Daniel Feinberg

Postural change of forced vital capacity predicts some respiratory symptoms in ALS

The detection of respiratory muscle weakness in ALS is necessary to plan initiation of noninvasive positive pressure ventilation and begin discussion of advanced directives. The authors measured the erect seated and supine forced vital capacity (FVC) in 38 patients with ALS and 15 controls. The supine FVC is significantly lower and the erect − supine FVC difference is significantly greater in patients with complaints of dyspnea, orthopnea, and daytime fatigue.

Pseudo-conduction block in vasculitic neuropathy.

The predominant electrophysiologic feature of vasculitic mononeuropathy multiplex is axonal loss. Electrophysiologic findings interpreted as conduction block have, however, also been reported to occur in neuropathy secondary to necrotizing vasculitis. We report 3 patients with mononeuropathy multiplex and biopsy proven vasculitis in whom eight nerves met criteria for conduction block. In each circumstance, serial study demonstrated conversion of the electrophysiologic findings to those most consistent with severe axonal loss. “Conduction block” in vasculitic mononeuropathy multiplex is secondary to focal axonal conduction failure presumably related to infarctive axonal injury. The term conduction block should be used with caution in this disorder and only if serial studies demonstrate findings consistent with this electrophysiologic diagnosis.

Distinct light microscopic changes in human immunodeficiency virus‐associated nemaline myopathy

The purpose of this study was to compare histologic characteristics of congenital nemaline myopathy (CNM), adult-onset nemaline myopathy (AONM), and human immunodeficiency virus-associated adult-onset nemaline myopathy (HAONM). There was no difference between the pathology of CNM and AONM; however, HAONM had distinctive pathologic features by light microscopy. The fibers in HAONM showed marked intrasar-coplasmic changes, including small vacuoles and granular degeneration.

Amplitude-dependent slowing of conduction in amyotrophic lateral sclerosis and polyneuropathy.

The mechanism of motor nerve conduction slowing in amyotrophic lateral sclerosis (ALS) is thought primarily to be loss of large, fast‐conducting motor fibers; this is less certain in axonal polyneuropathy. We compared motor conduction studies in 64 patients with axonal polyneuropathy with 72 patients with ALS. Compound motor action potential amplitude, distal motor latency, and conduction velocity were converted to a percentage of the upper or lower limit of normal and then represented as a square root (SQRT) transformation, plotted with SQRT amplitude as the independent variable and SQRT latency or SQRT conduction velocity as the dependent variables. Regression analysis of the lower extremity nerve data showed that prolongation of latency and slowing of velocity were amplitude‐dependent and were virtually identical in ALS and polyneuropathy. In the upper extremity, amplitude‐dependent prolongation of latency was similar in both groups, but amplitude‐dependent slowing of velocity was seen in ALS and not in axonal polyneuropathy. Our data support the hypothesis that the major mechanism of slowing is similar in both polyneuropathy and ALS and is the loss of large, fast‐conducting fibers. However, the presence of distal but not proximal slowing in the upper extremity of axonal polyneuropathy suggests that additional mechanisms may be contributory.

Suprascapular neuropathy related to a glenohumeral joint cyst

A man with shoulder pain and complaints of weakness had examination findings consistent with a suprascapular neuropathy with predominant involvement of the infraspinatus muscle. Electrodiagnostic studies confirmed an axon‐loss suprascapular neuropathy with greater involvement of the infraspinatus muscle. Magnetic resonance imaging (MRI) demonstrated a large ganglion cyst originating from the glenohumeral joint. The clinical, electrodiagnostic, and radiologic evaluation of suprascapular neuropathy is discussed.

Neurologists for patient safety : Where we stand, time to deliver

Neurologists have a professional opportunity, an ethical responsibility, and sound clinical and economic reasons for engaging in efforts to improve patient safety. Better communication with patients and other providers, closer follow-up of consultation cases, and more focused supervision of trainees will help to reduce current patterns of error and misunderstanding. Patient education with attention to health literacy should improve adherence to management plans and help to bridge transitions of care across providers and sites. Through teaching and by example, neurologists can profoundly influence successive generations of clinicians to adopt safer practices, a culture of openness, and enhanced professionalism. The federal Safety and Quality Improvement Act of 2005, once implemented, should increase the evidence basis for safer care through voluntary, legally protected reporting of errors and adverse events within the framework of patient safety organizations.

TNFα contributes to diabetes impaired angiogenesis in fracture healing

Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.

Distinct light microscopic changes in HIV-associated nemaline myopathy

To the Editor: The morphologic comparative study by Feinberg et al.1 suggests that HIV-associated adult-onset nemaline myopathy (HAONM) has pathologic features distinct from the classic form of adult-onset nemaline myopathy (AONM). However, nothing is mentioned about the clinical course of HAONM. Since 1990, 139 out of 290 HIV-infected patients referred to our Muscle Research Unit underwent muscle biopsy. Rod bodies were identified in 7 muscle specimens, 3 of which were from patients diagnosed with HAONM. Similar to Feinberg et al.,1 we compared the HAONM patients with those affected by AONM2 on the basis of both histologic and clinical findings. From a histologic point of view, we found that muscle samples from patients with HAONM had fewer myocytes containing rods (1%, 10%, and 20%) compared with AONM (which ranged from 3 to 80% of affected cells). Type I muscle fiber atrophy was more consistent in classic forms. …

Chondrocytes promote vascularization in fracture healing through a FOXO1 dependent mechanism

Chondrocytes play an essential role in fracture healing by producing cartilage, which forms an anlage for endochondral ossification that stabilizes the healing fracture callus. More recently it has been appreciated that chondrocytes have the capacity to produce factors that may affect the healing process. We examined the role of chondrocytes in angiogenesis during fracture healing and the role of the transcription factor forkhead box‐O 1 (FOXO1), which upregulates wound healing in soft tissue. Closed fractures were induced in experimental mice with lineage‐specific FOXO1 deletion by Cre recombinase under the control of a collagen‐2α1 promoter element (Col2α1Cre+FOXO1L/L) and Cre recombinase negative control littermates containing flanking loxP sites (Col2α1Cre–FOXO1L/L). Experimental mice had significantly reduced CD31+ new vessel formation. Deletion of FOXO1 in chondrocytes in vivo suppressed the expression of vascular endothelial growth factor‐A (VEGFA) at both the protein and mRNA levels. Overexpression of FOXO1 in chondrocytes in vitro increased VEGFA mRNA levels and VEGFA transcriptional activity whereas silencing FOXO1 reduced it. Moreover, FOXO1 interacted directly with the VEGFA promoter and a deacetylated FOXO1 mutant enhanced VEGFA expression whereas an acetylated FOXO1 mutant did not. Lastly, FOXO1 knockdown by siRNA significantly reduced the capacity of chondrocytes to stimulate microvascular endothelial cell tube formation in vitro. The results indicate that chondrocytes play a key role in angiogenesis which is FOXO1 dependent and that FOXO1 in chondrocytes regulates a potent angiogenic factor, VEGFA. These studies provide new insight into fracture healing given the important role of vessel formation in the fracture repair process.

The Role of FOXO1 and FOXO3 in the Adaptive Immune Response: Dendritic Cells, T-cells, B-cells and Hematopoietic Stem Cells.

Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin αvβ3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway.