Endovenous valve transfer for chronic deep venous insufficiency.

OBJECTIVES: The aims of the study were to test the safety and efficacy of a custom-made endovenous valve transfer stent, and delivery system in animals and humans. METHODS: The internal jugular veins of 16 sheep, weighing 45-55 kg, were used. A segment of vein with venous valve was enclosed circumferentially with a barbed stent. This segment from the internal jugular vein was introduced and deployed remotely into the contralateral internal jugular vein. Harvesting occurred acutely (one sheep) and at 1, 3, and 6 months postoperatively (five sheep per group). Operative competence testing, histological and scanning electron microscopic (SEM) examinations were performed. Four males with recalcitrant ulcers (mean age of 22 years) had axillary veins transferred from the popliteal vein and were followed for a mean of 3.8 years. RESULTS: At harvest, all the transferred valves were competent, with no evidence of thrombosis, tilting, endoleak, or migration with normal macroscopic and SEM findings. Although only 50% of the ulcers completely healed in humans, the remainder were improved, with all valves being competent and patent. CONCLUSIONS: Endovenous valve transfer with a custom-made circumferential stent produces near perfect results in sheep and encouraging results in a small pilot study.

Popliteal vein compression syndrome: obesity, venous disease and the popliteal connection.

OBJECTIVES: Obesity and venous disease are commonly encountered together. The aetiological relationship, however, has not been clear. Popliteal venous compression (PVC) has been encountered both on ultrasound and venographically. In this study, patients with symptoms and/or signs of chronic venous hypertension with PVC were investigated and the relationship to obesity was defined. METHODS: A total of 89 patients were included in the study, of which 49 limbs were classified as having PVC defined as a greater than 90% reduction in the maximum internal diameter (ID) of the popliteal vein (POPV) with knee locking. Forty consecutive limbs with venous disease with no evidence of PVC were used as controls. The body mass index (BMI) of each group was calculated and the clinical symptoms and signs were documented. After the failure of conservative treatment, 30 of the 49 underwent open popliteal decompression. RESULTS: Patients with PVC were found to have a BMI of 34.6 +/- 6.2 compared with 25.3 +/- 3.0 of the controls. The POPV ID in the PVC group before and after knee locking changed from 11.7 +/- 5.0 to 1.0 +/- 2.1 mm, respectively. Postoperatively, the POPV ID before and after knee locking changed from 10.2 +/- 2.2 to 9.0 +/- 1.5 mm, respectively. At 16.2 +/- 12.1 months follow-up, all the major clinical parameters improved at a statistically significant level. CONCLUSIONS: There appears to be a relationship between obesity, chronic venous disease and PVC. POPV compression syndrome may clarify the previously unexplained venous presentations. Surgical decompression provides good results in patients unresponsive to conservative treatment.

Recurrence rates following external valvular stenting of the saphenofemoral junction: a comparison with simultaneous contralateral stripping of the great saphenous vein.

OBJECTIVES: The incidence of recurrent varicose veins remains high despite the development of new ablative treatments for varicose veins associated with incompetence of the saphenofemoral junction. External valvular stenting (EVS) of the terminal and/or subterminal valves of the great saphenous vein (GSV) provides a reparative, physiological approach that requires long-term evaluation. The aim of this study was to compare recurrences following EVS with perforate invaginate (PIN) stripping of the GSV. METHODS: Included in the study were 193 patients (386 limbs) all of whom underwent simultaneous PIN-stripping of the GSV in one limb and EVS in the contralateral limb. Duplex scanning of the GSV and venous valves established suitability for each procedure. Only valves with visible, mobile cusps on ultrasound imaging are suitable for EVS. Stents were specifically designed Dacron reinforced silicone for left and right saphenofemoral junctions and for the subterminal valve. In a separate group of patients identified from a database where unilateral and bilateral stents had been implanted, 39 limbs with recurrent varices were examined clinically and ultrasonically to determine the aetiology of recurrences. RESULTS: Follow up was available to a maximum of 147 months. The total recurrence rate was 12.4%; stripping (22.2%) and EVS (4.6%) (P<0.01). The residual reflux as measured by postoperative Valsalva on duplex was 9% but rarely was associated with recurrences. The most common cause of recurrence was incompetent perforators and ovarian vein incompetence filling varices of the pudendal veins. CONCLUSION: This non-randomised study included more severely affected limbs in the PIN stripping limbs, favouring a better outcome in the EVS group. In those patients at an early stage of the disease process where venous valve structure is essentially intact, EVS is a physiological alternative to PIN stripping in the treatment of varicose veins.

