Paracellin-1 gene mutation with multiple congenital abnormalities

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.

Late-onset manifestation of antenatal Bartter syndrome as a result of residual function of the mutated renal Na+-K+-2Cl- co-transporter

Genetic defects of the Na+-K+-2Cl- (NKCC2) sodium potassium chloride co-transporter result in severe, prenatal-onset renal salt wasting accompanied by polyhydramnios, prematurity, and life-threatening hypovolemia of the neonate (antenatal Bartter syndrome or hyperprostaglandin E syndrome). Herein are described two brothers who presented with hyperuricemia, mild metabolic alkalosis, low serum potassium levels, and bilateral medullary nephrocalcinosis at the ages of 13 and 15 yr. Impaired function of sodium chloride reabsorption along the thick ascending limb of Henle's loop was deduced from a reduced increase in diuresis and urinary chloride excretion upon application of furosemide. Molecular genetic analysis revealed that the brothers were compound heterozygotes for mutations in the SLC12A1 gene coding for the NKCC2 co-transporter. Functional analysis of the mutated rat NKCC2 protein by tracer-flux assays after heterologous expression in Xenopus oocytes revealed significant residual transport activity of the NKCC2 p.F177Y mutant construct in contrast to no activity of the NKCC2-D918fs frameshift mutant construct. However, coexpression of the two mutants was not significantly different from that of NKCC2-F177Y alone or wild type. Membrane expression of NKCC2-F177Y as determined by luminometric surface quantification was not significantly different from wild-type protein, pointing to an intrinsic partial transport defect caused by the p.F177Y mutation. The partial function of NKCC2-F177Y, which is not negatively affected by NKCC2-D918fs, therefore explains a mild and late-onset phenotype and for the first time establishes a mild phenotype-associated SLC12A1 gene mutation.

Skin rejuvenation without a scalpel. I. Fillers

Fillers are an important tool in the armamentarium of the physician combating aging phenomena. A wide variety of filler substances are now available that meet many, but by far not all, needs in aesthetic medicine. The most commonly used substances now are hyaluronic acid and collagen preparations that have slightly different indications, but collagen requires pre-use testing to rule out inflammatory complications. Poly-L-lactic acid has gained its place in the filling of adipose tissue wasting in HIV-infected patients. Autologous fat is easy to harvest and inject and has virtually no risk of adverse side effects. Permanent fillers may be of advantage but carry the risk of permanent adverse reactions. Skillful combination of different fillers as well as with botulinum toxin injections and other cosmetic procedures may give optimal results.

Introduction of a novel dose saving acquisition mode for the PortalVision aS500 EPID to facilitate on-line patient setup verification

In external beam radiotherapy, electronic portal imaging becomes more and more an indispensable tool for the verification of the patient setup. For the safe clinical introduction of high dose conformal radiotherapy like intensity modulated radiation therapy, on-line patient setup verification is a prerequisite to ensure that the planned dosimetric coverage of the tumor volume is actually realized in the patient. Since the direction of setup fields often deviates from the direction of the treatment beams, extra dose is delivered to the patient during the acquisition of these portal images which may reach clinical relevance. The aim of this work was to develop a new acquisition mode for the PortalVision aS500 electronic portal imaging device from Varian Medical Systems that allows one to take portal images with reduced dose while keeping good image quality. The new acquisition mode, called RadMode, selectively enables and disables beam pulses during image acquisition allowing one to stop wasting valuable dose during the initial acquisition of "reset frames." Images of excellent quality can be taken with 1 MU only. This low dose per image facilitates daily setup verification with considerably reduced extra dose.

Myotonic dystrophy as a potential killer

A 19-year-old man suffered a cardiac arrest during a promenade with his friends. Cardiac resuscitation was started immediately. Anamnesis uncovered that the father as well as a cousin of the patient suffered from myotonic dystrophy (MD). Follow-up ECG monitoring showed intercurrent III degree AV-block as well as several asymptomatic episodes of ventricular tachycardias, atrial flutter with changing conduction and atrial fibrillation. Neuromuscular testing and genetic analyses confirmed the diagnosis of a myotonic dystrophy. Myotonic dystrophy (MD) is a chronic, slowly progressing, autosomal dominant inherited multisystemic disease.The clinical presentation is characterized by wasting of the muscles with delayed relaxation, cataracts and endocrine changes. MD is associated with both cardiac conduction disturbances and structural heart abnormalities. Electrocardiographic abnormalities include conduction disturbances or tachyarrhythmias. This case illustrates that potentially lethal arrhythmias inducing sudden cardiac death may occur in MD patients even in the absence of neurologic symptoms characterizing the systemic illness.

