HSV-1 establishes life-long latency that can result in clinical relapses or in asymptomatic virus shedding. Although virtually all adults have been exposed to HSV-1, the clinical course varies remarkably. Genetic host variability could be related to this clinical diversity. In this study, we analyzed the contribution of gene families in chromosomes 1, 6, 12, and 19, which encode key regulators of the innate and adaptive immunity, in a cohort of 302 individuals. Class I and class II alleles of the HLA system, the copy-number variation of NK cell receptor genes (KIR and NKG2C), the combinations of killer cell Ig-like receptor and their HLA ligands, and CD16A and CD32A allotypes of variable affinity for IgG subclasses were all studied. Although no major susceptibility locus for HSV-1 was identified, our results show that the risk of suffering clinical HSV-1 infection is modified by MHC class I allotypes (B*18, C*15, and the group of alleles encoding A19), the high-affinity receptor/ligand pair KIR2DL2/HLA-C1, and the CD16A-158V/F dimorphism. Conversely, HLA class II and CD32A polymorphisms and NKG2C deletion did not seem to influence the clinical course of herpetic infection. Collectively, these findings support an important role in host defense against herpetic infection for several polymorphic genes implicated in adaptive immunity and in surveillance of its subversion. They confirm the crucial role of cytotoxic cells (CTL and NK) and the contribution of genetic diversity to the clinical course of HSV-1 infection.

Lutein, a non-provitamin A xanthophyll, is widely distributed in fruits and vegetables frequently consumed. In human serum, lutein is transported by lipoproteins and selectively accumulated in certain tissues (eg the retina). Epidemiological studies suggest that high intake and serum levels of lutein are associated with a lower risk of cataracts and age-related maculopathy. Subjects diagnosed with cataracts (CA; n = 5) or age-related macular degeneration (ARMD; n = 5) agreed to take three lutein capsules per week. Each capsule potentially provided about 12 mg of all-trans-lutein, 3 mg of 13/15-cis-lutein and 3.3 mg of a-tocopherol, as revealed by HPLC. Zeaxanthin was not detected. Average supplementation time was 13 months (range 4±20 months) for ARMD subjects and 26 months (range 16±36 months) for CA subjects. Blood samples for carotenoid analysis were collected every 3 months, coinciding with ophthalmological revision. In serum, concentrations of lutein, 13-cis-lutein and two ketocarotenoids increased signi®cantly. Maximum increments were observed at 3±6 months, reaching levels above the 95th percentile of the reference population (>0.44 mmol l À1 ). Ophthalmological evaluation showed an average increment in visual acuity of 0.4, and glare sensitivity also improved. No signi®cant side effects such as hypercarotenemia, carotenodermia or changes in biochemical or haematological pro®le were observed. Thus, lutein supplementation at achievable dietary levels increased and maintained serum lutein levels, which were associated with an improvement in the visual function of the patients.

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The uterosacral ligaments (USL) have been reported to be the most common site of deep endometriosis (DE) in the pelvis 1 . A nodule within the USL may infiltrate the parametrium, increasing the complexity of surgical resection, and larger nodules (≥ 17 mm) noted on transvaginal ultrasound (TVS) should raise suspicion of ureteral involvement 2 . Nodules may also invade the torus uterinus, which is the thickening between the insertion of the USL behind the posterior cervix. The diagnostic test accuracy of TVS for USL DE is only moderate, with sensitivity and specificity of 67% and 86%, respectively 3 , which may be related to the absence of a standardized technique for its assessment. We present a method that allows easier identification of normal and abnormal USL and classification of USL DE nodules.The proposed method for TVS assessment of USL is summarized in Videoclip S1 and consists of the following steps.1. Insert the TVS probe into the posterior vaginal fornix behind the cervix and uterus. 2. Decrease the penetration depth of field and position the focal point nearest to the probe. 3. Angle the probe toward the rectum in the midsagittal position ( Figure S1). Visualize the hypoechoic posterior vaginal fornix nearest to the probe; adjacent is the hyperechoic pouch of Douglas peritoneum. Follow this hyperechoic line closely in the next step. 4. To evaluate the right USL, simultaneously sweep the ultrasound beam to the patient's right ( Figure S1) and rotate clockwise (usually not more than 45 • ); the hyperechoic line (peritoneum) should begin to thicken. The USL should be evaluated at the thickest point of the hyperechoic line. For the left USL, follow the same procedure, but instead rotating the probe counterclockwise. 5. If a hypoechoic lesion is seen within the hyperechoic USL ( Figures S2 and S3), measure it in three orthogonal planes ( Figure S4). 6. Evaluate the portion of the nodule that is within the borders of the USL and characterize the lesion according to the proposed USL DE classification system (Table 1, Figures 1 and 2), in line with the leiomyoma subclassification of submucosal leiomyomas 4 . 7. Evaluation of the ureters should always be performed ( Figure S5). A ureter of ≥ 6 mm in diameter should be considered as dilated. The kidneys should be assessed for hydronephrosis 5 .We believe that the proposed USL DE classification system (Table 1) provides a simple and standardized approach to describe such lesions, which may assist sonographers and surgeons in predicting ureteral involvement and/or the need for ureterolysis. Corresponding surgical images of USL DE with parametrial involvement are shown in Figure S6. Of course, evaluation of the USL DE classification system for its utility in diagnosis and/or preoperative planning is required before clinical implementation is considered.

