Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction. OBJECTIVES: To characterize patients with PC with symptomatic mucosal involvement. METHODS: We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction. CONCLUSIONS: It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.

Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening.

The inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of genodermatoses, characterized by thickening of the epidermis of the palms and soles. No classification system satisfactorily unites clinical presentation, pathology and molecular pathogenesis. There are four patterns of hyperkeratosis - striate, focal, diffuse and punctate. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate, but also in focal and diffuse PPKs. We report seven unrelated pedigrees with dominantly inherited PPK owing to mutations in the DSG1 gene, with marked phenotypic variation. Genomic DNA from each family was isolated, and individual exons amplified by polymerase chain reaction. Sanger sequencing was employed to identify mutations. Mutation analysis identified novel mutations in five families (p.Tyr126Hisfs*2, p.Ser521Tyrfs*2, p.Trp3*, p.Asp591Phefs*9 and p.Met249Ilefs*6) with striate palmar involvement and varying focal or diffuse plantar disease, and the recurrent mutation c.76C>T, p.Arg26*, in two families with variable PPK patterns. We report one recurrent and five novel DSG1 mutations, causing varying patterns of PPK, highlighting the clinical heterogeneity arising from mutations in this gene.

Stabilizing Entanglement via Symmetry-Selective Bath Engineering in Superconducting Qubits.

Bath engineering, which utilizes coupling to lossy modes in a quantum system to generate nontrivial steady states, is a tantalizing alternative to gate- and measurement-based quantum science. Here, we demonstrate dissipative stabilization of entanglement between two superconducting transmon qubits in a symmetry-selective manner. We utilize the engineered symmetries of the dissipative environment to stabilize a target Bell state; we further demonstrate suppression of the Bell state of opposite symmetry due to parity selection rules. This implementation is resource efficient, achieves a steady-state fidelity F=0.70, and is scalable to multiple qubits.

A near-quantum-limited Josephson traveling-wave parametric amplifier.

Detecting single-photon level signals­carriers of both classical and quantum information­is particularly challenging for low-energy microwave frequency excitations. Here we introduce a superconducting amplifier based on a Josephson junction transmission line. Unlike current standing-wave parametric amplifiers, this traveling wave architecture robustly achieves high gain over a bandwidth of several gigahertz with sufficient dynamic range to read out 20 superconducting qubits. To achieve this performance, we introduce a subwavelength resonant phase-matching technique that enables the creation of nonlinear microwave devices with unique dispersion relations. We benchmark the amplifier with weak measurements, obtaining a high quantum efficiency of 75% (70% including noise added by amplifiers following the Josephson amplifier). With a flexible design based on compact lumped elements, this Josephson amplifier has broad applicability to microwave metrology and quantum optics.

Pachyonychia congenita cornered: report on the 11th Annual International Pachyonychia Congenita Consortium Meeting.

This is a report of the research presented at the 11th Annual Meeting of the International Pachyonychia Congenita Consortium, held on 6 May 2014 in Albuquerque, NM, U.S.A. This year's meeting was divided into five corners concerning pachyonychia congenita (PC) research: (i) 'PC Pathogenesis Cornered', an overview of recent keratin research, for PC and other skin disorders; (ii) 'From All Corners of …', an outline of other genetic disorders that we can learn from; (iii) 'Fighting For Our Corner', an outline of National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases programmes and U.S. funding opportunities applicable to rare skin disorders; (iv) 'The PC Corner', focusing on recent clinical studies related to PC; and (v) 'Clinical Corners: Turning the Corner?', an update on ongoing PC clinical trials.

Observation of measurement-induced entanglement and quantum trajectories of remote superconducting qubits.

The creation of a quantum network requires the distribution of coherent information across macroscopic distances. We demonstrate the entanglement of two superconducting qubits, separated by more than a meter of coaxial cable, by designing a joint measurement that probabilistically projects onto an entangled state. By using a continuous measurement scheme, we are further able to observe single quantum trajectories of the joint two-qubit state, confirming the validity of the quantum Bayesian formalism for a cascaded system. Our results allow us to resolve the dynamics of continuous projection onto the entangled manifold, in quantitative agreement with theory.

The molecular genetic analysis of the expanding pachyonychia congenita case collection.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17. OBJECTIVES: To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years. METHODS: Genomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced. RESULTS: Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105. CONCLUSIONS: By identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families.

