Congenital Factor XIII Deficiency With the Presence of Inhibitor: A Case Study.

Coagulation factor XIII (FXIII) is a fibrin-stabilizing factor with additional roles in wound healing and interactions between the decidua and fetus. Congenital FXIII deficiency is rare bleeding disorder. Inhibitor development against FXIII in inherited FXIII deficency is also uncommon, but may cause severe, life-threatening bleeding. FXIII is the last step in the coagulation cascade with normal coagulation paramaters (PT, aPTT), the detection of inhibitor to FXIII is quite difficult. The treatment of inhibitor-positive congenital FXIII deficiency is challenging due to the lack of a role of by-pass agents such as FVII. The best known ways of treatment in these cases are the use of high-dose FXIII concentrates and immunosuppression. Herein, we report the management of postoperative bleeding diathesis in a patient with FXIII deficiency who developed inhibitors, and to follow the clinical course of the disease with FXIII concentrate and immunosuppression.

Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction.

Mutations in the genes encoding the mechanosensitive cation channels PIEZO1 and PIEZO2 are responsible for multiple hereditary human diseases. Loss-of-function mutations in the human PIEZO1 gene cause autosomal recessive congenital lymphatic dysplasia. Gain-of-function mutations in the human PIEZO1 gene cause the autosomal dominant hemolytic anemia, hereditary xerocytosis (also known as dehydrated stomatocytosis). Loss-of-function mutations in the human PIEZO2 gene cause an autosomal recessive syndrome of muscular atrophy with perinatal respiratory distress, arthrogryposis, and scoliosis. Gain-of-function mutations in the human PIEZO2 gene cause three clinical types of autosomal dominant distal arthrogryposis. This chapter will review the hereditary diseases caused by mutations in the PIEZO genes and will discuss additional physiological systems in which PIEZO channel dysfunction may contribute to human disease pathophysiology.

BH3 domain-independent apolipoprotein L1 toxicity rescued by BCL2 prosurvival proteins.

The potent trypanolytic properties of human apolipoprotein L1 (APOL1) can be neutralized by the trypanosome variant surface antigen gene product known as serum resistance-associated protein. However, two common APOL1 haplotypes present uniquely in individuals of West African ancestry each encode APOL1 variants resistant to serum resistance-associated protein, and each confers substantial resistance to human African sleeping sickness. In contrast to the dominantly inherited anti-trypanosomal activity of APOL1, recessive inheritance of these two trypanoprotective APOL1 alleles predisposes to kidney disease. Proposed mechanisms of APOL1 toxicity have included BH3 domain-dependent autophagy and/or ion channel activity. We probed these potential mechanisms by expressing APOL1 in Xenopus laevis oocytes. APOL1 expression in oocytes increased ion permeability and caused profound morphological deterioration (toxicity). Coexpression of BCL2 family members rescued APOL1-associated oocyte toxicity in the order MCL1 ∼ BCLW > BCLXL ∼ BCL2A1 ≫ BCL2. Deletion of nine nominal core BH3 domain residues abolished APOL1-associated toxicity, but missense substitution of the same residues abolished neither oocyte toxicity nor its rescue by coexpressed MCL1. The APOL1 BH3 domain was similarly dispensable for the ability of APOL1 to rescue intact mice from lethal trypanosome challenge. Replacement of most extracellular Na(+) by K(+) also reduced APOL1-associated oocyte toxicity, allowing demonstration of APOL1-associated increases in Ca(2+) and Cl(-) fluxes and oocyte ion currents, which were similarly reduced by MCL1 coexpression. Thus APOL1 toxicity in Xenopus oocytes is BH3-independent, but can nonetheless be rescued by some BCL2 family proteins.

IgG-anti-IgA antibodies: an autoimmune finding in patients with psoriasis vulgaris.

AIM: Psoriasis is thought to be an autoimmune disease caused by inappropriate activation of the cellular immune system. In this study, we aimed to search out IgG-anti-IgA antibody levels, serum immunoglobulins and antinuclear antibodies (ANA). METHODS: The study enrolled 38 psoriasis vulgaris patients and 40 healthy controls. RESULTS: Mean IgG-anti-IgA levels were significantly higher in psoriasis patients. The frequency of positive ANA testing was 21.1%; however, there was no correlation between IgG-anti-IgA antibody levels and ANA positivity. Only one patient had low IgA levels without high IgG-anti-IgA concentrations. CONCLUSION: The data about high IgG-anti-IgA antibody levels are noteworthy for a new evidence of autoimmune mechanism.

