AGS is a Mendelian disorder of aberrant immune activation Growin

AGS is a Mendelian disorder of aberrant immune activation. Growing evidence

suggests that an accumulation of endogenous nucleic acid species, perhaps derived from retro-elements, provokes a type I interferon response with subsequent recruitment of the adaptive immune system. The disease is associated with significant morbidity and a high rate of mortality. Designing effective therapeutic approaches will be enhanced by an improved understanding of disease pathophysiology. Following proof-of-principle studies in the Trex1-null mouse, treatment strategies of immediate interest include type I interferon blockade, interruption of the generation of the products of reverse transcription and a depletion of B and T cells. Therapies already exist relating to each of these strategies. In the future, inhibition of selleck kinase inhibitor components of the relevant cytosolic signalling pathways (for example, in the case of TREX1 – cGAS, TBK1, STING and IRF3) might also represent

attractive targets. The difficulties of randomization and controlled studies in rare disorders with small populations are relevant to AGS. It may be useful to consider using an historical cohort as a control population in a treatment trial; to that end, careful attention to natural history is crucial at this time. Additionally, outcome measures to selleck chemicals llc determine the effectiveness of treatments need to be established, and their best use carefully considered. Disease manifestations, e.g. radiological findings and clinical outcomes, are frequently difficult to measure objectively. Thus, the relevance and specificity of biomarkers needs to be established in anticipation of clinical trials. Combinations of

outcomes may prove to be the most useful. Therapy is most likely to be beneficial in the early stages of the disease, making rapid diagnosis of the utmost importance. However, ongoing disease and later-onset phenotypes mean that treatment will also probably have a role in at least some older patients. Unanswered questions as to whether one therapy will be appropriate for disease due to any genotype will become clearer as our understanding Sclareol of AGS-related protein function improves and other animal models are developed. For example, the possibilities of using treatment with hydroxyurea to deplete the pool of deoxyribonucleotide triphosphates (dNTPs) might be relevant in the context of SAMHD1-related disease, but not other subtypes of AGS. Finally, it will be interesting to determine if treatments developed in the context of AGS are germane to other phenotypes including familial chilblain lupus, retinal vasculopathy with cerebral leucodystrophy and some cases of systemic lupus erythematosus. We thank sincerely the families and clinicians who have contributed to our collective work. Y.J.C. would like to thank Diana Chase for her expert proof-reading. Y.J.C.

What is the impact of pDC accumulation in the pathogenesis and pr

What is the impact of pDC accumulation in the pathogenesis and progression of diseases? As we explain in the following sections, pDC may have either negative or positive effects (Fig. 1). The accumulation Selleck AZD1152 HQPA of pDC contributes to pathogenesis in several viral models and disease settings. pDC infiltration and excessive IFN-I production are hallmarks of psoriasis and SLE 2, 59–64. During psoriasis, pDC accumulate in the skin and produce IFN-I in response

to self-DNA complexed with the antimicrobial peptide LL-37 65. Blocking IFN-I strongly inhibits the T-cell-dependent progression of psoriasis, thus implicating pDC as critical mediators of disease 19. As peripheral blood mononuclear cells from SLE patients have an IFN-α/β signature in the transcriptome that Adriamycin correlates with disease severity 66–69 and pDC infiltrate the skin and secrete IFN-I in response to self-DNA/RNA/immunocomplexes, pDC are often considered to be the culprits in promoting SLE. Additionally, pDC-derived IFN-I has been implicated in the initiation of type I diabetes in NOD mice 46. pDC accumulate in the pancreatic LN and produce IFN-I in response to apoptotic β-cell debris, hence activating DC and autoreactive T cells. Thus, it would appear that pDC, upon activation and IFN-I secretion, aggravate, and even perhaps instigate the diseases mentioned above, although it

remains unclear whether pDC are really the perpetrators. mTOR inhibitor Prolonged pDC activation and secretion of IFN-I have been associated with the progressive loss of CD4+ T cells and the chronic activation of CD8+ T cells in HIV infection 70, 71. Additionally, pDC may participate in HIV pathogenesis by recruiting T cells to sites of HIV replication where they can become infected. pDC preferentially secrete the chemokines CXCL9 (MIG), CXCL10 (IP-10), CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) 72, which can attract naïve and activated CD4+ and CD8+ T cells to sites of infection 73, 74. It has been shown that pDC accumulate in the vagina of rhesus macaques that are intravaginally infected with SIV 50. This accumulation resulted in increased levels of

