Ochronosis: a report of a case and a review of literature

A patient with alkaptonuria and ochronotic pigment deposited in articular cartilage and sclerae clinically manifested a serious osteoarthritis of the peripheral and axial joints and synchondrosis, typically involved in long lasting cases of this hereditary defect of homogentisic acid oxidase. This is the first patient with this disorder reported, where a non-cemented total knee prosthesis (PCAR) was applied on both knees. This was possible due to the good quality of the bone stock, which did not seem to be impaired by ochronosis. Our patient had no cardiac symptoms or murmurs, but had a slight calcification in the annulus of aorta observed with echocardiography, a useful new method for screening this disease manifestation. A third new aspect reported is the immunopathology of the synovial tissue. Small pieces of torn-off cartilage were seen embedded in the synovial stroma. This was associated with a slight hyperplasia of the C3bi-receptor positive and proline hydroxylase positive type A and B synovial lining cells. Perivenular infiltrates contained CD2 positive T lymphocytes, mostly belonging to the CD4 subset, and some C3bi-receptor positive monocytes. Activated CD25 positive and immunoglobulin light chain positive T and B lymphocytes were absent or few. Because modern medicine has much to offer to those suffering from this ancient inborn error of metabolism in the form of new specific diagnostic methods and new surgical modes of treatment, such as endoprosthesis surgery and cardiac valve replacement, we also present a literature overview of this interesting condition.     