Body composition and fuel metabolism after kidney grafting

Kidney transplant patients display decreased muscle mass and increased fat mass. Whether this altered body composition is due to glucocorticoid induced altered fuel metabolism is unclear. To answer this question, 16 kidney transplant patients were examined immediately after kidney transplantation (12 +/- 4 days, mean +/- SEM) and then during months 2, 5, 11 and 16, respectively, by whole body dual energy X-ray absorptiometry (Hologic QDR 1000W) and indirect calorimetry. Results were compared with those of 16 age, sex and body mass index matched healthy volunteers examined only once. All patients received dietary counselling with a step 1 diet of the American Heart Association and were advised to restrict their caloric intake to the resting energy expenditure plus 30%. Immediately after transplantation, lean mass of the trunk was higher by 7 +/- 1% (P < 0.05) and that of the limbs was lower by more than 10% (P < 0.01) in patients than in controls. In contrast, no difference in fat mass and resting energy expenditure could be detected between patients and controls. During the 16 months of observation, total fat mass increased in male (+4.9 +/- 1.5 kg), but not in female patients (0.1 +/- 0.8 kg). The change in fat mass observed in men was due to an increase in all subregions of the body analysed (trunk, arms+legs as well as head+neck), whereas in women only an increase in head+neck by 9 +/- 2% (P = 0.05) was detected. Body fat distribution remained unchanged in both sexes over the 16 months of observation. Lean mass of the trunk mainly decreased between days 11 and 42 (P < 0.01) and remained stable thereafter. After day 42, lean mass of arms and legs (mostly striated muscle) and head+neck progressively increased over the 14 months of observation by 1.6 +/- 0.6 kg (P < 0.05) and 0.4 +/- 0.1 kg (P < 0.01), respectively. Resting energy expenditure was similar in controls and patients at 42 days (30.0 +/- 0.7 vs. 31.0 +/- 0.9 kcal kg-1 lean mass) and did not change during the following 15 months of observation. However, composition of fuel used to sustain resting energy expenditure in the fasting state was altered in patients when compared with normal subjects, i.e. glucose oxidation was higher by more than 45% in patients (P < 0.01) during the second month after grafting, but gradually declined (P < 0.01) over the following 15 months to values similar to those observed in controls. Protein oxidation was elevated in renal transplant patients on prednisone at first measurement, a difference which tended to decline over the study period. In contrast to glucose and protein oxidation, fat oxidation was lower in patients 42 days after grafting (P < 0.01), but increased by more than 100% reaching values similar to those observed in controls after 16 months of study. Mean daily dose of prednisone per kg body weight correlated with the three components of fuel oxidation (r > 0.93, P < 0.01), i.e. protein, glucose and fat oxidation. These results indicate that in prednisone treated renal transplant patients fuel metabolism is regulated in a dose-dependent manner. Moreover, dietary measures, such as caloric and fat intake restriction as well as increase of protein intake, can prevent muscle wasting as well as part of the usually observed fat accumulation. Furthermore, the concept of preferential upper body fat accumulation as consequence of prednisone therapy in renal transplant patients has to be revised.

Tuberculosis caused by Mycobacterium microti in South American camelids

BACKGROUND: Infection with Mycobacterium microti can cause chronic disease in animals and threaten human health through its zoonotic potential. OBJECTIVE: To describe clinical findings, diagnostic investigations, necropsy, and epidemiology results in South American camelids (SAC) infected with M. microti, member of the Mycobacterium tuberculosis complex. ANIMALS: Eleven SAC with tuberculous lesions. METHODS: Description of 10 llamas and 1 alpaca, aged 4-18 years, from 6 herds with a history of wasting and weakness admitted to the Vetsuisse-Faculty of Berne over 8 years. RESULTS: Clinical signs included weight loss, recumbency, and anorexia in late stages of the disease. Respiratory problems were seen in 6 animals of 11. No consistent hematologic abnormalities were identified. Suspect animals were examined in detail by abdominal ultrasonography and thoracic radiology. Abnormal findings such as enlarged mediastinal, mesenteric, or hepatic lymph nodes were seen only in animals with advanced disease. Single comparative intradermal tuberculin test with bovine protein purified derivate (PPD) and avian PPD was negative in all animals. At necropsy, typical tuberculous lesions were found, and confirmed by bacteriological smear and culture, molecular methods, or both. CONCLUSIONS AND CLINICAL IMPORTANCE: Infection caused by M. microti should be considered a differential diagnosis in chronic debilitating disease with or without respiratory signs in SAC. Antemortem confirmation of the diagnosis remains challenging at any stage of infection. Because cases of M. microti infection have been reported in immunocompromized human patients, the zoonotic potential of the organism should be kept in mind when dealing with this disease in SAC.

