Rapid clearance of herpes simplex virus type 2 by CD8+ T cells requires high level expression of effector T cell functions

CD8(+) T cells are important for resolution of HSV-2 lesions from the female genital epithelium. It is uncertain whether optimal clearance of viruses such as HSV-2 that cause a limited, non-systemic infection solely requires expression of effector functions by infiltrating CD8(+) T lymphocytes, or if the clearance rate is reflective of the expression level of critical effector functions. To address this, CD8(+) T cells from normal OT-I mice or OT-I mice deficient in IFNγ (IFNγ(-/-)) or the IFNγ receptor (IFNγR(-/-)) were activated in vitro in the presence of IFNγ or IL-4 to generate a series of effector populations (Tc1 and Tc2-like respectively) that secreted different levels of IFNγ and expressed different levels of HSV-specific cytolytic function. Compared with Tc1 cells, Tc2-like cells produced the type 2 cytokines IL-4 and IL-5, exhibited decreased IFNγ secretion, diminished proliferation in vitro, and decreased antigen-specific cytolysis in vivo. Clearance of an ovalbumin-expressing HSV-2 strain (HSV-2 tk(-) OVA) by adoptively transferred Tc2-like cells was delayed relative to Tc1 cell recipients. Because donor Tc2-like cells proliferated in vivo and infiltrated the infected genital epithelium similar to Tc1 cells, the diminished virus clearance by Tc2-like effector cells correlated with reduced expression of critical effector functions. Together, these results suggest that high level expression of protective T cell functions by effector T cells is necessary for optimal clearance of HSV-2 from the genital epithelium. These results have important implications for vaccines designed to elicit CD8(+) T cells against viruses such as HSV-2 that infect the genital tract.     

Dying at home: a qualitative study of family carers’ views of support provided by GPs community staff

Background

Dying at home is the preference of many patients with life-limiting illness. This is often not achieved and a key factor is the availability of willing and able family carers.

Aim

To elicit family carers’ views about the community support that made death at home possible.

Design and setting

Qualitative study in East Devon, North Lancashire, and Cumbria.

Method

Participants were bereaved family carers who had provided care at the end of life for patients dying at home. Semi-structured interviews were conducted 6–24 months after the death.

Results

Fifty-nine bereaved family carers were interviewed (54% response rate; 69% female). Two-thirds of the patients died from cancer with median time of home care being 5 months and for non-cancer patients the median time for home care was 30 months. An overarching theme was of continuity of care that divided into personal, organisational, and informational continuity. Large numbers and changes in care staff diluted personal continuity and failure of the GPs to visit was viewed negatively. Family carers had low expectations of informational continuity, finding information often did not transfer between secondary and primary care and other care agencies. Organisational continuity when present provided comfort and reassurance, and a sense of control.

Conclusion

The requirement for continuity in delivering complex end-of-life care has long been acknowledged. Family carers in this study suggested that minimising the number of carers involved in care, increasing or ensuring personal continuity, and maximising the informational and organisational aspects of care could lead to a more positive experience.     

The impact of a phase-change cooling vest on heat strain and the effect of different cooling pack melting temperatures

Cooling vests (CV) are often used to reduce heat strain. CVs have traditionally used ice as the coolant, although other phase-change materials (PCM) that melt at warmer temperatures have been used in an attempt to enhance cooling by avoiding vasoconstriction, which supposedly occurs when ice CVs are used. This study assessed the effectiveness of four CVs that melted at 0, 10, 20 and 30 °C (CV₀, CV₁₀, CV₂₀, and CV₃₀) when worn by 10 male volunteers exercising and then recovering in 40 °C air whilst wearing fire-fighting clothing. When compared with a non-cooling control condition (CON), only the CV₀ and CV₁₀ vests provided cooling during exercise (40 and 29 W, respectively), whereas all CVs provided cooling during resting recovery (CV₀ 69 W, CV₁₀ 66 W, CV₂₀ 55 W and CV₃₀ 29 W) (P < 0.05). In all conditions, skin blood flow increased when exercising and reduced during recovery, but was lower in the CV₀ and CV₁₀ conditions compared with control during exercise (observed power 0.709) (P < 0.05), but not during resting recovery (observed power only 0.55). The participants preferred the CV₁₀ to the CV₀, which caused temporary erythema to underlying skin, although this resolved overnight after each occurrence. Consequently, a cooling vest melting at 10 °C would seem to be the most appropriate choice for cooling during combined work and rest periods, although possibly an ice-vest (CV₀) may also be appropriate if more insulation was worn between the cooling packs and the skin than used in this study.     

Minimal progesterone support required for the maintenance of pregnancy in mice

A study of the degree of progesterone support required for the maintenance of various stages of pregnancy was undertaken in mice. Mated females were ovariectomized at various stages of pregnancy and progesterone and oestradiol support provided by s.c. Silastic implants with known release characteristics. In the earliest stages of pregnancy (days 1-5), very low concentrations of progesterone (<25% of normal physiological values) were sufficient to maintain pre-implantation stages and allow implantation. In the immediate post-implantation period (days 5-9), the development of implantation sites and decidualization required considerably higher progesterone support. In mid-pregnancy (days 11-14), progesterone alone could not maintain pregnancy unless present in very high amounts; however, the presence of oestradiol during this period lowered the progesterone requirements to well within the physiological range. This effect of oestradiol started on day 11 but required the level of oestradiol support to be kept within strictly defined limits, with high concentrations inducing abortion. Progesterone alone was able to maintain pregnancy from day 15. These results indicate that the minimal progesterone support required for pregnancy in mice varies considerably at different stages of pregnancy and is at least partly modulated by oestradiol.      

