An epidemiological study of orofacial clefts in Croatia 1988-1998.

INTRODUCTION: The objective of this epidemiological study was to assess the incidence at birth of orofacial clefts in Croatia. AIM: The aim of the present study was to analyse the character and incidence of orofacial clefts in Croatia and to compare the data with reports from other countries. MATERIAL AND METHODS: All the material for the epidemiological study was retrieved from the documented files from all the neonatal units and hospitals in Croatia providing surgical treatment. RESULTS: A total of 525,298 livebirths were documented during 11 years (1988-1998); 903 among them with orofacial clefts, 24 (2.7%) of them twins. Sixty (6.6%) infants died between birth and the age of 6 months. The incidence of orofacial clefts during the study period was 1.71 per thousand. When eliminating syndromic clefts, the incidence of non-syndromic clefts was 1.56 per thousand. Analysis of cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate only (CP) revealed their incidence to be 1.05 and 0.66 per 1000, respectively. Of all types of clefting, CL and CLA was found in 17.2%, CL+/-P in 43.9%, CP in 38.2% and atypical facial clefts (AFC) in 0.8% of children. Left-sided clefts were most common (51%), followed by bilateral (30.5%) and right-sided (18.5%) clefts. The male to female ratio was 1.3. CL+/-P predominated in male and CP in female children. In 220 cases (24.4%) orofacial clefts were either associated with other anomalies or the clefts occurred as one feature of a syndrome. CONCLUSION: Data obtained from different sources yielded a cleft incidence of 1.71 per 1000 in Croatia. There were no differences in the incidences of orofacial clefts in comparison with similar data from other European countries.     

Assessment of the involvement of the macrophage migration inhibitory factor–glucocorticoid regulatory dyad in the expression of matrix metalloproteinase‐2 during periodontitis

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine and counter‐regulator of endogenous glucocorticoids (GCs). It is implicated in acute and chronic inflammatory diseases. This study investigated the role of the MIF–GC regulatory dyad in the expression and release of matrix metalloproteinase‐2 (MMP‐2) during periodontitis, in vivo and in vitro. In a Mif‐knockout (KO) mouse model of ligature‐induced periodontitis, gingival tissues and blood were collected and analysed for levels of interleukin‐6 (IL‐6), MIF, MMP‐2, and corticosterone. In addition, human gingival fibroblasts (HGFs) were tested for production of IL‐6 and MMP‐2 after stimulation with hydrocortisone (HC), MIF, tumour necrosis factor‐alpha (TNF‐α), or Fusobacterium nucleatum, a pathogen known to elicit immune responses during periodontitis. Wild‐type (WT) mice showed a local and systemic increase of MIF levels during inflammation, which was confirmed by increased local IL‐6 concentrations. Systemic GC levels were reduced in WT and Mif‐KO mice during inflammation, with overall lower concentrations in Mif‐KO mice. In vivo and in vitro, MMP‐2 production was not dependent on MIF or inflammatory stimuli, but was inhibited by HC. Therefore, MIF does not appear to stimulate expression of MMP‐2 in the gingival tissues, whereas GC upregulates MIF and downregulates MMP‐2. Our findings further suggest that MIF may regulate systemic GC levels.     

PDC expressing CD36, CD61 and IL-10 may contribute to propagation of immune tolerance

Human plasmacytoid dendritic cells (PDC) are blood dendritic cell antigen 2 (BDCA2) and blood dendritic cell antigen 4 (BDCA4) positive leukocytes that do not express common lineage markers. They have been described as proinflammatory innate immune cells and are the major source of αIFN in the human body. PDC-derived secretion of type I IFNs upon triggering of nucleic acid-sensing toll-like receptors (TLR) primes immune cells to rapidly respond to microbial stimuli and promotes a Th1 response. Here, we report that human PDC express CD36 and CD61 (β3 integrin), both involved in uptake of apoptotic cells and in induction of tolerance. Freshly isolated PDC and PDC within human blood leukocytes constitutively express IL-10. Thus, PDC may possess a so far neglected role in propagation of immune tolerance.     

