Neutropenia and Primary Immunodeficiency Diseases

Primary immunodeficiency diseases (PID) are a heterogeneous group of congenital disorders of the immune system leading to recurrent infections, autoimmunity, malignancies, and hematological disorders. This review focuses specifically on inherited disorders associated with neutropenia, which may occur in isolation or as a feature of more complex immune disorders. It has been known for a long time that defined immunodeficiency syndromes, such as CD40L deficiency, WHIM syndrome, or Chédiak Higashi syndrome, may be associated with neutropenia even though the mechanisms are poorly understood. In some PID, neutropenia may result from chronic viral infection or from autoimmunity. Recently, the identification of several novel genetic defects (e.g., p14-deficiency, HAX1-deficiency, AK2-deficiency) has shed light on the pathophysiology of congenital neutropenia. This review summarizes the clinical, immunological, and genetic features of congenital neutropenia syndromes.     

Femoral Strength Changes Faster With Age Than BMD in Both Women and Men: A Biomechanical Study

Although a large number of studies have addressed the age‐related changes in bone mineral density (BMD), there is a paucity of data for the assessment of femoral strength loss with age in both genders. We determined the variation of strength with age in femurs of women and men by mechanical tests on a cohort of 100 cadaveric femurs. In addition, the age‐related neck BMD loss in our cadaveric cohort was found to be similar with BMD loss of four published population‐based studies. Given the strong correlation found in our cadaveric study between BMD and femoral strength, we also estimated the femoral strength of the four populations based on their reported neck BMDs. Our study showed that men's femurs in our cadaveric cohort were stronger than women's femurs by about 800 N at the same BMD level, and by 1750 N at the same age. The strength differences were not explained satisfactorily by the size difference between men's and women's bones. Similar to the findings of clinical studies, the BMD values of men at all ages were larger than that of women. The age‐related loss rates in BMD and strength were not statistically different between the two genders of our cadaveric cohort. After normalization, strength decreased more than 40% faster than BMD. On average, men reached a certain BMD value about 16 years later than women, and for strength about 23 years later, which may explain the higher rate of hip fracture in postmenopausal women. In patient population cohorts men reached a similar BMD value about 16 to 25 years later than women, whereas for estimated strength, sometimes more than 40 years later. © 2015 American Society for Bone and Mineral Research.     

Corneal Confocal Microscopy Identifies Small-Fiber Neuropathy in Subjects With Impaired Glucose Tolerance Who Develop Type 2 Diabetes

OBJECTIVEImpaired glucose tolerance (IGT) through to type 2 diabetes is thought to confer a continuum of risk for neuropathy. Identification of subjects at high risk of developing type 2 diabetes and, hence, worsening neuropathy would allow identification and risk stratification for more aggressive management.RESULTSTen subjects who developed type 2 diabetes had a significantly lower CNFD (P = 0.003), CNBD (P = 0.04), and CNFL (P = 0.04) compared with control subjects at baseline and a further reduction in CNFL (P = 0.006), intraepidermal nerve fiber density (IENFD) (P = 0.02), and mean dendritic length (MDL) (P = 0.02) over 3 years. Fifteen subjects who remained IGT and 5 subjects who returned to normal glucose tolerance had no significant baseline abnormality on CCM or IENFD but had a lower MDL (P < 0.0001) compared with control subjects. The IGT subjects showed a significant decrease in IENFD (P = 0.02) but no change in MDL or CCM over 3 years. Those who returned to NGT showed an increase in CNFD (P = 0.05), CNBD (P = 0.04), and CNFL (P = 0.05), but a decrease in IENFD (P = 0.02), over 3 years.CONCLUSIONSCCM and skin biopsy detect a small-fiber neuropathy in subjects with IGT who develop type 2 diabetes and also show a dynamic worsening or improvement in corneal and intraepidermal nerve morphology in relation to change in glucose tolerance status.     

Small Nerve Fiber Quantification in the Diagnosis of Diabetic Sensorimotor Polyneuropathy: Comparing Corneal Confocal Microscopy With Intraepidermal Nerve Fiber Density

OBJECTIVE

Quantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard.

RESEARCH DESIGN AND METHODS

Eighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy.

RESULTS

Manual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14).

CONCLUSIONS

This study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN.     

Development trends for generation of single-chain antibody fragments

Recombinant antibodies are increasingly being employed as therapeutic agents especially in combination with anti-cancer drugs. The single-chain antibody fragments are small antigen-binding proteins which provide the most commonly used antibody formats for diagnostic and therapeutic purposes. These antibody fragments have more rapid tumor penetration and clearance from the serum relative to full-length monoclonal antibodies. There are in vitro antibody-display technologies such as phage display, cell surface display, ribosome display and mRNA display that can be used to isolate high specificity and affinity single-chain antibodies against a wide variety of targets. We review these strategies for generation of stable and active antibody fragments in the present article.     

Protective effects of copper against aluminum toxicity on acetylcholinesterase and catecholamine contents of different regions of rat’s brain

The probable protective effects of copper on the acetylcholinesterase activity and the catecholamine levels in cerebellum, cortex and mid-brain of rat, which was intoxicated by aluminum, were studied during short and long terms. In this respect, male Wistar rats weighing 200–250 g were received daily intraperitoneal doses of aluminum, copper and also combined doses of both metals for 15 days (Al 10 mg kg^?1 BW and Cu 1 mg kg^?1 BW), 30 days (Al 5 mg kg^?1 BW and Cu 0.5 mg kg^?1 BW) and 60 days (Al 1 mg kg^?1 BW and Cu 0.1 mg kg^?1 BW), respectively. The results obtained from the short period of exposure (15 days) showed that aluminum produced significant (P < 0.05) decreases in the acetylcholinesterase activity by 24.14, 23.30 and 25.81 %. Similarly, the catecholamine levels were reduced by 10.69, 12.25 and 12.64 % in cerebellum, cortex and mid-brain, respectively. Treatment with copper increases both acetylcholinesterase activity and catecholamine contents of cerebellum, cortex and mid-brain. Simultaneous injection of copper and aluminum increased both acetylcholinesterase activity and catecholamine contents in all three parts of rat brain when compared to aluminum-treated group. Same results were also observed following 30 and 60 days of exposures. In overall, it has been found that copper may have a protective-like ability to hinder aluminum toxicity in the brain.