Lack of association between catalase gene polymorphism (T/C exon 9) and susceptibility to vitiligo in a Turkish population.

Accumulation of hydrogen peroxide (H(2)O(2)) and low catalase (CAT) activity have been demonstrated in the epidermis of vitiligo patients. We investigated a possible association between the CAT exon 9 (Asp-389) gene and vitiligo susceptibility in the Turkish population. Thirty-four patients with vitiligo and 49 gender, age and ethnic matched controls were enrolled in the study. Genotyping was done by PCR-RFLP. The CAT exon 9 (Asp-389) genotype and allele frequencies of vitiligo patients did not differ significantly from those of healthy controls. We found no association between CAT (Asp-389) gene polymorphism and vitiligo susceptibility in Turkish vitiligo patients.

Cell-type specific distribution of chloride transporters in the rat suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN) is a circadian oscillator and biological clock. Cell-to-cell communication is important for synchronization among SCN neuronal oscillators and the great majority of SCN neurons use GABA as a neurotransmitter, the principal inhibitory neurotransmitter in the adult CNS. Acting via the ionotropic GABA(A) receptor, a chloride ion channel, GABA typically evokes inhibitory responses in neurons via Cl(-) influx. Within the SCN GABA evokes both inhibitory and excitatory responses although the mechanism underlying GABA-evoked excitation in the SCN is unknown. GABA-evoked depolarization in immature neurons in several regions of the brain is a function of intracellular chloride concentration, regulated largely by the cation-chloride cotransporters NKCC1 (sodium/potassium/chloride cotransporter for chloride entry) and KCC1-4 (potassium/chloride cotransporters for chloride egress). It is well established that changes in the expression of the cation-chloride cotransporters through development determines the polarity of the response to GABA. To understand the mechanisms underlying GABA-evoked excitation in the SCN, we examined the SCN expression of cation-chloride cotransporters. Previously we reported that the K(+)/Cl(-) cotransporter KCC2, a neuron-specific chloride extruder conferring GABA's more typical inhibitory effects, is expressed exclusively in vasoactive intestinal peptide (VIP) and gastrin-releasing peptide (GRP) neurons in the SCN. Here we report that the K(+)/Cl(-) cotransporter isoforms KCC4 and KCC3 are expressed solely in vasopressin (VP) neurons in the rat SCN whereas KCC1 is expressed in VIP neurons, similar to KCC2. NKCC1 is expressed in VIP, GRP and VP neurons in the SCN as is WNK3, a chloride-sensitive neuron-specific with no serine-threonine kinase which modulates intracellular chloride concentration via opposing actions on NKCC and KCC cotransporters. The heterogeneous distribution of cation-chloride cotransporters in the SCN suggests that Cl(-) levels are differentially regulated within VIP/GRP and VP neurons. We suggest that GABA's excitatory action is more likely to be evoked in VP neurons that express KCC4.

Quality of life and its relation with disease severity in Behçet's disease.

OBJECTIVE: Since Behçet's disease (BD) is a systemic vasculitis, it may deteriorate the quality of life of the patients. We aimed to investigate the relationship between the disease severity and the quality of life in patients with BD. METHODS: We studied 195 BD patients and 195 healthy controls who were matched with regard to age, gender and socio-economic status. Krause score was calculated to assess disease severity, while Short-form-36 (SF-36) and The World Health Organization Quality of Life (WHOQOL-100) were used to evaluate the quality of life in BD. RESULTS: The overall SF-36 and WHOQOL-100 scale scores, as well as their domains were significantly lower in BD patients. In BD patients, "general health", "role-physical", domains of SF-36, and "psychological", "level of independence", "environment", "environmental-public" domains of WHOQOL-100 showed significantly negative linear correlations with Krause scores. In BD patients with arthritis, the scores of "general health", "physical functioning", "role emotional" domains of SF-36, and the scores of "psychological", "level of independence" and "social relations" domains of WHOQOL-100 were significantly worse than without arthritis. The scores of "pain" domain of SF-36 and "level of independence" domain of WHOQOL-100 were significantly worse in BD patients with vascular involvement, while the scores of "mental health" domain of SF-36 and "psychological" domain of WHOQOL-100 were significantly worse in BD patients with eye involvement. CONCLUSION: Based on the evaluation of SF-36 and WHOQOL-100 scores, quality of life is impaired and related with disease severity in BD. Arthritis, eye involvement and vascular involvement seem to contribute to this impairment.

