Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?

We identified 68 patients with clonal T-large granular lymphocyte (T- LGL) proliferations who were seen at the Mayo Clinic between 1984 and 1992. Nineteen (28%) were asymptomatic at diagnosis, while the rest experienced fatigue (60%), B-symptoms (12%), and recurrent infections (15%). Associated comorbid conditions included rheumatoid arthritis (RA) in 26%. Severe anemia (hemoglobin [Hb] < 8g/dL) and neutopenia (absolute neutrophil count [ANC] < 500/microL) were seen in 19% and 40% of patients, respectively. Immunophenotypic studies showed CD3+, CD8+ phenotype in the majority (72%). Twenty-one patients (31%) have required no therapy, and remain relatively stable with a median follow- up period of 50 months. Treatment was required at either diagnosis (36 patients) or at subsequent follow-up (11 patients). Initial response rates were similar in patients treated with cyclophosphamide (CTX) with or without prednisone (69%), or prednisone alone (73%). Overall, 61 patients (90%) are alive with a median follow-up of 44 months. Actuarial median survival of this entire cohort is 161 months. The presence of anemia or symptoms does not appear to correlate with the tumor burden. In patients requiring therapy, a lower ANC and the presence of B-symptoms/infection were independently associated with a significantly lower probability of achieving a molecular or hematologic complete remission (H-CR). Intermittent immunosuppressive therapy is effective in achieving durable responses in a number of patients. T-LGL proliferations are associated with a favorable prognosis and response to therapy. However, significant heterogeneity exists in clinical presentation and associated comorbid conditions. These disorders should be included in the differential diagnosis of patients with unexplained cytopenias, particularly in the setting of RA and other autoimmune disorders. Analogous to the situation with monoclonal gammopathies, a term such as T-cell clonopathy of undetermined significance (TCUS) may be more appropriate to describe these patients.     

Risk of high‐level viraemia in HIV‐infected patients on successful antiretroviral treatment for more than 6 months

Objectives

According to the Swiss Federal Commission for HIV/AIDS, HIV‐infected patients on successful antiretroviral treatment have a negligible risk of transmitting HIV sexually. We estimated the risk that patients considered to have an undetectable viral load (VL) are actually viraemic.

Methods

A Danish, population‐based nationwide cohort study of HIV‐infected patients with VL <51 HIV‐1 RNA copies/mL for more than 6 months was carried out for the study period 2000–2008. The observation time was calculated from 6 months after the first VL <51 copies/mL to the last measurement of VL or the first VL >50 copies/mL. The time at risk of transmitting HIV sexually was calculated as 50% of the time from the last VL <51 copies/mL to the subsequent VL if it was >1000 copies/mL. The outcome was the time at risk of transmitting HIV sexually divided by the observation time.

Results

We identified 2680 study subjects contributing 9347.7 years of observation time and 56.4 years of risk of transmitting HIV (VL>1000 copies/mL). In 0.6% [95% confidence interval (CI) 0.5–0.8%] of the overall observation time the patients had VL >1000 copies/mL. In the first 6 months this risk was substantially higher (7.9%; 95% CI 4.5–11.0%), but thereafter decreased and was almost negligible after 5 years (0.03%; 95% CI 0.0–0.2%). The risk was higher in injecting drug users, but otherwise did not differ between subgroups of patients.

Conclusion

The risk of viraemia and therefore the risk of transmitting HIV sexually are high in the first 12 months of successful antiretroviral treatment, but thereafter are low.     

Soft tissue management of children's open tibial fractures �C a review of seventy children over twenty years

INTRODUCTION

The management of open tibial fractures in children represents a unique reconstructive challenge. The aim of the study was to evaluate the management of paediatric open tibial fractures with particular regard to soft tissue management.

PATIENTS AND METHODS

A retrospective case-note analysis was performed for all children presenting with an open tibial fracture at a single institution over a 20-year period for 1985 to 2005.

RESULTS

Seventy children were reviewed of whom 41 were males and 29 females. Overall, 91% (n = 64) of children suffered their injury as a result of a vehicle-related injury. The severity of the fracture with respect to the Gustilo classification was: Grade I, 42% (n = 29); Grade II, 24% (n = 17); Grade III, 34% (n = 24; 7 Grade 3a, 16 Grade 3b, 1 Grade 3c). The majority of children were treated with external fixation and conservative measures, with a mean hospital in-patient stay of 13.3 days. Soft tissue cover was provided by plastic surgeons in 31% of all cases. Four cases of superficial wound infection occurred (6%), one case of osteomyelitis and one case of flap failure. The limb salvage was greater than 98%.

CONCLUSIONS

In this series, complications were associated with delayed involvement of plastic surgeons. Retrospective analysis has shown a decreased incidence of open tibial fractures which is reported in similar studies. Gustilo grade was found to correlate with length of hospital admission and plastic surgery intervention. We advocate, when feasible, the use of local fas-ciocutaneous flaps (such as distally based fasciocutaneous and adipofascial flaps), which showed a low complication rate in children.     