Charge of a quasiparticle in a superconductor

Nonlinear charge transport in superconductor–insulator–superconductor (SIS) Josephson junctions has a unique signature in the shuttled charge quantum between the two superconductors. In the zero-bias limit Cooper pairs, each with twice the electron charge, carry the Josephson current. An applied bias V_SD leads to multiple Andreev reflections (MAR), which in the limit of weak tunneling probability should lead to integer multiples of the electron charge ne traversing the junction, with n integer larger than 2Δ/eV_SD and Δ the superconducting order parameter. Exceptionally, just above the gap eV_SD ≥ 2Δ, with Andreev reflections suppressed, one would expect the current to be carried by partitioned quasiparticles, each with energy-dependent charge, being a superposition of an electron and a hole. Using shot-noise measurements in an SIS junction induced in an InAs nanowire (with noise proportional to the partitioned charge), we first observed quantization of the partitioned charge q = e*/e = n, with n = 1–4, thus reaffirming the validity of our charge interpretation. Concentrating next on the bias region eV_SD ～ 2Δ, we found a reproducible and clear dip in the extracted charge to q? ～ 0.6, which, after excluding other possibilities, we attribute to the partitioned quasiparticle charge. Such dip is supported by numerical simulations of our SIS structure.Excitations in superconductors (Bogoliubov quasiparticles) can be described according to the Bardeen–Cooper–Schrieffer (BCS) theory (1) as an energy-dependent superposition of an electron with amplitude u(ε), and a hole with amplitude v(ε), where the energy ε is measured relative to the Fermi energy (2). Evidently, the expectation value of the charge operator (applied to the quasiparticle wave function), which we address as the quasiparticle charge e* = q(ε)e, is smaller than the charge of an electron, q(ε) = |u(ε)|² ? |ν(ε)|² (3). Solving the Bogoliubov–de Gennes equations, one finds that |u(ε)|2=1/2[1+(ε2−Δ2/ε)] and |v(ε)|2=1/2[1−(ε2−Δ2/ε)], with the expected charge evolving with energy according to q(ε)=ε2−Δ2/ε––vanishing altogether at the superconductor gap edges (3). Note, however, that the quasiparticle wave function is not an eigenfunction of the charge operator (3, 4). Properties of quasiparticles, such as the excitation spectra (5), lifetime (6–10), trapping (11), and capturing by Andreev bound states (12, 13), had already been studied extensively; however, studies of their charge are lagging. In the following we present sensitive shot-noise measurements in a Josephson junction, resulting in a clear observation of the quasiparticle charge being smaller than e, q(eV_SD∼2Δ) < 1, and evolving with energy, as expected from the BCS theory.To observe the BCS quasiparticles in transport we study a superconductor–insulator–superconductor (SIS) Josephson junction in the nonlinear regime. The overlap between the wave functions of the quasiparticles in the source and in the drain is expected to result in a tunneling current of their effective charge. This is in contrast with systems which are incoherent (14, 15) or with an isolated superconducting island, where charge conservation leads to traversal of multiples of e – Coulomb charge (16). As current transport in the nonlinear regime results from “multiple Andreev reflections” (MAR), it is prudent to make our measurements credible by first measuring the charge in this familiar regime.In short, the MAR process, described schematically in Fig. 1, carries a signature of the shuttled charge between the two superconductors (SCs), being a consequence of n traversals through the junction (as electron-like and hole-like quasiparticles), with n an integer larger than 2Δ/eV_SD. A low transmission probability t (via tunneling through a barrier) in the bias range 2Δ/n < eV_SD < 2Δ/(n ? 1) assures dominance of the lowest order MAR process (higher orders are suppressed as tⁿ), with the charge evolving in nearly integer multiples of the electron charge. Although there is already a substantial body of theoretical (3, 17–23) and experimental (24–29) studies of the MAR process, charge determination without adjustable parameters is still missing. An important work by Cron et al. (27) indeed showed a staircase-like behavior of the charge using “metallic break junctions;” however, limited sensitivity and the presence of numerous conductance channels some of which with relatively high transmission probabilities did not allow exact charge quantization. Our shot-noise measurements, performed on a quasi-1D Josephson junction (single-mode nanowire) allowed clear observation of charge quantization without adjustable parameters. To count a few advantages: (i) the transmission of the SIS junction could be accurately controlled using a back-gate; (ii) this, along with our high sensitivity in noise measurements, enabled us to pinch the junction strongly (thus suppressing higher MAR orders); and (iii) with the Fermi level located near the 1D channel van Hove singularity, a rather monoenergetic distribution could be injected (SI Appendix, section S7).Open in a separate windowFig. 1.MAR. Illustrations of the leading processes contributing to the current as function of bias. In general, for 2Δ/(n ? 1) > eV_SD > 2Δ/n the leading charge contribution to the current is ne. An electron-like quasiparticle is denoted by a full circle, whereas a hole-like quasiparticle is denoted by an empty circle. (A) When the bias is larger than the energy gap, eV_SD > 2Δ, the leading process is a single-path tunneling of single quasiparticles from the full states (Left) to the empty states (Right). This current is proportional to the transmission coefficient t. Higher-order MAR process (dashed box), being responsible for tunneling of Cooper pairs, is suppressed as t². (B) For 2Δ > eV_SD > Δ, the main charge contributing to the current is 2e with probability t². (C) For Δ > eV_SD > 2Δ/3, the main charge contributing to the current is 3e with probability t³.     

Report of a case of a giant phytobezoar in a patient with a duodenal bulb ulcer.

A case of a large phytobezoar (750 g weight and with the length of 29 cm) due to Khormalou (Persimmon) is being reported in a young patient with chief complaint of abdominal pains and concomitant duodenal ulcer. Review of the literature in this subject shows that bezoars of this size and weight are relatively rare in healthy individuals.     