Functional coupling of apical Cl-/HCO3- exchange with CFTR in stimulated HCO3- secretion by guinea pig interlobular pancreatic duct.

Pancreatic ductal epithelium produces a HCO(3)(-)-rich fluid. HCO(3)(-) transport across ductal apical membranes has been proposed to be mediated by both SLC26-mediated Cl(-)/HCO(3)(-) exchange and CFTR-mediated HCO(3)(-) conductance, with proportional contributions determined in part by axial changes in gene expression and luminal anion composition. In this study we investigated the characteristics of apical Cl(-)/HCO(3)(-) exchange and its functional interaction with Cftr activity in isolated interlobular ducts of guinea pig pancreas. BCECF-loaded epithelial cells of luminally microperfused ducts were alkalinized by acetate prepulse or by luminal Cl(-) removal in the presence of HCO(3)(-)-CO(2). Intracellular pH recovery upon luminal Cl(-) restoration (nominal Cl(-)/HCO(3)(-) exchange) in cAMP-stimulated ducts was largely inhibited by luminal dihydro-DIDS (H(2)DIDS), accelerated by luminal CFTR inhibitor inh-172 (CFTRinh-172), and was insensitive to elevated bath K(+) concentration. Luminal introduction of CFTRinh-172 into sealed duct lumens containing BCECF-dextran in HCO(3)(-)-free, Cl(-)-rich solution enhanced cAMP-stimulated HCO(3)(-) secretion, as calculated from changes in luminal pH and volume. Luminal Cl(-) removal produced, after a transient small depolarization, sustained cell hyperpolarization of approximately 15 mV consistent with electrogenic Cl(-)/HCO(3)(-) exchange. The hyperpolarization was inhibited by H(2)DIDS and potentiated by CFTRinh-172. Interlobular ducts expressed mRNAs encoding CFTR, Slc26a6, and Slc26a3, as detected by RT-PCR. Thus Cl(-)-dependent apical HCO(3)(-) secretion in pancreatic duct is mediated predominantly by an Slc26a6-like Cl(-)/HCO(3)(-) exchanger and is accelerated by inhibition of CFTR. This study demonstrates functional coupling between Cftr and Slc26a6-like Cl(-)/HCO(3)(-) exchange activity in apical membrane of guinea pig pancreatic interlobular duct.

Acute regulation of mouse AE2 anion exchanger requires isoform-specific amino acid residues from most of the transmembrane domain.

The widely expressed anion exchanger polypeptide AE2/SLC4A2 is acutely inhibited by acidic intracellular (pH(i)), by acidic extracellular pH (pH(o)), and by the calmodulin inhibitor, calmidazolium, whereas it is acutely activated by NH(4)(+). The homologous erythroid/kidney AE1/SLC4A1 polypeptide is insensitive to these regulators. Each of these AE2 regulatory responses requires the presence of AE2's C-terminal transmembrane domain (TMD). We have now measured (36)Cl(-) efflux from Xenopus oocytes expressing bi- or tripartite AE2-AE1 chimeras to define TMD subregions in which AE2-specific sequences contribute to acute regulation. The chimeric AE polypeptides were all functional at pH(o) 7.4, with the sole exception of AE2((1-920))/AE1((613-811))/AE2((1120-1237)). Reciprocal exchanges of the large third extracellular loops were without effect. AE2 regulation by pH(i), pH(o) and NH(4)(+) was retained after substitution of C-terminal AE2 amino acids 1120-1237 (including the putative second re-entrant loop, two TM spans and the cytoplasmic tail) with the corresponding AE1 sequence. In contrast, the presence of this AE2 C-terminal sequence was both necessary and sufficient for inhibition by calmidazolium. All other tested TMD substitutions abolished AE2 pH(i) sensitivity, abolished or severely attenuated sensitivity to pH(o) and removed sensitivity to NH(4)(+). Loss of AE2 pH(i) sensitivity was not rescued by co-expression of a complementary AE2 sequence within separate full-length chimeras or AE2 subdomains. Thus, normal regulation of AE2 by pH and other ligands requires AE2-specific sequence from most regions of the AE2 TMD, with the exceptions of the third extracellular loop and a short C-terminal sequence. We conclude that the individual TMD amino acid residues previously identified as influencing acute regulation of AE2 exert that influence within a regulatory structure requiring essential contributions from multiple regions of the AE2 TMD.