MIP-1β, which attracted activated T cells that are susceptible to SIV infection, facilitating the generation of a local infection focus that can subsequently spread to the draining LN. pDC may also facilitate the recruitment of T cells to the liver during HCV infection. Liver biopsies from patients with HCV revealed infiltrates containing both pDC and T cells 39. Although CTL are critical for eradicating many viral infections, in the case of hepatitis virus, robust CTL responses induce severe liver damage. pDC have been shown to promote tolerance, particularly during cancer. Although activated pDC appear to behave as immunogenic cells, unstimulated or alternatively stimulated pDC can alleviate protective immunogenic responses to tumor cells through the induction of Treg.

PMNs, 2 × 104 cells/ml in PBS+/+, were incubated with increasing

PMNs, 2 × 104 cells/ml in PBS+/+, were incubated with increasing concentrations (1 μM–0·1 nM) of the FPR2/ALX agonists (15-epi-LXA4 or compound 43) or CysTL1 antagonists (montelukast or MK-571) for 30 min at 37°C or vehicle (DMSO < 0·1%) in 96-well plates. Human recombinant IL-8 (100 nM) was added to the wells and incubated for 4 h. After covering the bottom of the plate with the adhesive non-translucid paper, the caspase 3/7 reagent was added

and incubated for 30 min. Caspase 3/7 activity was measured by luminometry using a Luminoskan Ascent (Thermo Labsystems, Bar Hill, Cambridge, UK). Caspase inhibitor I (5 μM) was used as a control of apoptosis inhibition and staurosporine (1 μg/ml) as a control of apoptosis induction. In order to avoid LPS contamination, fresh buffers were prepared using sterile and filtered solutions on the same day of the apoptosis assay. PMNs at 1 × 106 cells/ml in PBS+/+ were incubated with the FPR2/ALX agonists (15-epi-LXA4 and compound 43) and CysTL1 antagonists (montelukast and MK-571) (100 nM) for 30 min at 37°C or vehicle (DMSO < 0·1%) in 24-well plates. Human recombinant IL-8 (100 nM) was added to the wells and incubated for 4 h. After incubation cells were transferred to a clean FACS tube and washed with PBS (×2). Briefly, cells were resuspended with ×1 binding buffer (500 μl) and 5 μl FDA-approved Drug Library purchase of annexin V-FITC (Sigma, Saint

Louis, MO, USA) and 10 μl of propidium iodide were added. Cells were incubated

at room temperature for 10 min and fluorescence was measured immediately by flow cytometry using a FACSCanto (BD Biosciences, Franklin Lakes, NJ, USA). Dose–response curves were set up in duplicate. Half maximal inhibitory concentration (IC50) and Half maximal effective concentration (EC50) calculations O-methylated flavonoid were performed using the four-parameter logistic (4PL) non-linear regression [log (inhibitor) versus response with variable slope equation] using GraphPad Prism software. IC50 values are reported as geometric mean (GeoMean) ± standard error of the mean. Values for chemotaxis and apoptosis assessment were analysed by Student’s t-test. In order to study the signalling pathway triggered by activation of FPR2/ALX and CysLT1 by each reference compound, cAMP and GTPγ binding assays in FPR2/ALX recombinant cells and membranes and binding and calcium flux assays in CysLT1 recombinant cells were performed. IC50 and percentage of inhibition of the reference compounds in agonist and antagonist mode in FPR2/ALX and CysLT1 are shown in Table 1 and Fig. 2, respectively. 15-Epi-LXA4 was inactive (0% of inhibition at 100 μM) in either GTPγ binding or cAMP assays in both agonist or antagonist mode in FPR2/ALX-expressing cells (Table 1 and Fig. 2a). Calcium release was not increased after stimulation of FPR2/ALX recombinant cells by 15-epi-LXA4 (data not shown).