Micro-venous valves in the superficial veins of the human lower limb.

It is commonly believed that venous valves are not present in veins smaller than 2 mm in diameter. Venous valves, however, have been identified recently in small veins in several regions of the body. This study was undertaken to determine the size distribution of venous valves in the human lower limb micro-venous circulation. Vascular casts were made from six adult lower limbs and the sampled areas were viewed by scanning electron microscopy. In total, 2,376 valves were identified from 410 cm(3) of subcutaneous tissue. The vast majority (94%) of the valves were in veins less than 300 microm in luminal diameter, with 65% of the valves present in venous channels less than 100 microm in luminal diameter. The smallest valves identified were present in venous channels 18 microm in diameter. All valves were bicuspid and often associated with a tributary. Endothelial cells on the vein wall not associated with a valve were fusiform and arranged parallel to the long axis of the vessel, however, the endothelial cells on the luminal and valve sinus surfaces of the cusp were more polyhedral in shape and showed no obvious pattern of alignment. This study provides direct evidence to show that small superficial veins of the human lower limb do contain abundant venous valves and, for the first time, shows that the majority of these valves are present within venous channels less than 100 microm in luminal diameter.

Vpr is preferentially targeted by CTL during HIV-1 infection.

The HIV-1 accessory proteins Vpr, Vpu, and Vif are essential for viral replication, and their cytoplasmic production suggests that they should be processed for recognition by CTLs. However, the extent to which these proteins are targeted in natural infection, as well as precise CTL epitopes within them, remains to be defined. In this study, CTL responses against HIV-1 Vpr, Vpu, and Vif were analyzed in 60 HIV-1-infected individuals and 10 HIV-1-negative controls using overlapping peptides spanning the entire proteins. Peptide-specific IFN-gamma production was measured by ELISPOT assay and flow-based intracellular cytokine quantification. HLA class I restriction and cytotoxic activity were confirmed after isolation of peptide-specific CD8(+) T cell lines. CD8(+) T cell responses against Vpr, Vpu, and Vif were found in 45%, 2%, and 33% of HIV-1-infected individuals, respectively. Multiple CTL epitopes were identified in functionally important regions of HIV-1 Vpr and Vif. Moreover, in infected individuals in whom the breadth of HIV-1-specific responses was assessed comprehensively, Vpr and p17 were the most preferentially targeted proteins per unit length by CD8(+) T cells. These data indicate that despite the small size of these proteins Vif and Vpr are frequently targeted by CTL in natural HIV-1 infection and contribute importantly to the total HIV-1-specific CD8(+) T cell responses. These findings will be important in evaluating the specificity and breadth of immune responses during acute and chronic infection, and in the design and testing of candidate HIV vaccines.

Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection.

Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-1 infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201-restricted CTL response is directed towards the epitope SLYNTVATL ("SL9") in p17 Gag (residues 77-85). This epitope is targeted by 75% of HLA-A*0201-positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide-major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201-positive subjects with acute HIV-1 infection (P = 2 x 10(-6)), even when assays were repeated using the SL9 peptide variant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201-positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.

Immune control of HIV-1 after early treatment of acute infection.

