Cytomegalovirus pp65 limits dissemination but is dispensable for persistence

The most abundantly produced virion protein in human cytomegalovirus (HCMV) is theimmunodominant phosphoprotein 65 (pp65), which is frequently included in CMVvaccines. Although it is nonessential for in vitro CMV growth, pp65 displaysimmunomodulatory functions that support a potential role in primary and/or persistentinfection. To determine the contribution of pp65 to CMV infection and immunity, wegenerated a rhesus CMV lacking both pp65 orthologs (RhCMVΔpp65ab). Whiledeletion of pp65ab slightly reduced growth in vitro and increased defective particleformation, the protein composition of secreted virions was largely unchanged.Interestingly, pp65 was not required for primary and persistent infection in animals.Immune responses induced by RhCMVΔpp65ab did not prevent reinfection withrhesus CMV; however, reinfection with RhCMVΔUS2-11, which lacks viral-encodedMHC-I antigen presentation inhibitors, was prevented. Unexpectedly, induction ofpp65b-specific T cells alone did not protect against RhCMVΔUS2-11 challenge,suggesting that T cells targeting multiple CMV antigens are required for protection.However, pp65-specific immunity was crucial for controlling viral disseminationduring primary infection, as indicated by the marked increase of RhCMVΔpp65abgenome copies in CMV-naive, but not CMV-immune, animals. Our data provide rationalefor inclusion of pp65 into CMV vaccines but also demonstrate that pp65-induced T cellresponses alone do not recapitulate the protective effect of natural infection.     

Designing a CBT service for an acute inpatient setting: A pilot evaluation study

A frequent complaint by service‐users of psychiatric inpatient units is the unavailability of talking therapy at precisely the time when they need to make sense of their situation. However, conventional models of cognitive–behavioural therapy (CBT) delivery, with set numbers of sessions and diagnostic specificity, are not well suited to the conditions of the acute ward, with variable and unpredictable lengths of stay and multiple and indistinct presentations. This pilot study describes a modification of CBT designed to deliver an effective, brief therapy in these conditions. The approach is grounded on the cognitive science‐based model, interacting cognitive subsystems, and draws on dialectical behaviour therapy and other recent, mindfulness‐based CBT approaches to provide a combination of simple formulation and skills‐based treatment. Evaluation in the inpatient setting also presents challenges, and these have been met by choosing measures that tap into self‐efficacy and confidence in the management of emotions rather than symptomatic change. The evaluation data on a small number of cases suggest the effectiveness of the approach and the need for wider testing of the model. Copyright © 2007 John Wiley & Sons, Ltd.     

Mouse hepatitis virus strain — Related patterns of tissue tropism in suckling mice

Summary The pattern of tissue tropism for several prototype and uncharacterized strains of mouse hepatitis virus (MHV) was studied by intranasal inoculation of each virus strain into groups of neonatal Swiss mice under otherwise identical conditions. Mice were killed at intervals up to 18 days after inoculation, and their tissues were examined for the presence of MHV antigen by indirect immunofluorescence. Two patterns of infection were apparent. Prototype MHV strains 1, 3, A59, JHM, S and uncharacterized MHV strains Tettnang and wt-1 produced a respiratory pattern, in which nose and lung were consistently involved with dissemination to other organs in a vascular distribution. Pulmonary vascular endothelium and alveolar septal cells, but not airway epithelium, were infected. An enteric pattern was observed with MHV-Y and wt-2 in which MHV antigen was largely restricted to the nose and bowel, with limited dissemination to other abdominal organs but not lung. Intestinal lesions in these mice were severe compared to those manifesting the respiratory pattern of infection. These results indicate that, like coronaviruses of other species, different strains of MHV possess different primary and secondary organotropisms following a natural route of inoculation in a susceptible host.With 3 Figures     

Optimizing staging for hepatocellular carcinoma before liver transplantation: A retrospective analysis of the UNOS/OPTN database.