Activated allergen-specific Th2 cells produce IL-4, IL-5, IL-9 an

Activated allergen-specific Th2 cells produce IL-4, IL-5, IL-9 and IL-13, which play a key role in the maintenance of allergen-specific IgE levels, eosinophilia, recruitment of inflammatory cells to inflamed tissues, production of mucus and decreased threshold of contraction of smooth muscles 5, 9. As a consequence of these events, the more severe clinical manifestations of allergy, such as chronic persistent asthma, allergic rhinitis, atopic dermatitis,

and in extreme cases, systemic anaphylactic reactions appear. Recently, MK 2206 newly identified cytokines such as IL-25, IL-31 and IL-33 have been shown to participate in the Th2 response and inflammation 10–12. Additionally, other effector T-cell subsets can contribute to ongoing allergic reactions. Depending on the specific disease model and stage

of inflammation, Th1 cells can either exacerbate the effector phase, for example, by inducing apoptosis of the epithelium in asthma and atopic dermatitis 13, 14, or dampen allergic inflammation 15. Recently, it has been shown that IL-32 induced by IFN-γ and TNF-α is an essential player in keratinocytes apoptosis in atopic dermatitis, which leads to eczema formation 16. An increase in activation-induced cell death of high amounts of IFN-γ-producing Th1 cells, as determined by intracellular RG7204 order staining and flow cytometry, also contributes to the predominant Th2 profile in atopic selleck chemicals llc diseases 17. It has also been demonstrated that neutralization of IL-17 and Th17-related functions in an experimental asthma model reduces neutrophilia,

while increasing eosinophil infiltration in the lung 18. In addition, recently, two new subsets of effector Th cells have been identified according to their cytokine signature, Th9 and Th22 cells. Although Th9 and Th22 cells’ potential contribution to allergic inflammation requires further investigations, Th9 cells may represent an IL-9- and IL-10-producing subset that lack suppressive function and promote tissue inflammation 19, while Th22 cells contribute to epidermal hyperplasia in inflammatory skin diseases 20, 21. In addition to the above-mentioned effector Th cell subsets, T cells with immunoregulatory properties exist and these are broadly referred as Treg. Other cell subsets with suppressive capacity include CD8+ T cells, γδ T cells, CD4−CD8− T cells, IL-10-producing B cells, IL-10-producing NK cells, IL-10-producing DC and some macrophage subsets 9, 22. The main role of all these cell subsets is to maintain integrity of the body through avoiding misguided or excessive immune responses that may result in harmful immune pathology, as well as to keep a state of tolerance to innocuous substances. Treg have the ability to control and modify the development of allergic diseases altering the ongoing sensitization and effector phases via several major pathways (Fig. 1).

Further investigations will doubtless reveal new information that

Further investigations will doubtless reveal new information that will lead to a better understanding of the relationships selleckchem between these molecules. This work was supported by Grants-in-Aid nos. 23590390 (to Y.T.) and 23240049 (to H.T.) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology,

Japan. “
“Y. Kawamoto, H. Ito, Y. Kobayashi, Y. Suzuki, I. Akiguchi, H. Fujimura, S. Sakoda, H. Kusaka, A. Hirano and R. Takahashi (2010) Neuropathology and Applied Neurobiology36, 331–344 HtrA2/Omi-immunoreactive intraneuronal inclusions in the anterior horn of patients with sporadic and Cu/Zn superoxide dismutase (SOD1) mutant amyotrophic lateral sclerosis Aims: HtrA2/Omi is a mitochondrial serine protease that promotes the apoptotic processes, but the relationship between HtrA2/Omi and amyotrophic lateral sclerosis (ALS) is still unknown. The purpose of the present study was to determine whether abnormal expression of HtrA2/Omi occurs in patients with ALS. Methods: We prepared autopsied spinal cord tissues from selleck 7 control subjects, 11 patients with sporadic ALS (SALS) and 4 patients with Cu/Zn superoxide dismutase (SOD1)-related familial ALS (FALS). We then performed immunohistochemical studies on HtrA2/Omi using formalin-fixed, paraffin-embedded

sections from all of the cases. Results: In the control subjects, the anterior horn cells were mildly to moderately immunostained with HtrA2/Omi. In the patients with SALS, strong HtrA2/Omi immunoreactivity

was found in some skein-like inclusions and round hyaline inclusions as well as many spheroids, but Bunina bodies were immunonegative for HtrA2/Omi. In the patients with SOD1-related FALS, Lewy body-like hyaline inclusions were observed in three cases and conglomerate inclusions were observed in the remaining case, and both types of inclusions were intensely immunopositive for HtrA2/Omi. Conclusions: These results suggest that abnormal accumulations of HtrA2/Omi may occur in several types of motor neuronal inclusions in the anterior horn from SALS and SOD1-linked FALS cases, and that HtrA2/Omi may be associated next with the pathogenesis of both types of ALS. “
“Based on the cerebral tans-activation response DNA protein 43 (TDP-43) immunohistochemistry, frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) is classified into four subtypes: type A has numerous neuronal cytoplasmic inclusions (NCIs) and dystrophic neurites (DNs); type B has numerous NCIs with few DNs; type C is characterized by DNs which are often longer and thicker than DNs in type A, with few NCIs; and type D has numerous neuronal intranuclear inclusions and DNs with few NCIs.

