Variation of Muscular Structure in Congenital Insensitivity to Pain and Anhidrosis

Congenital insensitivity to pain with anhidrosis is a rare disease affecting the nervous system. The patients present with unexplained fever from poor thermoregulation and inability to sweat. Because of the indifference to pain, they manifest frequent traumatic and infectious injuries. Evaluations of these patients include investigation of the hypotonia and weakness evident in this group of patients. We report four patients presenting characteristic features of congenital insensitivity to pain with anhidrosis who carry an identical mutation in the TRK-A gene and who underwent nerve and skeletal muscle biopsies. All four patients had normal sensory and motor conduction studies but lacked sympathetic skin responses. Examination of the skeletal muscles biopsies obtained from two of the patients disclosed marked myopathic changes. The muscle biopsy of a third patient showed mild variation in muscle fibers and the fourth patient's muscle biopsy showed type 1 fiber predominance. Electron microscopy studies revealed remarkable decrease in the number of small caliber-myelinated and unmyelinated nerve fibers. We assume that the variable histological findings in the muscle biopsies of these patients reflect a variation in congenital insensitivity to pain with anhidrosis patients that is not related to their genetic mutation.     

Amyloid-β disrupts ongoing spontaneous activity in sensory cortex

The effect of Alzheimer’s disease pathology on activity of individual neocortical neurons in the intact neural network remains obscure. Ongoing spontaneous activity, which constitutes most of neocortical activity, is the background template on which further evoked-activity is superimposed. We compared in vivo intracellular recordings and local field potentials (LFP) of ongoing activity in the barrel cortex of APP/PS1 transgenic mice and age-matched littermate Controls, following significant amyloid-β (Aβ) accumulation and aggregation. We found that membrane potential dynamics of neurons in Aβ-burdened cortex significantly differed from those of nontransgenic Controls: durations of the depolarized state were considerably shorter, and transitions to that state frequently failed. The spiking properties of APP/PS1 neurons showed alterations from those of Controls: both firing patterns and spike shape were changed in the APP/PS1 group. At the population level, LFP recordings indicated reduced coherence within neuronal assemblies of APP/PS1 mice. In addition to the physiological effects, we show that morphology of neurites within the barrel cortex of the APP/PS1 model is altered compared to Controls. These results are consistent with a process where the effect of Aβ on spontaneous activity of individual neurons amplifies into a network effect, reducing network integrity and leading to a wide cortical dysfunction.     

Steroid‐responsive,progressive, focal measles virus brain infection

Chronic measles virus infection of the brain causes subacute sclerosing panencephalitis (SSPE), a progressive, relentless fatal disorder. We report a 52‐year‐old male who developed focal, chronic persistent measles virus infection of the brain following interferon and ribavirin therapy for hepatitis C, and who responded to steroid therapy. This case, diametrically different from SSPE, has 2 unique features, its focal nature and its permissive response to steroids, that may add to the understanding of the pathogenesis of SSPE and the mechanism enabling viruses to evade the immune response and establish persistent brain infection. Ann Neurol 2014;75:967–970     

Quantitative and qualitative changes in anti-Neu5Gc antibody response following rabbit anti-thymocyte IgG induction in kidney allograft recipients

Antibodies of non-human mammals are glycosylated with carbohydrate antigens, such as galactose-α-1-3-galactose (α-Gal) and N-glycolylneuraminic acid (Neu5Gc). These non-human carbohydrate antigens are highly immunogenic in humans due to loss-of-function mutations of the key genes involved in their synthesis. Such immunogenic carbohydrates are expressed on therapeutic polyclonal rabbit anti-human T-cell IgGs (anti-thymocyte globulin; ATG), the most popular induction treatment in allograft recipients. To decipher the quantitative and qualitative response against these antigens in immunosuppressed patients, particularly against Neu5Gc, which may induce endothelial inflammation in both the graft and the host. We report a prospective study of the antibody response against α-Gal and Neu5Gc-containing glycans following rabbit ATG induction compared to controls. We show a drop in the overall levels of anti-Neu5Gc antibodies at 6 and 12 months post-graft compared to the pre-existing levels due to the major early immunosuppression. However, in contrast, in a cross-sectional study there was a highly significant increase in anti-Neu5Gc IgGs levels at 6 months post-graft in the ATG-treated compared to non-treated patients(P = 0.007), with a clear hierarchy favouring anti-Neu5Gc over anti-Gal response. A sialoglycan microarray analysis revealed that the increased anti-Neu5Gc IgG response was still highly diverse against multiple different Neu5Gc-containing glycans. Furthermore, some of the ATG-treated patients developed a shift in their anti-Neu5Gc IgG repertoire compared with the baseline, recognizing different patterns of Neu5Gc-glycans. In contrast to Gal, Neu5Gc epitopes remain antigenic in severely immunosuppressed patients, who also develop an anti-Neu5Gc repertoire shift. The clinical implications of these observations are discussed.     

