT lot-to-lot consistency and non-inferiority of ACWY-TT as compared with MenPS groups were demonstrated according to pre-specified criteria. The percentages of subjects with a vaccine response (VR = rSBA titer ≥ 1:32 in initially seronegative; ≥ 4-fold increase in initially seropositive) to ACWY-TT vs. MenPS were 80.1%/69.8% (serogroup A), 91.5%/ 92.0% (C), 90.2%/85.5% (W-135), 87.0%/78.8% (Y). Exploratory analyses showed that for serogroups A, W-135 and Y, VR rates and GMTs were significantly higher for ACWY-TT compared with MenPS. For each serogroup, ≥ 98.0% of subjects had rSBA titers ≥ 1:128. Grade 3 solicited AEs were reported in ≤ 1.6% of subjects in any group. The immunogenicity of ACWY-TT vaccine was non-inferior to MenPS for all four serogroups in adults, with significantly higher VR rates to serogroups A, W-135 and Y and an acceptable safety profile. Consistency of 3 ACWY-TT production lots was demonstrated. These data suggest that, if licensed, ACWY-TT conjugate vaccine may be used for protection against invasive meningococcal disease in healthy adults. This study is registered at clinicaltrials.gov NCT00453986.