The present work presents evidence that a progressively growing,

The present work presents evidence that a progressively growing, endogenous tumor indeed fails to activate NK-cell effector functions. Escape from NK-cell surveillance seems

to be more complex than the hypothesis of failing priming or failing triggering might suggest. Possibly, NK cells are exhausted as a consequence of prolonged activation, as it was described for T cells 44. Alternately, developing tumors might actively paralyze NK cells. These observations should be considered when establishing, e.g. approaches find more of adoptive NK-cell transfer. All cell lines were cultured in RPMI 1640 (Invitrogen, Karlsruhe, Germany) medium supplemented with 5% heat-inactivated FBS, 2 mM L-Glutamine, 100 U/mL penicillin and streptomycin, non essential aa, and 50 μM 2-ME. Cells were kept

at 37°C in a humidified 5% CO2 atmosphere. A20 and MPC11 are BALB/c-derived B-cell lymphoma cell lines 45, 46. The variant A20low expressing reduced levels of MHC class I was generated by transfection of A20 with an mCMV-derived gene 6. The murine lymphoma cell line YAC-1 served as a target for NK-cell killing in cytotoxicity assays 47. DC were generated exactly as previously described 22. λ-myc cell lines myc-B, myc-E and 291S were generated by seeding primary lymphoma cells from λ-myc mice on irradiated MRC-5 fibroblasts as a feeding layer. After about 2 wk of culture, cells were able Selleck Tanespimycin to grow independently. All animals were kept under specific pathogen-free conditions in our animal facility. C57BL/6 and BALB/c WT mice were purchased from Bommice (Ry, Denmark). λ-myc mice 29 are of C57BL/6 origin and were bred in our own facility. All animal experiments were in accordance with relevant regulations and had been approved by the Regierung von Oberbayern. Groups of at least six age-matched mice were used for experiments. Animals were treated with 10 nMol

CpG-ODN 1668 (Metabion, Martinsried, Germany) that was injected i.p. in 1- to 2-wk intervals 6 or received 5×105 DC subcutaneously as described earlier 22. NK-cell depletion was done by using anti-asialo GM1 Ab (Wako, Neuβ, Germany). 100–300 μL were administered i.v. and i.p. 1 day before each CpG-ODN injection in λ-myc mice; 300 μL were given i.p. 1 day before as well as 2 and 9 days after challenge with myc-B tumor cells in WT mice. NKT cells were not affected by treatment with anti-asialo GM1. In total, 104 to 105 myc-B, myc-E, 291S or MPC11 cells or 106 A20 or A20low cells were injected i.v. Phenotyping of NK cells was done by labeling with the following mAb: CD49b (DX5, BD Pharmingen, Heidelberg, Germany), CD45R (RA3-6B2, BD Pharmingen), NKG2D (CX5, eBioscience, San Diego, USA), Ly49D (4E5, BD Pharmingen), Ly49I (YLI-90, BD Pharmingen), CD69 (H1.

65 Not surprisingly, NGAL measurements as an outcome variable are

65 Not surprisingly, NGAL measurements as an outcome variable are currently included in several ongoing clinical trials formally listed in The approach of using NGAL as a trigger to initiate and monitor novel therapies, and as a safety biomarker when using potentially nephrotoxic agents, is expected to increase. It is also hoped that the use of predictive and sensitive biomarkers such as NGAL as endpoints in clinical

trials will result in a reduction in required sample sizes, and hence the cost incurred. A number of studies have demonstrated the utility of early NGAL measurements for predicting the severity and clinical outcomes of AKI. In children undergoing cardiac surgery, early post-operative plasma NGAL levels strongly correlated with duration and severity of AKI, length Selleckchem Acalabrutinib of hospital stay

and mortality.66 In a similar cohort, early urine NGAL levels highly correlated with duration and severity of AKI, length of hospital stay, dialysis requirement and death.67 In a multicentre study of children with diarrhoea-associated haemolytic uraemic syndrome, urine NGAL obtained early during the hospitalization predicted the severity of AKI and dialysis requirement with high sensitivity.68 Early urine NGAL levels were also predictive of duration of AKI (AUC 0.79) selleck screening library in a heterogeneous cohort of critically ill paediatric subjects.51 In adults undergoing cardiopulmonary bypass, those who subsequently required renal replacement therapy (RRT) were found to have the highest

