Immune-mediated denervation of the pineal gland underlies sleep disturbance in cardiac disease.

Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.

Strength of Occipital Hair as an Explanation for Pilonidal Sinus Disease Caused by Intruding Hair.

BACKGROUND: Pilonidal sinus disease is thought to be caused by intrusion of hair into healthy skin; loose hair in the intergluteal fold is thought to promote disease. However, compelling evidence to support these postulates is lacking; the cause of pilonidal sinus disease remains uncertain. OBJECTIVE: To determine whether particular properties of hair are associated with susceptibility to pilonidal sinus disease, we compared physical properties of hairs of patients with pilonidal sinus disease with hairs from control subjects who were matched for sex, BMI, and age. DESIGN: This was an experimental study with establishment of a mechanical strength test for single hairs to quantify the maximum vertical force that a hair could exert, following tests of strength of occipital, lumbar, and intergluteal hair. SETTINGS: Hair from patients with pilonidal sinus disease and matched control subjects were harvested from patients of the St. Marienhospital Vechta Department of Procto-Surgery. PATIENTS: A total of 17 adult patients with pilonidal sinus disease and 217 control subjects were included. MAIN OUTCOME MEASURES: ANOVA and intraclass and interclass variations of data gained from mechanical strength tests of occipital, lumbar, and intergluteal hair were included. RESULTS: Vertical hair strength was significantly greater in patients with pilonidal sinus disease. Occipital hair exhibited 20% greater, glabella sacralis 1.1 times greater, and intergluteal hair 2 times greater strength in patients with pilonidal sinus disease than in matched control subjects (all p = 0.0001). In addition, patients with pilonidal sinus disease presented with significantly more hair at the glabella sacralis and in the intergluteal fold. LIMITATIONS: The study was limited by its relatively small number of patients from a specific cohort of European patients. CONCLUSIONS: Occipital hair exhibited considerable vertical strength. Because occipital hair exerted the greatest force and cut hair fragments were found in the pilonidal nest in large quantities, these data suggest that pilonidal sinus disease is promoted by occipital hair. See Video Abstract at http://links.lww.com/DCR/A435.

Immunohistochemical detection of intra-neuronal VZV proteins in snap-frozen human ganglia is confounded by antibodies directed against blood group A1-associated antigens.

Varicella-zoster virus (VZV) causes chickenpox, establishes latency in trigeminal (TG) and dorsal root ganglia (DRG), and can lead to herpes zoster upon reactivation. The VZV proteome expressed during latency remains ill-defined, and previous studies have shown discordant data on the spectrum and expression pattern of VZV proteins and transcripts in latently infected human ganglia. Recently, Zerboni and colleagues have provided new insight into this discrepancy (Zerboni et al. in J Virol 86:578-583, 2012). They showed that VZV-specific ascites-derived monoclonal antibody (mAb) preparations contain endogenous antibodies directed against blood group A1 proteins, resulting in false-positive intra-neuronal VZV staining in formalin-fixed human DRG. The aim of the present study was to confirm and extend this phenomenon to snap-frozen TG (n=30) and DRG (n=9) specimens of blood group genotyped donors (n=30). The number of immunohistochemically stained neurons was higher with mAb directed to immediate early protein 62 (IE62) compared with IE63. The IE63 mAb-positive neurons always co-stained for IE62 but not vice versa. The mAb staining was confined to distinct large intra-neuronal vacuoles and restricted to A1(POS) donors. Anti-VZV mAb staining in neurons, but not in VZV-infected cell monolayers, was obliterated after mAb adsorption against blood group A1 erythrocytes. The data presented demonstrate that neuronal VZV protein expression detected by ascites-derived mAb in snap-frozen TG and DRG of blood group A1(POS) donors can be misinterpreted due to the presence of endogenous antibodies directed against blood group A1-associated antigens present in ascites-derived VZV-specific mAb preparations.

Nitric oxide-induced changes in endothelial expression of phosphodiesterases 2, 3, and 5.

OBJECTIVE: To investigate nitric oxide (NO)-mediated changes in expression of cyclic nucleotide degrading phosphodiesterases 2A (PDE2A), PDE3B, and PDE5A in human endothelial cells. BACKGROUND: Nitric oxide induces production of cyclic guanosine monophosphate (cGMP), which along with cyclic adenosine monophosphate (cAMP) is degraded by PDEs. NO donors and selective inhibitors of PDE3 and PDE5 induce migraine-like headache and play a role in endothelial dysfunction during stroke. The current study investigates possible NO modulation of cGMP-related PDEs relevant to headache induction in a cell line containing such PDEs. METHODS: Real time polymerase chain reaction and Western blots were used to show expression of PDE2A, PDE3B, and PDE5A in a stable cell line of human brain microvascular endothelial cells. Effects of NO on PDE expression were analyzed at specific time intervals after continued DETA NONOate administration. RESULTS: This study shows the expression of PDE2A, PDE3B, and PDE5A mRNA and PDE3B and PDE5A protein in human cerebral endothelial cells. Long-term DETA NONOate administration induced an immediate mRNA up-regulation of PDE5A (1.9-fold, 0.5 hour), an early peak of PDE2A (1.4-fold, 1 and 2 hours) and later up-regulation of both PDE3B (1.6-fold, 4 hours) and PDE2A (1.7-fold, 8 hours and 1.2-fold after 24 hours). Such changes were, however, not translated into significant changes in protein expression indicating few, if any, functional effects. CONCLUSIONS: Long-term NO stimulation modulated PDE3 and PDE5 mRNA expression in endothelial cells. However, PDE3 and PDE5 protein levels were unaffected by NO. The presence of PDE3 or PDE5 in endothelial cells indicates that selective inhibitors may have functional effects in such cells. A complex interaction of cGMP and cAMP in response to NO administration may take place if the mRNA translates into active protein. Whether or not this plays a role in the headache mechanisms remains to be investigated.

Tourniquet use in childhood: a harmless procedure?

Tourniquet ischemia is widely used in limb surgery in every age group. In adults, tourniquet-related deep vein thrombosis and pulmonary embolism are recognized complications of tourniquet use. In healthy children, tourniquet-associated alterations of blood clotting physiology are assumed to have no clinical impact. Antithrombotic prophylaxis is, therefore, recommended only in the presence of pertinent risk factors such as extensive surgery, congenital thrombophilia, prolonged immobilization, and indwelling central venous line, however, it is not practiced in obese, otherwise healthy children. We describe the first case of fatal pulmonary thromboembolism in an obese 12-year and 3-month old boy (body mass index 27.6 kg x m(-2)) following tourniquet-deflation after minor surgery on the lower extremity.

Deaths following methotrexate overdoses by medical staff.

Methotrexate (MTX) is an effective disease modifying antirheumatic drug (DMARD) with a relatively safe profile, and it is widely used to treat neoplastic diseases and dermatologic and rheumatologic disorders. As indications for use of MTX increase, more accidental overdoses are noted to occur. Typical problems include deficiencies in labeling, instructions, or packaging, as well as erroneous use. We describe 5 fatal cases of repeated oral overdose of MTX prescribed by physicians in the treatment of rheumatoid arthritis to focus attention on the design of the underlying system and the organizational practices as sources of problems.