Virus-specific T-helper cells are considered critical for the control of chronic viral infections. Successful treatment of acute HIV-1 infection leads to augmentation of these responses, but whether this enhances immune control has not been determined. We administered one or two supervised treatment interruptions to eight subjects with treated acute infection, with the plan to restart therapy if viral load exceeded 5,000 copies of HIV-1 RNA per millilitre of plasma (the level at which therapy has been typically recommended) for three consecutive weeks, or 50,000 RNA copies per ml at one time. Here we show that, despite rebound in viraemia, all subjects were able to achieve at least a transient steady state off therapy with viral load below 5,000 RNA copies per ml. At present, five out of eight subjects remain off therapy with viral loads of less than 500 RNA copies per ml plasma after a median 6.5 months (range 5-8.7 months). We observed increased virus-specific cytotoxic T lymphocytes and maintained T-helper-cell responses in all. Our data indicate that functional immune responses can be augmented in a chronic viral infection, and provide rationale for immunotherapy in HIV-1 infection.

Identification of dominant optimal HLA-B60- and HLA-B61-restricted cytotoxic T-lymphocyte (CTL) epitopes: rapid characterization of CTL responses by enzyme-linked immunospot assay.

Human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T-lymphocyte (CTL) responses play a major role in the antiviral immune response, but the relative contribution of CTL responses restricted by different HLA class I molecules is less well defined. HLA-B60 or the related allele B61 is expressed in 10 to 20% of Caucasoid populations and is even more highly prevalent in Asian populations, but yet no CTL epitopes restricted by these alleles have been defined. Here we report the definition of five novel HLA-B60-restricted HIV-1-specific CTL epitopes, using peripheral blood mononuclear cells in enzyme-linked immunospot (Elispot) assays and using CTL clones and lines in cytolytic assays. The dominant HLA-B60-restricted epitope, Nef peptide KEKGGLEGL, was targeted by all eight subjects with B60 and also by both subjects with B61 studied. This study additionally establishes the utility of the Elispot assay as a more rapid and efficient method of defining novel CTL epitopes. This approach will help to define new CTL epitopes that may play an important role in the immune control of HIV-1.

HIV-1 seroepidemiological profile in age groups and sexes in Benin City, Nigeria.

A pilot survey of 2,206 collected sera were screened for HIV-Ab by ELISA in the age groups 10-60 years. The age group 20-29 years recorded the highest HIV-1 Ab with 9/239 (3.77%). The age group 10-19, 30-39 and 40-49 recorded 3/192 (1.56%); 4/725 (0.55%) and 2/671 (0.3%), respectively. The age group > 50 years had 1/379 (0.26%). The relative rate was 3.29 between females and male with 95% confidence intervals of 1.33-8.14, p = 0.0125 by Fisher's Exact test. Conditioned on marital status, there was no significant difference in HIV-1 Ab distribution for the various age groups using modified Chi-square, G2 = 18.08 at [symbol: see text] = 0.01.

PIP: HIV infection in Nigeria has not yet been manifested in major clinical terms, but the steady rate of increase in some African countries gives cause for concern. The authors assessed the prevalence of HIV-1 infection among 2206 male and female blood donors in Benin City, Nigeria. Benin City is located between HIV-1 and HIV-2 endemic zones, and is one of the five largest cities in Nigeria. Positive ELISA HIV-antibody test results were obtained for 19 donors, a seroprevalence of 0.9%; 11/1807 (0.6%) of the males and 8/399 (3.3%) of the females. The relative rate of infection between females and males was 3.29 with 95% confidence intervals of 1.33-8.14 by Fisher's Exact test. 9/239 (3.77%) of individuals aged 20-29 were HIV-seropositive, the highest prevalence of HIV infection among the age groups. Otherwise, the age groups 10-19 years, 30-39, 40-49, and 50 and over were infected as follows: 3/192 (1.56%), 4/725 (0.55%), 2/671 (0.3%), and 1/179 (0.26%), respectively. The marital status of the population studied made no difference with regard to the distribution of antibody to HIV.

Antibodies to Candida species after operations on the large intestine: observations on the association with oral and faecal yeast colonization.

The occurrence of agglutinating and precipitating antibodies to Candida species was determined in 50 patients undergoing operations on the large intestine. The number of patients with oral or faecal yeast colonization and the amount of faecal colonization increased during the period after operation. No patient developed overt fungal infection but 15 patients developed precipitins to mannan antigens and 9 patients developed percipitins to cytoplasmic antigens during this period. The association between the formation of precipitins and the extent of faecal colonization is discussed.