Effects of severe dietary restriction on male reproductive hormones

The reproductive hormone response to severe caloric restriction (600 Cal day-1) was studied in six men 33-67% over ideal body weight who completed a 32-day protocol consisting of three periods in the following order: control (4 days), maintenance protein and energy; diet A (14 days), 50 g lean beef protein plus 50 g casein; and diet B (14 days), 50 g lean beef protein plus 50 g carbohydrate. Weight loss (8.7-12.5 kg) was associated with a decrease in mean blood glucose [4.52 +/- 0.60 (+/- SEM), 3.49 +/- 0.29, and 3.80 +/- 0.30 mM] and an increase in beta-hydroxybutyrate (less than 0.10, 2.09 +/- 0.44, and 1.06 +/- 0.34 mM), as determined on the final morning of each period. On the same days, mean serum FSH and LH responses to LHRH infusion of 0.2 micrograms min-1 for 4 h (expressed as milliinternational units per ml area under the concentration-time curve) were: FSH, 1558 +/- 359, 1336 +/- 545, and 1337 +/- 321 (P = NS); and LH, 1730 +/- 545, 1612 +/- 481, and 1782 +/- 556 (P = NS), respectively. Basal serum FSH, LH, free testosterone (T), and total T changed, while 24-h urinary LH and FSH excretion increased on diet A only. Unlike 10 days of total fasting, during which the same amount of weight was lost, basal serum FSH and LHRH-stimulated serum FSH responses were both significantly diminished by 25%, and serum T was diminished by 19% (1), these same parameters were little changed by either low energy diet. The increased urinary excretion of FSH and LH during diet A suggests that greater ketosis increases renal gonadotropin clearance.     

Pseudohypoaldosteronism type II: marked sensitivity to thiazides,hypercalciuria, normomagnesemia,and low bone mineral density

Mutations in WNK kinases cause pseudohypoaldosteronism type II (PHA II) and may represent a novel signaling pathway regulating blood pressure and K(+) and H(+) homeostasis. PHA II is an autosomal dominant disorder characterized by hypertension, hyperkalemia, and metabolic acidosis, with normal glomerular filtration rate. Thiazide diuretics correct all abnormalities. Inactivating mutations in the thiazide-sensitive NaCl cotransporter cause Gitelman syndrome, featuring hypotension, hypokalemia, and metabolic alkalosis plus hypocalciuria and hypomagnesemia. We investigated whether hypercalciuria and hypermagnesemia occurred in a large family with PHA II. Eight affected and eight unaffected members of a PHA II family with the Q565E WNK 4 mutation were studied. In affected members blood and urinary chemistry were measured on and off hydrochlorothiazide (HCTZ), and bone mineral density was determined. Marked sensitivity to HCTZ was found. A mean dose of 20 mg/d reduced mean blood pressure in the six hypertensive subjects by 54.3 (systolic) and 24.5 (diastolic) mm Hg. In affected subjects, HCTZ reduced mean serum K(+) by 1.12 mmol/liter, mean serum Cl(-) by 6.2 mmol/liter, and mean urinary calcium by 65% and elevated mean serum calcium by 0.11 mmol/liter and mean serum urate by 118 micromol/liter. Compared with the literature, this represents an increase of 6-7 in HCTZ potency. Affected members had normomagnesemia, hypercalciuria (336 +/- 113 vs. 155 +/- 39 mg/d in unaffected relatives, P = 0.0002), and decreased bone mineral density. In PHA II the observed marked sensitivity to thiazides and the hypercalciuria are consistent with increased NaCl cotransporter activity. PHA II may serve as a model to investigate thiazides' beneficial effects and side effects.