Fate of a mutation in a fluctuating environment

Natural environments are never truly constant, but the evolutionary implications of temporally varying selection pressures remain poorly understood. Here we investigate how the fate of a new mutation in a fluctuating environment depends on the dynamics of environmental variation and on the selective pressures in each condition. We find that even when a mutation experiences many environmental epochs before fixing or going extinct, its fate is not necessarily determined by its time-averaged selective effect. Instead, environmental variability reduces the efficiency of selection across a broad parameter regime, rendering selection unable to distinguish between mutations that are substantially beneficial and substantially deleterious on average. Temporal fluctuations can also dramatically increase fixation probabilities, often making the details of these fluctuations more important than the average selection pressures acting on each new mutation. For example, mutations that result in a trade-off between conditions but are strongly deleterious on average can nevertheless be more likely to fix than mutations that are always neutral or beneficial. These effects can have important implications for patterns of molecular evolution in variable environments, and they suggest that it may often be difficult for populations to maintain specialist traits, even when their loss leads to a decline in time-averaged fitness.Evolutionary trade-offs are widespread: Adaptation to one environment often leads to costs in other conditions. For example, drug resistance mutations often carry a cost when the dosage of the drug decays (1), and seasonal variations in climate can differentially select for certain alleles in the summer or winter (2). Similarly, laboratory adaptation to specific temperatures (3, 4) or particular nutrient sources (5, 6) often leads to declines in fitness in other conditions. Related trade-offs apply to any specialist phenotype or regulatory system that incurs a general cost to confer benefits in specific environmental conditions (7). Despite the ubiquity of these trade-offs, it is not always easy to predict when a specialist phenotype can evolve and persist. How useful must a trait be on average to be maintained? How regularly does it need to be useful? How much easier is it to maintain in a larger population compared with a smaller one?The answers to these questions depend on two major factors. First, how often do new mutations create or destroy a specialist phenotype, and what are their typical costs and benefits across environmental conditions? This is fundamentally an empirical question, which depends on the costs and benefits of the trait in question, as well as its genetic architecture (e.g., the target size for loss-of-function mutations that disable a regulatory system). In this paper, we focus instead on the second major factor: given that a particular mutation occurs, how does its long-term fate depend on its fitness in each condition and on the details of the environmental fluctuations?To address this question, we must analyze the fixation probability of a new mutation that experiences a time-varying selection pressure. This is a classic problem in population genetics, and has been studied by a number of previous authors. The effects of temporal fluctuations are simplest to understand when the timescales of environmental and evolutionary change are very different. For example, when the environment changes more slowly than the fixation time of a typical mutation, its fate will be entirely determined by the environment in which it arose (8). On the other hand, if environmental changes are sufficiently rapid, then the fixation probability of a mutation will be determined by its time-averaged fitness effect (9, 10). In these extreme limits, the environment can have a profound impact on the fixation probability of a new mutation, but the fluctuations themselves play a relatively minor role. In both cases, the effects of temporal variation can be captured by defining a constant effective selection pressure, which averages over the environmental conditions that the mutation experiences during its lifetime. This result is the major reason why temporally varying selection pressures are neglected throughout much of population genetics, despite the fact that truly constant environments are rare.However, this simple result is crucially dependent on the assumption that environmental changes are much slower or much faster than all evolutionary processes. When these timescales start to overlap, environmental fluctuations can have important qualitative implications that cannot be summarized by any effective selection pressure, even when a mutation experiences many environmental epochs over its lifetime. As we will show below, this situation is not an unusual special case, but a broad regime that becomes increasingly relevant in large populations. In this regime, the fate of each mutation depends critically on its fitness in each environment, the dynamics of environmental changes, and the population size.Certain aspects of this process have been analyzed in earlier studies. Much of this earlier work focuses on the dynamics of a mutation in an infinite population (11–24). However, these infinite-population approaches are fundamentally unsuitable for analyzing the fixation probabilities of mutations that are neutral or deleterious on average (and even for mutations that are beneficial on average, population sizes must often be unrealistically large for this infinite population size approximation to hold). Another class of work has focused explicitly on finite populations, but only in the case where the environment varies stochastically from one generation to the next (25–31). Later work has extended this analysis to fluctuations on somewhat longer timescales, but this work is still restricted to the special case where selection cannot change allele frequencies significantly during an individual environmental epoch (9, 32, 33).These studies have provided important qualitative insights into various aspects of environmental fluctuations. However, we still lack both a quantitative and conceptual understanding of more significant fluctuations, where selection in each environment can lead to measurable changes in allele frequency. This gap is particularly relevant because significant changes in allele frequency are the most clearly observable signal of variable selection in natural populations.In this work, we analyze the fate of a new mutation that arises in an environment that fluctuates between two conditions either deterministically or stochastically on any timescale. We provide a full analysis of the fixation probability of a mutation when evolutionary and environmental timescales are comparable and allele frequencies can change significantly in each epoch. We find that even in enormous populations, natural selection is often very inefficient at distinguishing between mutations that are beneficial and deleterious on average. In addition, substitution rates of all mutations are dramatically increased by variable selection pressures. This can lead to counterintuitive results. For instance, mutations that result in a trade-off but are predominantly deleterious during their lifetime can be much more likely to fix than mutations that are always neutral or even beneficial. Thus, it may often be difficult for populations to maintain specialist traits, even when loss-of-function mutations are selected against on average. This can lead to important signatures on the genetic level, e.g., in elevated rates of nonsynonymous to synonymous substitutions (dN/dS) (34).     

