Cellular metabolism dictates T cell effector function in health and disease

In a healthy person, metabolically quiescent T lymphocytes (T cells) circulate between lymph nodes and peripheral tissues in search of antigens. Upon infection, some T cells will encounter cognate antigens followed by proliferation and clonal expansion in a context-dependent manner, to become effector T cells. These events are accompanied by changes in cellular metabolism, known as metabolic reprogramming. The magnitude and variation of metabolic reprogramming are, in addition to antigens, dependent on factors such as nutrients and oxygen to ensure host survival during various diseases. Herein, we describe how metabolic programmes define T cell subset identity and effector functions. In addition, we will discuss how metabolic programs can be modulated and affect T cell activity in health and disease using cancer and autoimmunity as examples.     

Podocyte loss involves MDM2‐driven mitotic catastrophe

Podocyte apoptosis as a pathway of podocyte loss is often suspected but rarely detected. To study podocyte apoptosis versus inflammatory forms of podocyte death in vivo, we targeted murine double minute (MDM)‐2 for three reasons. First, MDM2 inhibits p53‐dependent apoptosis; second, MDM2 facilitates NF‐κB signalling; and third, podocytes show strong MDM2 expression. We hypothesized that blocking MDM2 during glomerular injury may trigger p53‐mediated podocyte apoptosis, proteinuria, and glomerulosclerosis. Unexpectedly, MDM2 blockade in early adriamycin nephropathy of Balb/c mice had the opposite effect and reduced intra‐renal cytokine and chemokine expression, glomerular macrophage and T‐cell counts, and plasma creatinine and blood urea nitrogen levels. In cultured podocytes exposed to adriamycin, MDM2 blockade did not trigger podocyte death but induced G2/M arrest to prevent aberrant nuclear divisions and detachment of dying aneuploid podocytes, a feature of mitotic catastrophe in vitro and in vivo. Consistent with these observations, 12 of 164 consecutive human renal biopsies revealed features of podocyte mitotic catastrophe but only in glomerular disorders with proteinuria. Furthermore, delayed MDM2 blockade reduced plasma creatinine levels, blood urea nitrogen, tubular atrophy, interstitial leukocyte numbers, and cytokine expression as well as interstitial fibrosis. Together, MDM2‐mediated mitotic catastrophe is a previously unrecognized variant of podocyte loss where MDM2 forces podocytes to complete the cell cycle, which in the absence of cytokinesis leads to podocyte aneuploidy, mitotic catastrophe, and loss by detachment. MDM2 blockade with nutlin‐3a could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Chronic dysimmune neuropathies: Beyond chronic demyelinating polyradiculoneuropathy

The spectrum of chronic dysimmune neuropathies has widened well beyond chronic demyelinating polyradiculoneuropathy (CIDP). Pure motor (multifocal motor neuropathy), sensorimotor with asymmetrical involvement (multifocal acquired demylinating sensory and motor neuropathy), exclusively distal sensory (distal acquired demyelinating sensory neuropathy) and very proximal sensory (chronic immune sensory polyradiculopathy) constitute the variants of CIDP. Correct diagnosis of these entities is of importance in terms of initiation of appropriate therapy as well as prognostication of these patients. The rates of detection of immune-mediated neuropathies with monoclonal cell proliferation (monoclonal gammopathy of unknown significance, multiple myeloma, etc.) have been facilitated as better diagnostic tools such as serum immunofixation electrophoresis are being used more often. Immune neuropathies associated with malignancies and systemic vasculitic disorders are being defined further and treated early with better understanding of the disease processes. As this field of dysimmune neuropathies will evolve in the future, some of the curious aspects of the clinical presentations and response patterns to different immunosuppressants or immunomodulators will be further elucidated. This review also discusses representative case studies.     

Surgical management of pygopagus conjoined twins with spinal bifida

Purpose

Conjoined twins are a rare complication of 9 monozygotic twins and are associated with high perinatal mortality. Pygopagus are one of the rare types of conjoined twins with only a handful of cases reported in the literature.

Case summary

We present the case of one-and-half month-old male pygopagus conjoined twins, who were joined together dorsally in lower lumbar and sacral region and had spina bifida and shared a single thecal sac with combined weight of 6.14 kg. Spinal cord was separated at the level of the conus followed by duraplasty. They had uneventful recovery with normal 15 months follow-up.

Conclusion

Separation of conjoined twins is recommended in where this is feasible with the anticipated survival of both or one infant.

     

Controlled Active Mobilization After Dorsal Capsulodesis to Correct Capitolunate Dissociation

Study DesignCase Report. Capitolunate instability is a form of midcarpal instability. If conservative management is unsuccessful, surgical reconstruction is often indicated. However, the literature is limited regarding postoperative management after reconstruction. Often patients are immobilized for a 6- to 12-week period, which can produce secondary complications, including wrist stiffness, tendon adherence, and muscle atrophy. The purpose of the case report was to demonstrate that controlled early mobilization may be implemented postoperatively after dorsal capsulodesis procedures to correct capitolunate instability. This early mobilization may prevent secondary complications, which can be associated with lengthy immobilization periods. A 27-year-old female underwent a dorsal capsulodesis procedure to correct capitolunate instability. The intraoperative findings of the reconstruction and tension on the capsulodesis procedure were communicated to the therapist by the surgeon. This close communication allowed the therapist to institute early controlled mobilization immediately postoperatively using a hinged wrist splint. The patient was followed by our unit for 13 years. Early controlled mobilization using a hinged wrist splint may have maximized the subject’s recovery, with no secondary complications. At 13-year follow-up, fluoroscopic and radiographic examination was normal, and no symptoms of pain or instability had reoccurred. In conclusion, early controlled mobilization using a hinged wrist splint may optimize the recovery period while retaining the desired arc of motion that is set intraoperatively.Level of Evidence4.