Best treatment practices for pachyonychia congenita.

BACKGROUND: Numerous therapeutic modalities have been proposed to treat the manifestations of pachyonychia congenita (PC). While research hopes lie with molecular therapies, patients are in need of answers regarding the efficacy of conventional treatments. AIM OF THE STUDY: To determine patients' experience and preferences regarding conventional treatments for PC. METHODS: The study population included 120 PC patients from 20 countries. The study was based on a patient survey developed by physicians and researchers from the International Pachyonychia Congenita Consortium and conducted via the internet. Using an effectiveness scale of 1 to 5, the patients were asked to grade treatments for different manifestations, including keratoderma, cysts, follicular hyperkeratosis, fingernail and toenail involvement. RESULTS: Patients reported surgical treatments being most effective for cysts and mechanical treatments the most effective conventional therapeutic approach for all other investigated manifestations. The other conventional medical treatments were found to be non-effective to only slightly effective. Among patients with keratoderma, older people were more likely to report beneficial effect from mechanical treatments (P = 0.04), topical retinoids (P = 0.04) and topical steroids (P = 0.02). Likewise, females were more inclined to report filing and grinding beneficial than males (P = 0.02). Finally, carriers of KRT16 and KRT6a were more likely to benefit from keratolytics than carriers of mutations in KRT17 (P = 0.04). CONCLUSIONS: None of the currently available therapeutic options for PC are ideal, although they provide some relief, with mechanical/surgical options being preferred over medical therapies. These results emphasize the need for more efficient and targeted therapies.

Comparative study of high-resolution multifrequency ultrasound of the plantar skin in patients with various types of hereditary palmoplantar keratoderma.

BACKGROUND: High-variable-frequency ultrasound is used as an imaging tool for various cutaneous disorders. We utilized this tool in pachyonychia congenita (PC) patients, who typically present with plantar hyperkeratosis and often severely debilitating pain, compared to patients with epidermolytic palmoplantar keratoderma (EPPK) and mal de Meleda (MDM). OBJECTIVE: To ascertain the feasibility of ultrasound technology for the diagnosis of PC. METHODS: The study included a total of 16 patients, 7 with PC, 5 with EPPK and 4 with MDM, who underwent ultrasound examination of the plantar skin with high-resolution multifrequency ultrasound equipment. RESULTS: Ultrasound scans performed over the proximal and distal plantar foot calluses in PC patients demonstrated hyperechoic dots and lines within the epidermis compatible with hyperkeratosis, engorged varicose veins in the dermis and an anechoic layer interposed between the epidermis and the dermis, corresponding to blister fluid below the calluses. In contrast to PC patients, patients with MDM and EPPK demonstrated no blisters. CONCLUSION: PC patients, as opposed to a group of patients with MDM and EPPK, displayed subepidermal blistering beneath their calluses. This finding may help in the diagnosis of PC and in partially explaining plantar pain as part of PC symptomatology.

Impact of liver fibrosis on prognosis following liver resection for hepatitis B-associated hepatocellular carcinoma.

BACKGROUND: This study aims to evaluate the impact of liver fibrosis severity on prognosis following liver resection among HBV-HCC patients. METHODS: Data were extracted from a prospective database of 189 HBV-HCC patients treated at Mount Sinai between 1995 and 2008. Fibrosis staging of each surgical resection specimen using the modified Ishak method was performed by a single liver pathologist. RESULTS: A wide range of Ishak fibrosis stage was observed among this patient population, with 29% having established cirrhosis (Ishak stage 6). Ishak stage 6 was independently associated with poor overall and recurrence-free survival. In patients with Ishak stage 1-5, Ishak stage did not affect survival; rather, tumour size was associated with poor overall survival, and tumour size, histologic activity index and serum AFP>20 ng ml(-1) were associated with poor recurrence-free survival. In patients with Ishak stage 6, poorly differentiated histology and tumour size were associated with poor overall survival, and tumour size was associated with poor recurrence-free survival. CONCLUSION: HBV-HCC develops with varying degrees of underlying liver fibrosis; however, progressive liver fibrosis does not affect the outcomes following resection until cirrhosis is reached. Established cirrhosis, as defined histologically by Ishak stage 6, is an independent predictor of poor overall and recurrence-free survival among these patients.

Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16.