Dynamic SLA management with forecasting using multi-objective optimization

Cost-efficient operation while satisfying performance and availability guarantees in Service Level Agreements (SLAs) is a challenge for Cloud Computing, as these are potentially conflicting objectives. We present a framework for SLA management based on multi-objective optimization. The framework features a forecasting model for determining the best virtual machine-to-host allocation given the need to minimize SLA violations, energy consumption and resource wasting. A comprehensive SLA management solution is proposed that uses event processing for monitoring and enables dynamic provisioning of virtual machines onto the physical infrastructure. We validated our implementation against serveral standard heuristics and were able to show that our approach is significantly better.

Mass-movement and flood-induced deposits in Lake Ledro, southern Alps, Italy: implications for Holocene palaeohydrology and natural hazards

High-resolution seismic profiles and sediment cores from Lake Ledro combined with soil and riverbed samples from the lake's catchment area are used to assess the recurrence of natural hazards (earthquakes and flood events) in the southern Italian Alps during the Holocene. Two well-developed deltas and a flat central basin are identified on seismic profiles in Lake Ledro. Lake sediments have been finely laminated in the basin since 9000 cal. yr BP and frequently interrupted by two types of sedimentary events (SEs): light-coloured massive layers and dark-coloured graded beds. Optical analysis (quantitative organic petrography) of the organic matter present in soil, riverbed and lacustrine samples together with lake sediment bulk density and grain-size analysis illustrate that light-coloured layers consist of a mixture of lacustrine sediments and mainly contain algal particles similar to the ones observed in background sediments. Light-coloured layers thicker than 1.5 cm in the main basin of Lake Ledro are synchronous to numerous coeval mass-wasting deposits remoulding the slopes of the basin. They are interpreted as subaquatic mass-movements triggered by historical and pre-historical regional earthquakes dated to AD2005, AD1891, AD1045 and 1260, 2545, 2595, 3350, 3815, 4740, 7190, 9185 and 11 495 cal. yr BP. Darkcoloured SEs develop high-amplitude reflections in front of the deltas and in the deep central basin. These beds are mainly made of terrestrial organic matter (soils and lignocellulosic debris) and are interpreted as resulting from intense hyperpycnal flood event. Mapping and quantifying the amount of soil material accumulated in the Holocene hyperpycnal flood deposits of the sequence allow estimating that the equivalent soil thickness eroded over the catchment area reached up to 5mm during the largest Holocene flood events. Such significant soil erosion is interpreted as resulting from the combination of heavy rainfall and snowmelt. The recurrence of flash flood events during the Holocene was, however, not high enough to affect pedogenesis processes and highlight several wet regional periods during the Holocene. The Holocene period is divided into four phases of environmental evolution. Over the first half of the Holocene, a progressive stabilization of the soils present through the catchment of Lake Ledro was associated with a progressive reforestation of the area and only interrupted during the wet 8.2 event when the soil destabilization was particularly important. Lower soil erosion was recorded during the mid-Holocene climatic optimum (8000-4200 cal. yr BP) and associated with higher algal production. Between 4200 and 3100 cal. yr BP, both wetter climate and human activities within the drainage basin drastically increased soil erosion rates. Finally, from 3100 cal. yr BP to the present-day, data suggest increasing and changing human land use.

Reliability of operational data from pig herds and performance ratings by veterinarians and pig farmers collected during telephone interviews for the evaluation of a PCV2 piglet vaccination

BackgroundThe aim of the present study was to evaluate the feasibility of using a telephone survey in gaining an understanding of the possible herd and management factors influencing the performance (i.e. safety and efficacy) of a vaccine against porcine circovirus type 2 (PCV2) in a large number of herds and to estimate customers¿ satisfaction.ResultsDatasets from 227 pig herds that currently applied or have applied a PCV2 vaccine were analysed. Since 1-, 2- and 3-site production systems were surveyed, the herds were allocated in one of two subsets, where only applicable variables out of 180 were analysed. Group 1 was comprised of herds with sows, suckling pigs and nursery pigs, whereas herds in Group 2 in all cases kept fattening pigs. Overall 14 variables evaluating the subjective satisfaction with one particular PCV2 vaccine were comingled to an abstract dependent variable for further models, which was characterized by a binary outcome from a cluster analysis: good/excellent satisfaction (green cluster) and moderate satisfaction (red cluster). The other 166 variables comprised information about diagnostics, vaccination, housing, management, were considered as independent variables. In Group 1, herds using the vaccine due to recognised PCV2 related health problems (wasting, mortality or porcine dermatitis and nephropathy syndrome) had a 2.4-fold increased chance (1/OR) of belonging to the green cluster. In the final model for Group 1, the diagnosis of diseases other than PCV2, the reason for vaccine administration being other than PCV2-associated diseases and using a single injection of iron had significant influence on allocating into the green cluster (P¿<¿0.05). In Group 2, only unchanged time or delay of time of vaccination influenced the satisfaction (P¿<¿0.05).ConclusionThe methodology and statistical approach used in this study were feasible to scientifically assess ¿satisfaction¿, and to determine factors influencing farmers¿ and vets¿ opinion about the safety and efficacy of a new vaccine.