Dissection of a viral autoprotease elucidates a function of a cellular chaperone in proteolysis

Replication of positive-strand RNA viruses involves translation of polyproteins which are proteolytically processed into functional peptides. These maturation steps often involve virus-encoded autoproteases specialized in generating their own N or C termini. Nonstructural protein 2 (NS2) of the pestivirus bovine viral diarrhea virus represents such an enzyme. Bovine viral diarrhea virus NS2 creates in cis its own C terminus and thereby releases an essential viral replication factor. As a unique feature, this enzyme requires for proteolytic activity stoichiometric amounts of a cellular chaperone termed Jiv (J-domain protein interacting with viral protein) or its fragment Jiv90. To obtain insight into the structural organization of the NS2 autoprotease, the basis for its restriction to cis cleavage, as well as its activation by Jiv, we dissected NS2 into functional domains. Interestingly, an N-terminal NS2 fragment covering the active center of the protease, cleaved in trans an artificial substrate composed of a C-terminal NS2 fragment and two downstream amino acids. In the authentic NS2, the 4 C-terminal amino acids interfered with binding and cleavage of substrates offered in trans. These findings strongly suggest an intramolecular product inhibition for the NS2 autoprotease. Remarkably, the chaperone fragment Jiv90 independently interacted with protease and substrate domain and turned out to be essential for the formation of a protease/substrate complex that is required for cleavage. Thus, the function of the cell-derived protease cofactor Jiv in proteolysis is regulation of protease/substrate interaction, which ultimately results in positioning of active site and substrate peptide into a cleavage-competent conformation.     

Hemoptysis in a patient with a previous surgical correction of a tetralogy of Fallot

Aorto-bronchial fistula is a rare but associated with a height rare of mortality. Although most reported cases are secondary to infectious aneurysms, cases arising after surgery to correct congenital cardiovascular abnormalities have recently been described. We report the case of a 41-year-old patient with recurrent hemoptysis and a history of Fallot's tetralogy corrected in childhood. Given such a case of hemoptysis in a patient with a history of cardiovascular surgery, the correct diagnostic approach includes fiberoptic bronchoscopy, helicoidal CAT and/or NMR, and aortography. Diagnostic confirmation should be followed soon by corrective surgery.     

Image of a left atrial mass after a cardiopulmonary bypass in a child

Invagination of an appendage into the left atrium is a rare complication. It occurs spontaneously or after open‐heart surgery. In our case, a postoperative transesophageal echocardiogram, after closure of a ventricular septal defect in a 5‐month‐old infant, revealed a large mass in the left atrium. A diagnosis of a left appendage inversion was confirmed after external examination of the heart. Herein, we provide echocardiographic images before, during, and after manual reversion of the left appendage. Misdiagnosis of this complication could have led to an additional unnecessary surgical procedure that could have impacted on the patient's morbidity.     

On a generalization of a theorem of Erich Hecke

E. Hecke initiated the application of representation theory to the study of cusp forms. He showed that, for p a prime congruent to 3 mod 4, the difference of multiplicities of certain conjugate representations of SL(F_p) on cusp forms of degree 1, level p, and weight ≥2 is given by the class number h(-p) of the field Q(√-p). We apply the holomorphic Lefschetz theorem to actions on the Igusa compactification of the Siegel moduli space of degree 2 to compute the values of characters of the representations of Sp₄(F_p) on certain spaces of cusp forms of degree 2 and level p at parabolic elements of this group. Our results imply that here too, the difference in multiplicities of conjugate representations of Sp₄(F_p) is a multiple of h(-p).     