BACKGROUND: Pachyonychia congenita (PC) is an autosomal dominant, very rare keratin disorder caused by mutations in any of at least four genes (KRT6A, KRT6B, KRT16 or KRT17), which can lead to hypertrophic nail dystrophy and palmoplantar keratoderma, among other manifestations. Classically, patients with mutations in KRT6A and KRT16 have been grouped to the PC-1 subtype (Jadassohn-Lewandowsky type) and KRT6B and KRT17 to PC-2 (Jackson-Lawler type). OBJECTIVES: To describe clinical heterogeneity among patients with PC who have genetic mutations in KRT6A and KRT16. METHODS: In 2004, the Pachyonychia Congenita Project established the International PC Research Registry (IPCRR) for patients with PC. All patients reporting here underwent genetic testing and responded to a standardized, validated survey about their PC symptoms. We report results from 89 patients with KRT6A mutations and 68 patients with KRT16 mutations. RESULTS: Patients with PC who have KRT6A and KRT16 mutations display distinct phenotypic differences. Patients with PC-K6a experience earlier onset, more extensive nail disease and more substantial disease outside palms and soles, as they reported a higher prevalence of oral leucokeratosis (P < 0·001), cysts (P < 0·001) and follicular hyperkeratosis (P < 0·001) compared with their PC-K16 counterparts. CONCLUSION: Phenotypic differences between patients with KRT6A and KRT16 mutations support adoption of a new classification system based on the mutant gene (PC-6a, PC-16) rather than the PC-1 nomenclature.

Investigating neural primacy in Major Depressive Disorder: multivariate Granger causality analysis of resting-state fMRI time-series data.

Major Depressive Disorder (MDD) has been conceptualized as a neural network-level disease. Few studies of the neural bases of depression, however, have used analytical techniques that are capable of testing network-level hypotheses of neural dysfunction in this disorder. Moreover, of those that have, fewer still have attempted to determine the directionality of influence within functionally abnormal networks of structures. We used multivariate GC analysis, a technique that estimates the extent to which preceding neural activity in one or more seed regions predicts subsequent activity in target brain regions, to analyze blood-oxygen-level-dependent (BOLD) data collected during eyes-closed rest from depressed and never-depressed persons. We found that activation in the hippocampus predicted subsequent increases in ventral anterior cingulate cortex (vACC) activity in depression, and that activity in the medial prefrontal cortex and vACC were mutually reinforcing in MDD. Hippocampal and vACC activation in depressed participants predicted subsequent decreases in dorsal cortical activity. This study shows that, on a moment-by-moment basis, there is increased excitatory activity among limbic and paralimbic structures, as well as increased inhibition in the activity of dorsal cortical structures, by limbic structures in depression; these aberrant patterns of effective connectivity implicate disturbances in the mesostriatal dopamine system in depression. These findings advance the neural theory of depression by detailing specific patterns of limbic excitation in MDD, by making explicit the primary role of limbic inhibition of dorsal cortex in the cortico-limbic relation posited to underlie depression, and by presenting an integrated neurofunctional account of altered dopamine function in this disorder.

Interaction-induced shift of the cyclotron resonance of graphene using infrared spectroscopy.

We report a study of the cyclotron resonance (CR) transitions to and from the unusual n=0 Landau level (LL) in monolayer graphene. Unexpectedly, we find the CR transition energy exhibits large (up to 10%) and nonmonotonic shifts as a function of the LL filling factor, with the energy being largest at half filling of the n=0 level. The magnitude of these shifts, and their magnetic field dependence, suggests that an interaction-enhanced energy gap opens in the n=0 level at high magnetic fields. Such interaction effects normally have a limited impact on the CR due to Kohn's theorem [W. Kohn, Phys. Rev. 123, 1242 (1961)], which does not apply in graphene as a consequence of the underlying linear band structure.

Outcome for patients treated with laparoscopic versus open resection of hepatocellular carcinoma: case-matched analysis.