Tumour-derived prostaglandin E2 and transforming growth factor-β synergize to inhibit plasmacytoid dendritic cell-derived interferon-α

In previous studies we reported that plasmacytoid dendritic cells (PDC) infiltrating head and neck cancer tissue are functionally impaired, but the molecular basis for the functional deficiency remained unclear. Here we demonstrate that tumour-derived prostaglandin E2 (PGE₂) and transforming growth factor-β (TGF-β) increase interleukin-8 (IL-8) but synergistically inhibit interferon-α (IFN-α) and tumour necrosis factor (TNF) production of Toll-like receptor 7 (TLR7)- and Toll-like receptor 9 (TLR9)-stimulated PDC. The inhibitory effect of PGE₂ could be mimicked by the induction of cyclic AMP (cAMP) and by inhibitors of cyclooxygenase. The contribution of tumour-derived TGF-β was confirmed by the TGF-β antagonist SB-431542. Suppression of tumour-derived PGE₂ and TGF-β restored TLR-induced IFN-α production of PDC. Additionally, PGE₂- and TGF-β-treated PDC display a ‘tolerogenic’ phenotype because of a downregulation of CD40 accompanied by an upregulation of CD86. Finally, in TLR-stimulated PDC, PGE₂ and TGF-β reduce the CCR7 : CXCR4 ratio, suggesting that PDC are impaired in their ability to migrate to tumour-draining lymph nodes but are retained in stromal cell-derived factor 1 (SDF-1)-expressing tissues. Based on these data, cyclooxygenase inhibitors and TGF-β antagonists may improve TLR7- and TLR9-based tumour immunotherapy.     

Anti-angiogenesis in prostate cancer： knocked down but not out

Angiogenesis is a very complex physiological process, which involves multiple pathways that are dependent on the homeostatic balance between the growth factors （stimulators and inhibitors）. This tightly controlled process is stimulated by angiogenic factors, which are present within the tumor and surrounding tumor-associated stromal cells. The dependence of tumor propagation, invasion and metastasis on angiogenesis makes the inhibitors of new blood vessel formation attractive drugs for treating the malignancies. Angiogenesis can be disrupted by several distinct mechanisms： by inhibiting endothelial cells, by interrupting the signaling pathways or by inhibiting other activators of angiogenesis. This strategy has shown therapeutic benefit in several types of solid tumors, leading to Food and Drug Administration （FDA） approval of anti-angiogenic agents in the treatment of kidney, non-small cell lung, colon and brain cancers. Although no angiogenesis inhibitors have been approved for patients with metastatic prostate cancer, therapies that target new blood vessel formation are still an emerging and Dromising area of prostate cancer research.     

Sexual and reproductive health and human rights of women living with HIV: a global community survey

Objective

To determine the sexual and reproductive health priorities of women living with human immunodeficiency virus (HIV) and to allow the values and preferences of such women to be considered in the development of new guidelines.

Methods

A core team created a global reference group of 14 women living with HIV and together they developed a global community online survey. The survey, which contained mandatory and optional questions, was based on an appreciative enquiry approach in which the life-cycle experiences of women living with HIV were investigated. The same set of questions was also used in focus group discussions led by the global reference group.

Findings

The study covered 945 women (832 in the survey and 113 in the focus groups) aged 15–72 years in 94 countries. Among the respondents to the optional survey questions, 89.0% (427/480) feared or had experienced gender-based violence, 56.7% (177/312) had had an unplanned pregnancy, 72.3% (227/314) had received advice on safe conception and 58.8% (489/832) had suffered poor mental health after they had discovered their HIV-positive status.

Conclusion

The sexual and reproductive health needs and rights of women living with HIV are complex and require a stronger response from the health sector. The online survey placed the voices of women living with HIV at the start of the development of new global guidelines. Although not possible in some contexts and populations, a similar approach would merit replication in the development of guidelines for many other health considerations.