Cytomegalovirus Infection Leads to Microvascular Dysfunction and Exacerbates Hypercholesterolemia-Induced Responses

Cytomegalovirus (CMV) persistently infects more than 60% of the worldwide population. In immunocompetent hosts, it has been implicated in several diseases, including cardiovascular disease, possibly through the induction of inflammatory pathways. Cardiovascular risk factors promote an inflammatory phenotype in the microvasculature long before clinical disease is evident. This study determined whether CMV also impairs microvascular homeostasis and synergizes with hypercholesterolemia to exaggerate these responses. Intravital microscopy was used to assess endothelium-dependent and -independent arteriolar vasodilation and venular leukocyte and platelet adhesion in mice after injection with either mock inoculum or murine CMV (mCMV). Mice were fed a normal (ND) or high-cholesterol (HC) diet beginning at 5 weeks postinfection (p.i.), or a HC diet for the final 4 weeks of infection. mCMV-ND mice exhibited impaired endothelium-dependent vasodilation versus mock-ND at 9 and 12 weeks and endothelium-independent arteriolar dysfunction by 24 weeks. Transient mild leukocyte adhesion occurred in mCMV-ND venules at 7 and 21 weeks p.i. HC alone caused temporary arteriolar dysfunction and venular leukocyte and platelet recruitment, which were exaggerated and prolonged by mCMV infection. The time of introduction of HC after mCMV infection determined whether mCMV+HC led to worse venular inflammation than either factor alone. These findings reveal a proinflammatory influence of persistent mCMV on the microvasculature, and suggest that mCMV infection enhances microvasculature susceptibility to both inflammatory and thrombogenic responses caused by hypercholesterolemia.Cytomegalovirus (CMV) is a β-herpesvirus that infects a majority of the world''s population, primarily during early childhood. The virus establishes a lifelong infection, with periods of reactivation and latency.¹ While it can cause severe disease in immunocompromised hosts, CMV infection is asymptomatic in immunocompetent individuals. However, evidence is accumulating that CMV may contribute to other diseases, including cardiovascular disease^2–5 and inflammatory bowel disease.^6–8 The prevailing thought is that CMV is playing a role in these other pathologies by promoting inflammation,^9–11 a feature of this virus that is central to its dissemination and, therefore, survival strategy within the host.^12,13 CMV can infect many different cell types that are involved in cardiovascular disease, including leukocytes and endothelial cells, and primary infection of these cells leads to cellular adhesion molecule (CAM) up-regulation,^12,14–19 leukocyte^18,20,21 and platelet adhesion,²² and cytokine release,^15,17,20 all hallmarks of cardiovascular disease.^23–29 While these cell culture and in vivo studies have significantly advanced our understanding of CMV-induced inflammatory pathways in terms of vascular responses, less is known about the specific impact of CMV infection on vascular homeostasis in intact vessels during persistent infection. Therefore we sought to characterize the responses of both the arteriolar and venular sides of the microvasculature to primary and persistent CMV infection.The microvasculature is the site of events leading to tissue injury after exposure to inflammatory stimuli such as bacteria and ischemia/reperfusion. One of the first responses to an inflammatory signal is endothelial dysfunction, characterized by impaired endothelium-dependent vasodilation on the arteriolar side, and activation of the vascular endothelium in postcapillary venules resulting in the up-regulation of CAMs that support leukocyte and platelet recruitment. The microvessels in many organs have been shown to respond to cardiovascular risk factors in this manner.^30–32 Not only are these responses evident long before large vessel disease and the associated clinical symptoms appear, but this low-grade inflammation predisposes the tissue to worse injury responses to other stimuli including ischemia-reperfusion.^33–37 While little is known about the impact of CMV on the microvasculature, there is some evidence from transplanted organs that CMV infection is associated with thickening of the arteriolar walls during rejection,³⁸ vasculopathy,³⁹ and arteriolar dysfunction.⁴⁰ The present study uses a murine model to systematically assess the microvascular responses to CMV infection over the course of 6 months (primary and persistent infection). To this end we measured arteriolar vasodilation responses to endothelium-dependent and -independent vasodilators, acetylcholine and papaverine, respectively, as well as leukocyte and platelet recruitment in postcapillary venules of mock-inoculated and murine CMV (mCMV)-infected mice. To reflect the asymptomatic infection seen in immunocompetent humans, we used a mouse strain (C57BL/6J) that is relatively resistant to CMV infection and is well characterized in terms of vascular responses to cardiovascular risk factors.In terms of cardiovascular disease it is also noteworthy that the extent of disease is associated with risk factor burden.⁴¹ Because patients typically do not present to a cardiologist because of CMV infection, the possibility that CMV synergizes with other cardiovascular risk factors to induce microvascular inflammation should be considered. Such a scenario is supported by studies showing that mCMV infection accelerated atherosclerosis development in hyperlipidemic mice.^42–45 In these studies, the use of genetically hyperlipidemic mice necessitated the introduction of mCMV when they were already becoming hypercholesterolemic, however a majority of people are infected with CMV during early childhood before circulating cholesterol levels are elevated. Therefore the second part of our study was designed to determine whether the prior presence of mCMV infection exacerbates HC-induced microvascular dysfunction and whether the timing of this hypercholesterolemia relative to mCMV infection influences this synergism.