INTRODUCTION: This is a case-matched analysis of patients undergoing laparoscopic versus open hepatectomy for hepatocellular carcinoma (HCC), with specific regard to margin status and survival. METHODS: Laparoscopic cases were matched with open controls by cirrhosis and tumor size (within 10%). Data were evaluated by logistic regression using the generalized estimating equation method. Mixed linear regression models were used to assess operative duration in the groups. Overall and disease-free survival were compared using a Cox proportional frailty model. RESULTS: Twenty laparoscopic cases were matched to 56 open resections. Thirty patients (39%) developed recurrence and 13 patients (17%) died, including one (1.3%) death within 30 days. There were no significant differences in age, gender, cirrhosis or tumor size. Paired univariate and multivariate analyses showed cases of laparoscopic resection had similar rates of transfusion and positive margins compared with open resection. Operative duration was similar in laparoscopic (mean 161 +/- 37 min) and open (mean 165 +/- 53 min) groups. The adjusted odds of length of stay > or = 6 days was significantly lower in patients with laparoscopic resection [odds ratio (OR) = 0.07, 95% confidence interval (CI) = 0.02-0.27]. Both unadjusted and adjusted analyses showed no significant association between type of resection and overall or disease-free survival. DISCUSSION: Neither margin status, nor recurrence, nor survival was significantly different between the two cohorts. Laparoscopic resection for malignancy is safe, with a similar operative time as open hepatectomy. If tumor location is amenable, laparoscopic resection for HCC is a reasonable alternative to open resection with the added benefits of improved cosmesis and sooner discharge home.

Effect of ischemia-reperfusion on the incidence of acute cellular rejection and timing of histologic hepatitis C virus recurrence after liver transplantation.

BACKGROUND: Because of a critical shortage of deceased donor (DD) livers, more extended criteria allografts are being utilized; these allografts are at increased risk for ischemia-reperfusion injury (IRI). We assessed whether, in a large cohort of patients transplanted for hepatitis C virus (HCV) either via a DD or live donor (LD), there was a relationship between the degree of IRI and the frequency and timing of acute cellular rejection (ACR) and histologic HCV recurrence. METHODS: During an 8-year study, patients were separated into four groups based on peak alanine aminotransferase (ALT) levels and three groups based on severity of IRI on postreperfusion liver biopsy. RESULTS: The mean follow-up time of 433 DD and 44 LD recipients was 1212 days. We noted a strong correlation in DD between peak ALT and the histologic degree of IRI (P = .01). There was no difference in the incidence or grade of ACR among the four groups. There was no correlation between the severity of IRI and the incidence or time to histologic recurrence of HCV. CONCLUSIONS: The magnitude of peak ALT correlated with the severity of IRI on postreperfusion liver biopsy. Among this large HCV cohort, there was no correlation between the severity of IRI and the incidence or timing of histologic HCV recurrence or incidence of ACR.

The Mount Sinai experience with orthotopic liver transplantation for benign tumors: brief report and literature review: case reports.

Orthotopic liver transplantation (OLT) is performed for benign hepatic lesions that are symptomatic, too large to be resected, have a malignant transformation potential, cause debilitating/life-threatening manifestations, or in patients experiencing posthepatectomy acute liver failure. Among benign tumors, polycystic liver disease (PLD) is the most common indication for OLT alone, or combined liver-kidney transplantation. Our 10-year experience with OLT for benign tumors includes two patients with PLD and one with a benign giant fibrous tumor. In this report, we present our experience with OLT for benign liver tumors, commenting on relevant published studies.

Cyclotron resonance in bilayer graphene.

We present the first measurements of cyclotron resonance of electrons and holes in bilayer graphene. In magnetic fields up to B=18 T, we observe four distinct intraband transitions in both the conduction and valence bands. The transition energies are roughly linear in B between the lowest Landau levels, whereas they follow square root[B] for the higher transitions. This highly unusual behavior represents a change from a parabolic to a linear energy dispersion. The density of states derived from our data generally agrees with the existing lowest order tight binding calculation for bilayer graphene. However, in comparing data to theory, a single set of fitting parameters fails to describe the experimental results.

Chemical reaction fronts in ordered and disordered cellular flows with opposing winds.

We present experiments on the motion of chemical fronts in ordered and disordered vortex flows with imposed uniform winds. Fronts in a chain of alternating vortices are found to freeze (pin to the separatrix) for a wide range of opposing winds that grows nonlinearly with the characteristic strength of the underlying vorticity. Experiments in spatially disordered flows demonstrate that freezing of fronts is common to cellular flows; furthermore, it is not dependent on boundary conditions. We therefore anticipate similar pinning in a wide range of 2D cellular flows and front-producing systems.