Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets

A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4⁺ and CD8⁺ T cell subsets using a unique molecular identifier–based (UMI-based) RNA-seq method. Thorough analysis of 1.9 × 10⁸ T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 × 10⁸. Alterations of the TCR repertoire with age were observed in all 4 subsets of T cells. The greatest reduction was observed in naive CD8⁺ T cells, while the greatest clonal expansion was in memory CD8⁺ T cells, and the highest increased retention of TCR sequences was in memory CD8⁺ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8⁺ than CD4⁺ T cells, suggesting that aging has a more profound effect on cytotoxic as opposed to helper T cell functions. This may explain the increased susceptibility of older adults to novel infections.     

Oral mucosal lesions: association with the presence of antibodies to the human immunodeficiency virus

To assess the relationship between oral lesions and antibodies to the human immunodeficiency virus, oral examinations of 803 homosexual males were conducted at the time of serologic testing. Nineteen percent were HIV seropositive. Thirty percent of antibody-positive subjects had one or more oral lesion(s), as compared with 7% of antibody-negative subjects (p less than 0.001). The presence of oral lesions was significantly associated with HIV seropositivity: a subject was 5.7 times as likely to have serum antibodies if he had one or more oral lesions (95% confidence interval, 3.5 to 9.1; p less than 0.001). This significant association with HIV seropositivity was only partially explained by cigarette smoking (adjusted odds ratio 3.1; 1.4-6.8; less than 0.006). Specific conditions that were significantly associated with seropositivity included candidiasis, hairy leukoplakia, periodontal disease, and Kaposi's sarcoma. Other diseases identified included acute necrotizing ulcerative gingivitis, mucocutaneous ulcerations, and oral warts. Oral findings may occur earlier in the natural history of infection than previously reported.     

Prenatal prediction of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common cause of inherited morbidity and mortality in childhood. The wide range of phenotypes in SMA, uncertainty regarding its mode of inheritance, and the suggestion of linkage heterogeneity have complicated the genetic counselling of parents of affected children. The locus responsible for autosomal recessive SMA has been mapped to 5q11.2-q13.3. The most likely order of loci is cen-D5S6-(SMA,D5S125)-(JK53CA1/2,D5S112)-D5S3 9-qter, with highly polymorphic loci being identified at JK53CA1/2 and D5S39. We describe linkage studies with another highly polymorphic locus, D5S127, that is closely linked to D5S39. This genetic map can be used as the basis for genetic counselling in families with autosomal recessive SMA. Appropriate allowance can be made for sporadic cases owing to non-inherited causes and for linkage heterogeneity or misdiagnoses.     

Heterotopic nerve transfers: recent trends with expanding indication

There has been increasing enthusiasm for heterotopic nerve transfers for brachial plexus palsy as well as peripheral mononeural dysfunction. The concept of nerve transfer surgery is not new; the first publications on the topic date back to the early 1900s. A wide variety of potential donor nerves are available including the intercostal nerves, the spinal accessory nerve, the phrenic nerve, the ipsilateral medial pectoral nerve, partial ulnar nerve, partial median nerve, thoracodorsal nerve, radial nerve to the triceps, and the ipsilateral C7 or the contralateral C7 nerve roots. Treatment strategies include avoidance of interposed nerve grafting, isolated motor recipient nerve, early transfer, neurorrhaphy close to target motor end plates, and similar diameter between donor nerve and recipient nerves.     

Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina

Plasma viscosity, molecular markers of activated coagulation and fibrinolysis (fibrinopeptides A and B beta 15-42), coagulation factors (fibrinogen and factor VII) and antiplasmins were measured in 529 men aged 35-54 years and related to new angina pectoris (n = 117) and to coronary risk factors in controls without angina (n = 412). Five major risk factors (cigarette-smoking, blood pressure, cholesterol, triglyceride and body mass index) were each associated with increases in plasma viscosity, coagulation factors, and imbalance of coagulation over fibrinolysis (increased ratio of fibrinopeptide A/fibrinopeptide B beta 15-42). Increased viscosity and fibrinogen in smokers were partly reversed in ex-smokers, but the imbalance of coagulation and fibrinolysis persisted. Cholesterol and triglyceride were also associated with increased antiplasmin activity. In men with angina, only fibrinogen was elevated compared to controls. We suggest that increased plasma viscosity and an imbalance of coagulation over fibrinolysis may be mechanisms by which known risk factors promote arterial thrombosis, but are not present in stable angina.     

How should variable selection be performed with multiply imputed data?

Multiple imputation is a popular technique for analysing incomplete data. Given the imputed data and a particular model, Rubin's rules (RR) for estimating parameters and standard errors are well established. However, there are currently no guidelines for variable selection in multiply imputed data sets. The usual practice is to perform variable selection amongst the complete cases, a simple but inefficient and potentially biased procedure. Alternatively, variable selection can be performed by repeated use of RR, which is more computationally demanding. An approximation can be obtained by a simple ‘stacked’ method that combines the multiply imputed data sets into one and uses a weighting scheme to account for the fraction of missing data in each covariate. We compare these and other approaches using simulations based around a trial in community psychiatry. Most methods improve on the naïve complete‐case analysis for variable selection, but importantly the type 1 error is only preserved if selection is based on RR, which is our recommended approach. Copyright © 2008 John Wiley & Sons, Ltd.     

Lymphocyte beta-adrenergic receptor density of patients with recurrent affective illness

The binding characteristics of (-)3-[125I]iodocyanopindolol, a high specific activity antagonist for the lymphocyte beta-adrenoceptor, were determined in a group of euthymic lithium-treated patients and controls. There was a statistically significant reduction (less than 20%) in the density of beta-adrenoceptors in a group of 56 lithium-treated patients. Division of this group of patients into the unipolar and bipolar distinction indicated that the abnormality was based mainly in the bipolar group of patients. The unipolar patients with an endogenous form of the illness also showed this abnormality. Reduced beta-adrenoceptor density may be associated with endogenous affective illness. However, the results must be interpreted with caution since lymphocyte fractions prepared for beta-adrenoceptor assays can be contaminated with platelets and since platelets have been reported to have beta-receptors then a proportion of the total binding could be associated with platelet beta-adrenoceptors rather than with lymphocyte beta-adrenoceptors.