The frequency of nasal carriage in chronic urticaria patients.

OBJECTIVE: Chronic urticaria is characterized by oedema of the skin and mucous membranes. Although many agents have been implicated, aetiology is unknown in 70 to 75% of patients. Infections and foci of chronic infections are most commonly held responsible for chronic urticaria. In this study, the frequency of nasal carriage as the occult focus of infection and sensitivity to antimicrobials are explored in patients with chronic urticaria. MATERIAL AND METHOD: Ninety-four patients with chronic urticaria and 30 controls participated in the study, which was carried out at the Ege university medical faculty, department of dermatology between January 2004 and January 2005. Nasal swab specimens were taken from the patients and controls and incubated at 37 degrees C degrees for 48 h, and inoculated on standard bacterial medium (blood agar). Antimicrobial susceptibility of a growth from isolates of the nasal swab specimens was conducted. Data were analysed statistically using chi-square and Mann-Whitney U-tests. RESULTS: Ninety-four patients with chronic urticaria (72.3% female and 27.7% male) and 30 controls (63.3% female and 36.7% male) comprised the study group. Mean age of the patients and controls were 42.6 and 33.8 years, respectively. Staphylococcus aureus was detected in swab specimens from the nasal cavity in 50 of the 94 patients (53.2%) with chronic urticaria and four of the 30 controls (13.3%). Testing revealed that the most susceptible antibiotics were cefaclor, ceftriaxone, amoxycillin-clavulanic acid, amikacin, netilmicin, and fucidic acid. CONCLUSION: Growth on cultures prepared from nasal swab specimens of chronic urticaria patients was statistically higher than the control group. We detected resistance to growth against mupirocin, an antibiotic frequently used in nasal carriage. High nasal carriage of Staphylococcus aureus in patients with chronic urticaria compared to controls suggests that nasal carriage as a focus of infection should be kept in mind as aetiology.

Role of nonconserved charged residues of the AE2 transmembrane domain in regulation of anion exchange by pH.

The ubiquitous AE2/SLC4A2 anion exchanger is acutely and independently regulated by intracellular (pH(i)) and extracellular pH (pH(o)), whereas the closely related AE1/SLC4A1 of the red cell and renal intercalated cell is relatively pH-insensitive. We have investigated the contribution of nonconserved charged residues within the C-terminal transmembrane domain (TMD) of AE2 to regulation by pH through mutation to the corresponding AE1 residues. AE2-mediated Cl(-)/Cl(-) exchange was measured as 4,4'-di-isothiocyanatostilbene-2,2'-disulfonic acid-sensitive (36)Cl(-) efflux from Xenopus oocytes by varying pH(i) at constant pH(o), and by varying pH(o) at near-constant pH(i). All mutations of nonconserved charged residues of the AE2 TMD yielded functional protein, but mutations of some conserved charged residues (R789E, R1056A, R1134C) reduced or abolished function. Individual mutation of AE2 TMD residues R921, F922, P1077, and R1107 exhibited reduced pH(i) sensitivity compared to wt AE2, whereas TMD mutants K1153R, R1155K, R1202L displayed enhanced sensitivity to acidic pH(i). In addition, pH(o) sensitivity was significantly acid- shifted when nonconserved AE2 TMD residues E981, K982, and D1075 were individually converted to the corresponding AE1 residues. These results demonstrate that multiple conserved charged residues are important for basal transport function of AE2 and that certain nonconserved charged residues of the AE2 TMD are essential for wild-type regulation of anion exchange by pH(i) and pH(o).