Assignment of liver allocation priority for hepatocellular carcinoma is predicated on accurate imaging staging. We analyzed radiographically defined stage (radiologic stage [RS]) at listing and most recent extension and pathologic stage (PS) data from 789 liver transplant recipients for whom no pretransplant ablative treatment was given. There were no predetermined imaging or pathological protocols in this retrospective analysis of wait list data. Seventy-two (9.1%), 690 (87.5%), and 27 (3.4%) were listed as stage 1, 2 and >2, respectively. Computed tomography (CT) scan alone (46.4%), magnetic resonance image scan alone (37.1%), ultrasound alone (1.3%), and multiple imaging studies (15.2%) were used with no difference in time to transplant for listing or most recent scan among the recipient groups. Overall accuracy (RS = PS) was 44.1% and was not different if original listing RS or most recent RS was used for comparison with PS. No one type of imaging technique had superior accuracy (P = 0.13); however, CT scan used alone or in combination compared to not being used at all, had higher odds of being accurate (odds ratio [OR] 1.38 [1.03-1.84], P = 0.031). In addition, imaging done less than 90 days before transplant had higher odds of being accurate (OR 1.49 [1.06-2.08], P = 0.019) as did RS = 2 or 3 (OR 5.56 [2.70-11.11], P < 0.0001). We observed considerable variation in RS accuracy among the United Network for Organ Sharing and Organ Procurement and Transplantation Network regions that is unexplained. In conclusion, current imaging requirements for RS prior to liver transplantation are unacceptably inaccurate. Future policy should require more accurate modalities or combinations of techniques.     

Valproate-induced liver failure in one of two siblings with alpers disease

Alpers disease is a neurodegenerative disorder of childhood characterized by early developmental delay, intractable seizures, and death in childhood. Neuropathologic changes are most severe in the gray matter and consist of diffuse neuronal loss, spongiform changes, and astrocytosis. We report 2 siblings with Alpers disease who were discordant for exposure to valproate (VPA). Both had developmental delay, and a progressive seizure disorder beginning at 5 years of age. The proband died at age 8 years of complications of ongoing seizures, including epilepsia partialis continua, with only minimal liver abnormalities. Her younger brother was treated with VPA for new-onset seizures and developed fulminant liver failure 6 months later, which led to his death at 5 years of age. Neuropathologic abnormalities of both siblings were consistent with Alpers disease. These observations support classification of Alpers disease and Alpers disease with liver cirrhosis as a single disease. They also confirm previous reports indicating that VPA may accelerate fulminant liver failure in Alpers disease. We recommend that a diagnosis of Alpers disease be considered in children with unexplained early developmental delay, cerebellar signs, or partial seizures, especially epilepsia partialis continua. When Alpers disease is strongly suspected, use of VPA should be avoided.     

Semen analyses in adolescent diabetic patients

Summary We studied the semen quality and plasma testosterone levels (T) in 32 adolescent patients with insulin-dependent diabetes mellitus and in an aged-matched control group. Semen volume, motility and morphology were significantly lower in diabetics whereas seminal fructose and glucose were significantly higher. Even though the sperm count was lower in these adolescent diabetics, the difference was not significant when compared to the control group. No difference was observed in plasma testosterone levels. Patients were divided into two groups according to the presence of retinopathy and neuropathy, and degree of metabolic control. Spermiogram parameters, seminal fructose and glucose were lower in diabetics with neuropathy. No difference was observed in spermiogram parameters between diabetic patients with or without retinopathy, but seminal fructose, and glucose were lower in the former. All spermiogram parameters, as well as seminal fructose were lower in diabetics with poor metabolic control but seminal glucose was higher. No correlation was detected between clinical parameters (age at onset and duration of diabetes mellitus and time since first ejaculation), semen parameters, plasma T, glycemia and glycosuria. In conclusion, a deterioration of the quality of human semen occurs in adolescent diabetic patients. Neuropathy and poor metabolic control seem to be important factors of this deterioration. The presence of retinopathy does not correlate with T and semen quality. Supported in part by the Human Reproduction Programme/World Health Organization.