Visual dating of rockfall scars in Larix decidua trees

Dating past mass wasting with growth disturbances in trees is widely used in geochronology as the approach may yield dates of past process activity with up to subannual precision. Past work commonly focused on the extraction of increment cores, wedges, or stem cross sections. However, sampling has been shown to be constrained by sampling permissions, and the analysis of tree-ring samples requires considerable temporal efforts. To compensate for these shortcomings, we explore the potential of visual inspection of wound appearance for dating purposes. Based on a data set of 217 wood-penetrating wounds of known age inflicted to European larch (Larix decidua Mill.) by rockfall activity, we develop guidelines for the visual, noninvasive dating of wounds including (i) the counting of bark rings, (ii) a visual assessment of exposed wood and wound bark characteristics (such as the color and weathering status of wounds), and (iii) the relationship between wound age and tree diameter. A characterization of wounds based on photographs, randomly selected from the data set, reveals that young wounds typically can be dated with high precision, whereas dating errors gradually increase with increasing wound age. While visual dating does not reach the precision of dendrochronological dating, we clearly demonstrate that spatial patterns of and differences in rockfall activity can be reconstructed with both approaches. The introduction of visual dating approaches will facilitate fieldwork, especially in applied research, assist the conventional interpretation of tree-ring signals, and allow the reconstruction of geomorphic processes with considerably fewer temporal and financial efforts.

Sedimentological processes and environmental variability at Lake Ohrid (Macedonia, Albania) between 637 ka and the present

Lake Ohrid (Macedonia, Albania) is thought to be more than 1.2 million years old and host more than 300 endemic species. As a target of the International Continental scientific Drilling Program (ICDP), a successful deep drilling campaign was carried out within the scope of the Scientific Collaboration on Past Speciation Conditions in Lake Ohrid (SCOPSCO) project in 2013. Here, we present lithological, sedimentological, and (bio-)geochemical data from the upper 247.8 m composite depth of the overall 569 m long DEEP site sediment succession from the central part of the lake. According to an age model, which is based on 11 tephra layers (first-order tie points) and on tuning of bio-geochemical proxy data to orbital parameters (second-order tie points), the analyzed sediment sequence covers the last 637 kyr. The DEEP site sediment succession consists of hemipelagic sediments, which are interspersed by several tephra layers and infrequent, thin (< 5 cm) mass wasting deposits. The hemipelagic sediments can be classified into three different lithotypes. Lithotype 1 and 2 deposits comprise calcareous and slightly calcareous silty clay and are predominantly attributed to interglacial periods with high primary productivity in the lake during summer and reduced mixing during winter. The data suggest that high ion and nutrient concentrations in the lake water promoted calcite precipitation and diatom growth in the epilimnion during MIS15, 13, and 5. Following a strong primary productivity, highest interglacial temperatures can be reported for marine isotope stages (MIS) 11 and 5, whereas MIS15, 13, 9, and 7 were comparably cooler. Lithotype 3 deposits consist of clastic, silty clayey material and predominantly represent glacial periods with low primary productivity during summer and longer and intensified mixing during winter. The data imply that the most severe glacial conditions at Lake Ohrid persisted during MIS16, 12, 10, and 6, whereas somewhat warmer temperatures can be inferred for MIS14, 8, 4, and 2. Interglacial-like conditions occurred during parts of MIS14 and 8.