Transmembrane domain histidines contribute to regulation of AE2-mediated anion exchange by pH.

Activity of the AE2/SLC4A2 anion exchanger is modulated acutely by pH, influencing the transporter's role in regulation of intracellular pH (pH(i)) and epithelial solute transport. In Xenopus oocytes, heterologous AE2-mediated Cl(-)/Cl(-) and Cl(-)/HCO(3)(-) exchange are inhibited by acid pH(i) or extracellular pH (pH(o)). We have investigated the importance to pH sensitivity of the eight histidine (His) residues within the AE2 COOH-terminal transmembrane domain (TMD). Wild-type mouse AE2-mediated Cl(-)/Cl(-) exchange, measured as DIDS-sensitive (36)Cl(-) efflux from Xenopus oocytes, was experimentally altered by varying pH(i) at constant pH(o) or varying pH(o). Pretreatment of oocytes with the His modifier diethylpyrocarbonate (DEPC) reduced basal (36)Cl(-) efflux at pH(o) 7.4 and acid shifted the pH(o) vs. activity profile of wild-type AE2, suggesting that His residues might be involved in pH sensing. Single His mutants of AE2 were generated and expressed in oocytes. Although mutation of H1029 to Ala severely reduced transport and surface expression, other individual His mutants exhibited wild-type or near-wild-type levels of Cl(-) transport activity with retention of pH(o) sensitivity. In contrast to the effects of DEPC on wild-type AE2, pH(o) sensitivity was significantly alkaline shifted for mutants H1144Y and H1145A and the triple mutants H846/H849/H1145A and H846/H849/H1160A. Although all functional mutants retained sensitivity to pH(i), pH(i) sensitivity was enhanced for AE2 H1145A. The simultaneous mutation of five or more His residues, however, greatly decreased basal AE2 activity, consistent with the inhibitory effects of DEPC modification. The results show that multiple TMD His residues contribute to basal AE2 activity and its sensitivity to pH(i) and pH(o).

A human factors engineering paradigm for patient safety: designing to support the performance of the healthcare professional.

The goal of improving patient safety has led to a number of paradigms for directing improvement efforts. The main paradigms to date have focused on reducing injuries, reducing errors, or improving evidence based practice. In this paper a human factors engineering paradigm is proposed that focuses on designing systems to improve the performance of healthcare professionals and to reduce hazards. Both goals are necessary, but neither is sufficient to improve safety. We suggest that the road to patient and employee safety runs through the healthcare professional who delivers care. To that end, several arguments are provided to show that designing healthcare delivery systems to support healthcare professional performance and hazard reduction should yield significant patient safety benefits. The concepts of human performance and hazard reduction are explained.

Broad-band ultraviolet B phototherapy is associated with elevated serum thiobarbituric acid reactive substance and nitrite-nitrate levels in psoriatic patients.

BACKGROUND: Although the local anti-inflammatory, immunosuppressive and oxidative activity of UVB is known, the systemic effect of UVB phototherapy in dermatological patients has not been investigated. OBJECTIVE: We aimed to investigate the lipid peroxidation status (as represented by thiobarbituric acid reactive substance, TBARS) and nitrite-nitrate levels in psoriatic patients under broad-band ultraviolet B (BB-UVB) phototherapy in order to determine the systemic effects of UVB. SUBJECTS AND METHODS: Thirty-two psoriatic patients and 20 healthy controls were included. Blood samples were obtained at the beginning, after 6-10 exposures to BB UVB phototherapy (mean 5 weeks) and at the end of the therapy period (mean 21 weeks). Serum TBARS and nitrite-nitrate levels were evaluated. RESULTS: There was no statistically significant difference in serum TBARS and nitrite-nitrate levels between psoriatic patients (basal) and healthy volunteers. There was no statistically significant correlation between disease duration, disease severity, or the total cumulative dose of UVB and serum levels of TBARS and nitrite-nitrate in psoriatic patients. Total nitrite levels in samples obtained during and at the end of therapy were significantly higher than basal levels (P=0.033 and P=0.005, respectively). TBARS levels in samples obtained during and at the end of therapy were significantly higher than basal levels (P=0 and P=0.026, respectively). There was a negative correlation (r=-0.576, P=0.039) between the total nitrite and TBARS levels in psoriatic patients at the end of therapy. CONCLUSION: Our study showed that chronic exposure to UV irradiation may lead to a systemic effect on lipid peroxidation and NO levels, which are shown by a significant elevation in TBARS and nitrite-nitrate levels in serum.