MR shoulder arthrography in patients younger than 40 years of age: Frequency of rotator cuff tear versus labroligamentous pathology

The purpose of this study was to compare the frequency of rotator cuff pathology versus labroligamentous pathology in patients younger than 40 years and to determine whether routine MR arthrography is justified in all patients in this age group, regardless of the clinical symptoms. The MR arthrography was carried out on 332 patients 40 years of age and younger. Two hundred and forty‐three patients had clinical history of instability and possible labroligamentous pathology. Eighty‐nine patients had no history or physical signs of instability and were referred for reasons other than instability, such as assessment for rotator cuff tear. In the 243 patients younger than 40 years with clinical history of potential labral pathology, 39% (95/243) showed a labral tear and 2.1% (5/243) had a full‐thickness rotator cuff tendon tear. In the 89 patients with no history suggesting labral pathology, 19% (17/89) showed an unsuspected labral tear and 4.5% (4/89) had a full‐thickness rotator cuff tear. These findings suggest that, regardless of the clinical indication for referral, patients aged 40 and less referred for shoulder MRI should be imaged using MR arthrography because of the significant risk that symptoms are related to unsuspected labral pathology.     

Philadelphia-positive T-ALL in a patient with follicular lymphoma

Follicular lymphoma is a B cell malignancy prone to transformation into a large cell diffuse histology. This progression may be multi-clonal as determined by IgH rearrangement. Similar multi-clonal occurrences have been described in immunocompromised patients. However, the lymphoma cells remain predominantly of B cell type. Rarely, composite lymphomas with diffuse T cell histology have been reported arising from follicular lymphoma. The development of T cell leukaemia in a patient with a pre-existing B cell malignancy is an extremely rare event. The occurrence of T cell acute lymphoblastic leukaemia (T-ALL) following follicular lymphoma (FL) has not previously been reported. We report a case of Philadelphia positive (Ph+) T cell ALL developing in a patient who previously had FL which may give some insight into the cell of origin and the defects responsible for malignant transformation of the lymphocytes.     

Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.

The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-SCT) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MEDLINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus are (1) allo-SCT is a procedure with evidence-based efficacy in poor-risk CLL; (2) although definition of 'poor-risk CLL' requires further investigation, allo-SCT is a reasonable treatment option for younger patients with (i) non-response or early relapse (within 12 months) after purine analogues, (ii) relapse within 24 months after having achieved a response with purine-analogue-based combination therapy or autologous transplantation, and (iii) patients with p53 abnormalities requiring treatment; and (3) optimum transplant strategies may vary according to distinct clinical situations and should be defined in prospective trials. This is the first attempt to define standard indications for allo-SCT in CLL. Nevertheless, whenever possible, allo-SCT should be performed within disease-specific prospective clinical protocols in order to continuously refine transplant indications according to new developments in risk assessment and treatment of CLL.     

Fatal lactic acidosis in infancy with a defect of complex III of the respiratory chain

We report our studies on the metabolic defects which caused a newborn infant to present with a severe lactic acidemia (25 mM) and to die on the 3rd d after birth despite intensive supportive measures. The mitochondrial fractions prepared from skeletal muscle and liver oxidised NAD+-linked substrates and succinate slowly. Spectrophotometric assays for complexes I, II, and III of the respiratory chain demonstrate a specific defect of complex III in the skeletal muscle and liver mitochondrial fractions. The concentrations of cytochrome b were 75% lower in the skeletal muscle and heart mitochondria than in control preparations. The amount of non-heme iron sulphur protein of complex III was low in skeletal muscle, liver, and heart. This case differs from previous reports of complex III deficiency in three respects: the patient presented in the neonatal period, the defect was expressed in several tissues, and it was fatal.     

Prevention of neonatal respiratory distress syndrome by tracheal instillation of surfactant: a randomized clinical trial

With a randomized clinical trial, the possibility was assessed that a tracheal instillation of pulmonary surfactant prior to the first breath might prevent the development of some of the signs of neonatal respiratory distress syndrome. Of the 72 infants in the trial, all born at a gestational age of less than 30 weeks, 39 received 3 or 4 mL of surfactant, prepared from the lipids extracted from calf lung lavage. The treatment resulted in a significantly improved gas exchange during the first 72 hours of life. On the average, the arterial/alveolar PO2 ratio was 0.15 higher for the treated infants, and only about half as much extra oxygen had to be supplied. The respiratory support (peak inspiratory pressure X frequency) could be lowered significantly. Pulmonary interstitial emphysema occurred in 13 of the 33 control infants, but in only three of the 39 treated infants. Six of the control infants died in the neonatal period, but only one treated infant died. It is concluded that surfactant supplementation prior to the first breath is feasible and is of value as protection against the respiratory distress syndrome and the negative effects of hypoxia and ventilatory support.