CD8 epitope escape and reversion in acute HCV infection

In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70-80% of individuals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8-restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon gamma enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8-associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.     

Sensitivity of HIV type 1 subtype C isolates to the entry inhibitor T-20

T-20 is the first in a new class of antiretroviral drugs targeting the entry stage of the virus life cycle. It is a 36 amino acid peptide that binds to the HR1 region of gp41 preventing gp41-mediated fusion with the host cell membrane. T-20 was designed based on the HR2 sequence of HIV-1 subtype B gp41, a region that shows significant genetic variation with HIV-1 subtype C sequences. In order to assess the efficacy of T-20 to inhibit subtype C isolates, a total of 23 isolates were tested for their ability to replicate in the presence of T-20. This included 15 isolates that used CCR5, five that used both CCR5 and CXCR4, and three that used CXCR4. Five of these were from patients failing other antiretroviral therapies. Sequence analysis of the HR2 region indicated that there were 10-16 amino acid changes in the region corresponding to T-20. However, all isolates were effectively inhibited by T-20 at 1 microg/ml. There were no significant differences between viruses that used CCR5 or CXCR4 to enter cells. All isolates, except one, had GIV at positions 36-38 in the HR1 region. One isolate had a GVV motif but this did not affect its sensitivity to T-20. Therefore, T-20 inhibited subtype C viruses despite significant genetic differences in the HR2 region and there was no evidence for baseline resistance to T-20. These data suggest that T-20 would be highly effective in patients with HIV-1 subtype C infection, including those failing existing antiretroviral drug regimens.     

Association of angiomyolipoma and oncocytoma of the kidney: a case report and review of the literature

AIM: The association between renal carcinoma and angiomyolipoma is rare. Only 14 cases have been reported in the literature. The purpose of this paper is to present an additional case and review the literature on this association. PATIENT AND METHODS: A healthy 42 year old woman was found to have a left flank mass incidentally when she presented for a Papanicolaou smear. The computerised tomography scan revealed a left lower pole renal mass consistent with a renal cell carcinoma. A nephrectomy was performed and the patient recovered uneventfully. The nephrectomy specimen was processed routinely. In addition to haematoxylin and eosin staining, immunohistochemistry for CAM 5.2, vimentin, CD34, antismooth muscle actin, and HMB45 was carried out. Transmission electron microscopy was also performed. RESULTS: Macroscopically, the lower pole of the kidney contained a well circumscribed, non-encapsulated, tan coloured tumour with a large area of central haemorrhage measuring 10.5 cm. In addition, there was a 0.4 cm poorly circumscribed unencapsulated yellow nodule adjacent to the tumour. Microscopically, the larger tumour showed characteristic features of an oncocytoma. Numerous mitochondria were seen on electron microscopy. The smaller yellow nodule was an angiomyolipoma. CONCLUSIONS: This paper presents an additional case of oncocytoma associated with angiomyolipoma. Of the 15 cases described in the literature, three were associated with the tuberous sclerosis complex, all from a single study. In tuberous sclerosis, angiomyolipomas are more commonly associated with renal cell carcinoma. If angiomyolipomas are found incidentally in nephrectomy specimens together with other tumours, it is important to exclude tuberous sclerosis retrospectively.     

An unusual case of a compound depressed skull fracture after an assault with a stiletto heel

Compound depressed skull fractures occur commonly from assault with various sharp and blunt objects. The use of a stiletto heeled shoe as an offensive weapon has not been reported before as a cause of such an injury. However unusual the history of assault, a clear picture of the mechanism of the injury is vital. Patients with scalp lacerations following a direct blow to the head must be evaluated thoroughly. Early investigation and treatment are necessary to reduce the risk of complications, as illustrated by this case.     

Bilateral MRI-guided stereotactic cingulotomy for intractable pain.

As a treatment of patients with intractable cancer and noncancer pain, bilateral radiofrequency cingulotomy was performed in 10 patients. The technique involved stereotaxis using magnetic resonance guidance and local anesthesia, with the placement of a radiofrequency lesion (75 degrees, 60s). Of the 10 patients, 8 had metastatic lesions with musculoskeletal (6) or neurogenic (2) pain. Pain relief was judged excellent (4 patients), fair (1), poor (2) and excellent for 6 months poor in the last patient. The two benign lesions were neurofibromatosis with neurogenic pain and thalamic pain from an old stroke. Pain relief (with 1 year follow-up) in this group was judged excellent in one and poor in the other (thalamic pain).