Magnesium in cystic fibrosis - Systematic review of the literature

BACKGROUND The metabolism of sodium, potassium, and chloride and the acid-base balance are sometimes altered in cystic fibrosis. Textbooks and reviews only marginally address the homeostasis of magnesium in cystic fibrosis. METHODS We performed a search of the Medical Subject Headings terms (cystic fibrosis OR mucoviscidosis) AND (magnesium OR hypomagnes[a]emia) in the US National Library of Medicine and Excerpta Medica databases. RESULTS We identified 25 reports dealing with magnesium and cystic fibrosis. The results of the review may be summarized as follows. First, hypomagnesemia affects more than half of the cystic fibrosis patients with advanced disease; second, magnesemia, which is normally age-independent, relevantly decreases with age in cystic fibrosis; third, aminoglycoside antimicrobials frequently induce both acute and chronic renal magnesium-wasting; fourth, sweat magnesium concentration was normal in cystic fibrosis patients; fifth, limited data suggest the existence of an impaired intestinal magnesium balance. Finally, stimulating observations suggest that magnesium supplements might achieve an improvement in respiratory muscle strength and mucolytic activity of both recombinant and endogenous deoxyribonuclease. CONCLUSIONS The first comprehensive review of the literature confirms that, despite being one of the most prevalent minerals in the body, the importance of magnesium in cystic fibrosis is largely overlooked. In these patients, hypomagnesemia should be sought once a year. Furthermore, the potential of supplementation with this cation deserves more attention.

Human–climate interactions in the central Mediterranean region during the last millennia: The laminated record of Lake Butrint (Albania)

Lake Butrint (39°47 N, 20°1 E) is a ca. 21 m deep, coastal lagoon located in SW Albania where finely-laminated sediments have been continuously deposited during the last millennia. The multi-proxy analysis (sedimentology, high-resolution elemental geochemistry and pollen) of a 12 m long sediment core, supported by seven AMS radiocarbon dates and 137Cs dating, enable a precise reconstruction of the environmental change that occurred in the central Mediterranean region during the last ∼4.5 cal kyrs BP. Sediments consist of triplets of authigenic carbonates, organic matter and clayey laminae. Fluctuations in the thickness and/or presence of these different types of seasonal laminae indicate variations in water salinity, organic productivity and runoff in the lake's catchment, as a result of the complex interplay of tectonics, anthropogenic forcing and climate variability. The progradation of the Pavllo river delta, favoured by variable human activity from the nearby ancient city of Butrint, led to the progressive isolation of this hydrological system from the Ionian Sea. The system evolved from an open bay to a restricted lagoon, which is consistent with archaeological data. An abrupt increase in mass-wasting activity between 1515 and 1450 BC, likely caused by nearby seismic activity, led to the accumulation of 24 homogenites, up to 17 cm thick. They have been deposited during the onset of finely laminated sedimentation, which indicates restricted, anoxic bottom water conditions and higher salinity. Periods of maximum water salinity, biological productivity, and carbonate precipitation coincide with warmer intervals, such as the early Roman Warm Period (RWP) (500 BC–0 AD), the Medieval Climate Anomaly (MCA) (800–1400 AD) and recent times (after 1800 AD). Conversely, lower salinity and more oxic conditions, with higher clastic input were recorded during 1400–500 BC, the Late Roman and the Early Medieval periods (0–800 AD) and during the Little Ice Age (1400–1800 AD). Hydrological fluctuations recorded in Butrint are in phase with most central and western Mediterranean records and correlate with NAO variability. In contrast, opposite hydrological patterns have been recorded in the Eastern Balkans and the Levant during the last millennium, emphasizing a complex spatial variability in the region. Phases of maximum settlement intensity in Butrint (Roman-Late Antique) coincide with warmer and/or stable climate periods (0–800 AD and MCA, respectively), indicating a long-term influence of climatic conditions on human activities. The Late Holocene sedimentary record of Lake Butrint demonstrates the complex interplay of climate variability, tectonics and human impact in the recent evolution of coastal Mediterranean regions.

Geomorphology of the Imhotep region on comet 67P/Churyumov-Gerasimenko from OSIRIS observations

Context. Since August 2014, the OSIRIS Narrow Angle Camera (NAC) onboard the Rosetta spacecraft has acquired high spatial resolution images of the nucleus of comet 67P/Churyumov-Gerasimenko, down to the decimeter scale. This paper focuses on the Imhotep region, located on the largest lobe of the nucleus, near the equator. Aims. We map, inventory, and describe the geomorphology of the Imhotep region. We propose and discuss some processes to explain the formation and ongoing evolution of this region. Methods. We used OSIRIS NAC images, gravitational heights and slopes, and digital terrain models to map and measure the morphologies of Imhotep. Results. The Imhotep region presents a wide variety of terrains and morphologies: smooth and rocky terrains, bright areas, linear features, roundish features, and boulders. Gravity processes such as mass wasting and collapse play a significant role in the geomorphological evolution of this region. Cometary processes initiate erosion and are responsible for the formation of degassing conduits that are revealed by elevated roundish features on the surface. We also propose a scenario for the formation and evolution of the Imhotep region; this implies the presence of large primordial voids inside the nucleus, resulting from its formation process.