urine NGAL values soon after Selleck Fludarabine surgery.30–37 Similar results were documented in the adult critical care setting.53–59 Collectively, the published studies revealed an excellent overall AUC-ROC of 0.78 for prediction of subsequent dialysis requirement, when NGAL was measured within 6 h of clinical contact.41 Furthermore, a number of studies conducted in the cardiac surgery and critical care populations have identified early NGAL measurements as a very good mortality marker,30–32,54,55,59 with an overall AUC-ROC of 0.71 in these heterogeneous populations.41 Furthermore, there is now evidence for the utility of subsequent NGAL measurements in critically ill adults with established AKI. Serum NGAL measured at the inception of RRT was an independent predictor of 28-day mortality, with an AUC of 0.74.69 With respect to the sample source, the majority of AKI biomarkers described thus far have been measured in the urine. Urinary diagnostics have several advantages, including the non-invasive nature of sample collection, the reduced number of interfering proteins, and the potential for the development of patient self-testing kits.

The QTc interval has been reported to be increased and to be asso

The QTc interval has been reported to be increased and to be associated with high-risk ventricular arrhythmias and sudden death (2). Although renal transplantation improves survival, cardiovascular morbidity and Kinase Inhibitor Library molecular weight mortality still remain as a significant problem compared with nonrenal populations (3). The aim of this study is to evaluate the association between the QTc interval changes and arterial stiffness in kidney transplant recipients. Methods: One hundred kidney transplant recipients from our renal transplant outpatient clinic were enrolled

into the study. All patients were evaluated for their standard clinical (age, gender, duration of hemodialysis, post-transplant time), biochemical selleck antibody inhibitor parameters. Anthropometric and body composition analyses were performed for all patients. Body compositions were analyzed

by using the Body Composition Analyzer (Tanita BC- 420MA). PWv was determined from pressure tracing over carotid and femoral arteries using the SphygmoCor system. Pre- (retrospectively) and post-transplant electrocardiographic (ECG) evaluations were performed. Each QT interval was corrected for the patient’s heart rate using Bazett’s Formula. A QTc interval greater than 440 ms was considered abnormally prolonged. Results: After renal transplantation maxQTc intervals (456.7 ms to 414 ms) and QTdc (54 ms to 34 ms) of all patients were significantly decreased. In post transplantation period, patients with high QTc intervals had significantly higher PWv (p:.009) (Table 2) and higher serum CRP levels (p:.001) than patients with QTc < 440 ms. Patients with PWv ≥ 7 m/s had significantly higher maxQTc interval decline than patients with PWv < 7 m/s (p: –.05, r: –.206). Conclusion: High QTc interval after renal transplantation could 3-mercaptopyruvate sulfurtransferase be a predictor of arterial

stiffness in renal transplant recipients. Electrocardiographic evaluation is seem to be a cheap and reliable way to detect arterial stiffness. CHEMBO CAROLINE, MANLEY PAUL, DITTMER IAN Dept Renal Medicine, Auckland Hospital, NZ Introduction: Renal transplantation remains the best form of renal replacement therapy. The prevalence of hepatitis B infection in the dialysis population is declining but remains high in certain populations. The outcomes of renal transplantation in hepatitis B surface antigen patients has previosuly been reported to be poor. We report the outcomes in such patients who received renal transplants at our centre from 1981–2011. Methods: All patients transplanted from 1981 to 2011 who were HepB surface antigen positive prior to transplant were included in the analysis. Local databases and hospital records were reviewed for outcomes. Results: 20 patients were identified. They were predominantly male, of Maori ethnicity and received deceased donor organs. Mean age was 40 years (19–59). The majority of patients received lamivudin post-transplant.