Intermittent Torsion of a Megapouch: Report of a Case

We report an unusual presentation of pouch dysfunction because of excessive pouch enlargement or “mega pouch” and probable torsion. The patient presented with abdominal pain that was positional. Contrast-enhanced computerized tomography showed pouch anastomotic staples extending into the right upper quadrant. At operation, gross pouch enlargement with dilation of the afferent ileum was confirmed. Reduction pouch-plasty resulted in pain resolution and maintenance of satisfactory function.     

A case report of a lung abscess as a rare complication of a pyogenic liver abscess

Rationale:A hepatobronchial fistula and lung abscess following a pyogenic liver abscess is a rare entity and it is not easy to diagnose this condition based on the symptoms and chest radiography.Patient concerns:An 81-year-old man presented with productive cough and dyspnea.Diagnosis:Chest radiography indicated increased opacities in the right lower lung field with an air-fluid level suggestive of pneumonia complicated by a lung abscess. Chest and abdominal computed tomography revealed an abscess in the right lower lung field that bordered an abscess at segment 7 of the liver. Tubography confirmed a fistula between the liver and lung abscesses.Interventions:Due to communication between 2 abscesses, transhepatic approach was done instead of transpleural approach to avoid complications.Outcomes:A liver abscess complicated by a lung abscess was resolved following percutaneous transhepatic drainage of the liver abscess and antibiotic administration.Lessons:Though uncommon, the lack of suspicion of sub-diaphragmatic liver abscess often lead to a delay in diagnosis and proper treatment. Our case implies the importance of computed tomography in early diagnosis of liver abscess in case of lung abscess in the right lower lung field.     

Significant Rectal Bleeding as a Complication of a Fecal Collecting Device: Report of a Case

We report the case of 65-year-old man who developed massive rectal bleeding associated with the use of a fecal collecting device: the Flexi-Seal Fecal Management System. A colonoscopy showed an acute laceration of the anterior rectal wall mucosa, 6 cm from the anal verge, with active bleeding. The tear was most likely the result of an acute event, such as sudden movement of the device within the rectum or trauma sustained during insertion. Massive transfusion was required, and surgical endoscopic treatment was necessary to ensure hemostasis. This is, to our knowledge, the first such case to be reported.     

Endoscopic treatment of a large colonic polyp as a cause of colocolonic intussusception in a child

Colocolonic intussusception is an uncommon cause of intestinal obstruction in children. The most common type is idiopathic ileocolic intussusception. However, pathologic lead points occur approximately in 5% of cases. In pediatric patients, Meckel's diverticulum is the most common lead point, followed by polyps and duplication. We present a case of recurrent colocolonic intussusception which caused colonic obstruction in a 10-year-old boy. A barium enema revealed a large polypoid mass at the transverse colon. Colonoscopy showed a colonic polyp, 3.5 centimeters in diameter, which was successfully removed by endoscopic polypectomy.     

Rupture of a retro-esophageal diverticulum on a right aortic arch. Apropos of a case

Right aortic arch with retro-oesophageal left subclavian artery usually is an asymptomatic vascular abnormality. The evolutive potential of the associated retro-oesophageal diverticulum is unknown. Complications caused by the malformation are rare, but they may be extremely severe. A case of ruptured diverticulum in an adult patient is reported. The vascular abnormality, as well as the rupture, were confirmed by computerized tomography (CT) and angiography. Complications of retro-oesophageal diverticula are due to these formations being transformed into aneurysms, with compression of the oesophagus, dissection of the aorta or rupture. Such accidents raise the problems of detection of the abnormality, long-term surveillance of the diverticulum (facilitated by CT) and decision to be made when signs of transformation develop (resection of the diverticulum under extracorporeal circulation).