Endometriosis is a chronic systemic disease that can cause pain, infertility and reduced quality of life. Diagnosing endometriosis remains challenging, which yields diagnostic delays for patients. Research on diagnostic test accuracy in endometriosis can be difficult due to verification bias, as not all patients with endometriosis undergo definitive diagnostic testing. The purpose of this State-of-the-Art Review is to provide a comprehensive update on the strengths and limitations of the diagnostic modalities used in endometriosis and discuss the relevance of diagnostic test accuracy research pertaining to each. We performed a comprehensive literature review of the following methods: clinical assessment including history and physical examination, biomarkers, diagnostic imaging, surgical diagnosis and histopathology. Our review suggests that, although non-invasive diagnostic methods, such as clinical assessment, ultrasound and magnetic resonance imaging, do not yet qualify formally as replacement tests for surgery in diagnosing all subtypes of endometriosis, they are likely to be appropriate for advanced stages of endometriosis. We also demonstrate in our review that all methods have strengths and limitations, leading to our conclusion that there should not be a single gold-standard diagnostic method for endometriosis, but rather, multiple accepted diagnostic methods appropriate for different circumstances.

The combination of the TVS "sliding sign" and direct visualization of the bowel during TVS appears to provide the most accurate assessment for the identification of rectal/rectosigmoid DE preoperatively.

Herpes simplex virus type 1 (HSV-1) causes lifelong latent infections in most humans. Periodical virus reactivations from latency in the neurons of sensitive ganglia lead to transport to mucocutaneous regions and productive replication, which results in recurrent inflammatory herpetic lesions or in asymptomatic virus shedding. The medical consequences of such lesions and the frequency of recurrences vary greatly in different subjects. Furthermore, many infected individuals never suffer manifestations of the disease, even when exposed to stimuli that trigger clinical recurrences in other humans. The origin of the variability in the clinical course of HSV-1 infection remains unexplained. Herpesviruses and other pathogens sabotage the expression of major histocompatibility complex class I molecules by infected cells, thus subverting T-cell-mediated immunity. Subversion of antigen presentation is counteracted by natural killer cells, which survey the human leukocyte antigen (HLA) expression by specific receptors. These include the killer cell immunoglobulin-like receptors (KIRs), which are encoded by a complex of extremely diverse and rapidly evolving genes. Here, we analyze the contribution of KIR gene diversity to the variable clinical course of HSV-1 infection by comparing the distribution of these genes in humans with clinical manifestations of the disease with that in asymptomatically infected donors. This study provides preliminary evidence that the receptors KIR2DL2 and KIR2DS2 predispose to symptomatic HSV-1 infection and favor the frequently recurring forms of the disease. Possible contribution of the 'HLA-C1' ligand to HSV-1 disease was not statistically supported. Because of an absolute genetic linkage between KIR2DL2 and KIR2DS2, we could not determine which receptor was primarily responsible for the observed association, but our results suggest that presence in the genome of KIR2DL2 and KIR2DS2 hinders an effective cellular response to HSV-1.