Studies using the SCID-hu mouse showed similar abnormalities [19]

Studies using the SCID-hu mouse showed similar abnormalities [19]. Damage to the thymic epithelium may alter the thymic microenvironment and contribute to the immune suppression observed in acquired immune deficiency syndrome (AIDS) patients and models. Importantly, it has been observed that thymic epithelial fragments from AIDS children arrest T cell differentiation of normal bone marrow-derived CD34+ stem cells in vitro[25]. Similarly, HIV-1 infection has been shown to interrupt thymopoiesis in vivo in the SCID-hu mouse model [26]. The thymus releases mature lymphocytes into the periphery of the immune system. This

function can Erlotinib datasheet be evaluated through analysis of recent thymic emigrants (RTEs) [27], that themselves can be estimated by the presence of T cell receptor excision circles (Trecs), circular DNA fragments derived from the rearrangement of TCR genes, that remain within RTEs

[28]. Trec analysis in HIV and simian immunodefiency virus (SIV) infections revealed decreased numbers of Trec+ T lymphocytes in the peripheral blood compared with uninfected individuals [29,30]. Interestingly, specific highly active anti-retroviral therapy seems to correct this defect in AIDS patients [31]. Another important feature is that the thymic secretory function is also affected in HIV-infected individuals, as the blood levels INCB018424 clinical trial of thymic peptides are abnormal [23]. For example, thymosin α1 levels are elevated in many patients with AIDS, especially in the early stages PD-1 antibody inhibitor [23,32]. In contrast, a consistent and long-term diminution of thymulin secretion has been documented in AIDS patients, in terms of both serum levels and intrathymic contents of the hormone [24,33,34]. It is known that mouse hepatitis viruses (MHV), which are members of the Coronaviridae family, show a tropism to thymic stromal cells [35] and T lymphocytes [36]. Otherwise, thymus involution was described in MHV-A59-infected BALB/c mice

[37]. That involution was characterized by a severe transient atrophy resulting from apoptosis of immature CD4+CD8+ T cells that might be caused by infection of a small proportion of TEC. Marked thymic involution characterized by striking diminution of thymus weight and cellularity was also observed in CBA mice infected intraperitoneally with MHV-3, together with a significant decrease in thymocyte subpopulations and significant numbers of apoptotic cells [38]. In humans, Trec quantification revealed an impairment of RTEs, reflecting a thymic dysfunction in hepatitis C virus (HCV)-infected patients [39]. Measles, a member of the Paramyxoviridae family, is generally followed by immune suppression with transient lymphopenia and impaired cell-mediated immunity [40,41]. Impaired thymic function seems to contribute to measles virus-induced immune suppression. Indeed, measles virus infects TEC and monocytes in the thymus of humans and monkeys [42,43], leading to a decrease in the size of the thymic cortex [44,45].

In addition, studies that did not specify women’s HIV infection s

In addition, studies that did not specify women’s HIV infection status and only mentioned investigating STIs in general as outcomes of interest in the abstract were excluded. In addition to the limitations of the review itself, there are important methodological limitations within the studies included in this review, which may have affected

their findings. Most studies utilised a cross-sectional design, which severely limits their ability to make causal inferences. None of the studies NVP-BGJ398 purchase provided strong longitudinal, prospective information on the relationship between early sexual debut and women’s increased HIV risk, because a few cohort studies included in this review had short follow-up times or only included women in their sample who were already sexually active. In addition, asking women retrospectively about their age at their first sexual intercourse is prone to result in potential recall or response bias, especially given the potential sensitivity of the topic being explored, especially if first sexual debut was with a non-marital sexual

partner.[36] There may also potentially be variations in the quality of the research being presented, with a potential for bias being enhanced if surveys have not met standards of intensive interviewer Ku-0059436 cost training, careful translation into local languages of terms such as sexual intercourse and sexual partners.[30] Only a few studies included in this review reported implementing strategies or measures to reduce recall and social desirability biases when asking women about their age at their sexual debut.[14] In the review, we were also not able to ensure comparability in the definitions of early sexual debut Idoxuridine across studies and instead had to compile evidence from studies that used differing definitions. In practice, the majority of studies reviewed compared rates of HIV infection among women who had started having

sex before the age of 15 to rates among women who had their first sex after the age of 15. However, a few studies also used other age cut-offs, and a number of studies used multiple age categories, which made the comparisons and interpretations difficult. For example, they compared early sexual debut before the age of 15 with first sex after the age of 20 or even 25, while the majority of women in most studies had their first sex between the ages of 16–20. Existing evidence on the developmental stages of adolescents[37] seems to suggest that an age cut-off for early first sex before the age of 15 is the most sensible; however, this should be determined according to the cultural background, as first sex may often coincide with cultural norms or legal marriage age. Whichever cut-off point is chosen, it should be accompanied by a justification, which was rarely given in the reviewed studies.