A macro-ergonomic work system analysis of the diagnostic testing process in an outpatient health care facility for process improvement and patient safety.

The diagnosis of illness is important for quality patient care and patient safety and is greatly aided by diagnostic testing. For diagnostic tests, such as pathology and radiology, to positively impact patient care, the tests must be processed and the physician and patient must be notified of the results in a timely fashion. There are many steps in the diagnostic testing process, from ordering to result dissemination, where the process can break down and therefore delay patient care and reduce patient safety. This study was carried out to examine the diagnostic testing process (i.e. from ordering to result notification) and used a macro-ergonomic work system analysis to uncover system design flaws that contributed to delayed physician and patient notification of results. The study was carried out in a large urban outpatient health-care facility made up of 30 outpatient clinics. Results indicated a number of variances that contributed to delays, the majority of which occurred across the boundaries of different systems and were related to poor or absent feedback structures. Recommendations for improvements are discussed.

Large atherosclerotic plaque related severe right coronary artery dissection during coronary angiography.

Catheter-induced coronary artery dissection and occlusion is a rare but serious complication of diagnostic cardiac angiography. A 50 year-old man presented with unstable angina. ECG, exceptional of bradycardia, was normal (57 beat/min). Selective coronary angiography demonstrated 98% narrowing in the mid-portion of the left anterior descending coronary artery (LAD). During the right coronary angiography, following catheter manipulation in the vicinity of the aortic valve, the patient complained of severe chest discomfort, and he had electrocardiographic evidence of acute inferior wall myocardial infarction. Right coronary artery (RCA) was free of the significant obstruction, and it was observed to be having a dominant artery with a spiral dissection (NHLBI Grade IV) located between ostium and the proximal portion of the posterior descending and posterolateral artery bifurcation. The patient was immediately operated with off-pump coronary artery bypass surgery. Consequently, iatrogenic right coronary dissection that is a very rare condition as a cause of myocardial infarction, is discussed in this case report.

Erythromelanosis follicularis faciei et colli: report of involvement in two female patients.

Erythromelanosis follicularis faciei is a rare disease characterized by reddish brown pigmentation and follicular papules localized on certain areas such as the face and neck. Young men are usually affected, but young women or children may be affected. Bilateral distribution is usual, but it may occur unilaterally. Histopathologically, hyperkeratosis, increased melanization and dilatation of the hair follicle are characteristic. Two female patients with typical localizations and clinical findings of the disease are reported here.

Chronic intermittent hypoxia decreases the expression of Na/H exchangers and HCO3-dependent transporters in mouse CNS.

Chronic intermittent hypoxia (CIH) is a component of several disease states, including obstructive sleep apnea, which results in neurocognitive and cardiovascular morbidity. Because chronic hypoxia can induce changes in metabolism and pH homeostasis, we hypothesized that CIH induces changes in the expression of acid-base transporters. Two- to three-day-old mice, exposed to alternating cycles of 2 min of hypoxia (6.0-7.5% O2) and 3 min of normoxia (21% O2) for 8 h/day for 28 days, demonstrated decreases in specific acid-base transport protein expression in most of the central nervous system (CNS). Sodium/hydrogen exchanger isoform 1 (NHE1) and sodium-bicarbonate cotransporter expression were decreased in all regions of the CNS but especially so in the cerebellum. NHE3, which is only expressed in the cerebellum, was also significantly decreased. Anion exchanger 3 protein was decreased in most brain regions, with the decrease being substantial in the hippocampus. These results indicate that CIH induces downregulation of the major acid-extruding transport proteins, NHE1 and sodium-bicarbonate cotransporter, in particular regions of the CNS. This downregulation in acid-extruding capacity may render neurons more prone to acidity and possibly to injury during CIH, especially in the cerebellum and hippocampus. Alternatively, it is possible that O2 consumption in these regions is decreased after CIH, with consequential downregulation in the expression of certain cellular proteins that may be less needed under such circumstances.