Gitelman syndrome

Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia

The potato developer (D) locus encodes an R2R3 MYB transcription factor that regulates expression of multiple anthocyanin structural genes in tuber skin

A dominant allele at the D locus (also known as I in diploid potato) is required for the synthesis of red and purple anthocyanin pigments in tuber skin. It has previously been reported that D maps to a region of chromosome 10 that harbors one or more homologs of Petuniaan2, an R2R3 MYB transcription factor that coordinately regulates the expression of multiple anthocyanin biosynthetic genes in the floral limb. To test whether D acts similarly in tuber skin, RT-PCR was used to evaluate the expression of flavanone 3-hydroxylase (f3h), dihydroflavonol 4-reductase (dfr) and flavonoid 3′,5′-hydroxylase (f3′5′h). All three genes were expressed in the periderm of red- and purple-skinned clones, while dfr and f3′5′h were not expressed, and f3h was only weakly expressed, in white-skinned clones. A potato cDNA clone with similarity to an2 was isolated from an expression library prepared from red tuber skin, and an assay developed to distinguish the two alleles of this gene in a diploid potato clone known to be heterozygous Dd. One allele was observed to cosegregate with pigmented skin in an F1 population of 136 individuals. This allele was expressed in tuber skin of red- and purple-colored progeny, but not in white tubers, while other parental alleles were not expressed in white or colored tubers. The allele was placed under the control of a doubled 35S promoter and transformed into the light red-colored cultivar Désirée, the white-skinned cultivar Bintje, and two white diploid clones known to lack the functional allele of D. Transformants accumulated pigment in tuber skin, as well as in other tissues, including young foliage, flower petals, and tuber flesh

Mixing induces long-term hyperthermia in growing pigs

The purpose of this experiment was to determine whether body temperature is a sensitive parameter to measure long-term effects of stress in pigs. Mixing of unacquainted pigs is a severe stressor that has detrimental effects on health, production and welfare. We measured deep body temperature after mixing growing pigs. Five pigs of 15 weeks of age, each individually housed with a companion pig, were mixed with two unacquainted congeners. Deep body temperature, heart rate and activity were recorded by radiotelemetry 9 days prior to until 8 days after mixing. These parameters were also recorded in dive control pigs (individually housed with a companion pig) during the same time span. Behaviour during the light period was recorded on videotape on the day of mixing and on three subsequent days. Mixing induced a significant rise ill body temperature that lasted for 8 h after mixing. Although heart rate and general activity level did not significantly differ between mixed and control pigs, mixing significantly increased the frequency of fighting and reduced the frequency of earing. In conclusion, the present experiment shows that mixing induces a long-lasting hyperthermia in pigs. Thus, deep body temperature may be used as a sensitive parameter to measure long-term effects of stress in pigs

Ultrasonic characterization of ultrasound contrast agents

The main constituent of an ultrasound contrast agent (UCA) is gas-filled microbubbles. An average UCA contains billions per ml. These microbubbles are excellent ultrasound scatterers due to their high compressibility. In an ultrasound field they act as resonant systems, resulting in harmonic energy in the backscattered ultrasound signal, such as energy at the subharmonic, ultraharmonic and higher harmonic frequencies. This harmonic energy is exploited for contrast enhanced imaging to discriminate the contrast agent from surrounding tissue. The amount of harmonic energy that the contrast agent bubbles generate depends on the bubble characteristics in combination with the ultrasound field applied. This paper summarizes different strategies to characterize the UCAs. These strategies can be divided into acoustic and optical methods, which focus on the linear or nonlinear responses of the contrast agent bubbles. In addition, the characteristics of individual bubbles can be determined or the bubbles can be examined when they are part of a population. Recently, especially optical methods have proven their value to study individual bubbles. This paper concludes by showing some examples of optically observed typical behavior of contrast bubbles in ultrasound fields

Binding of CML-Modified as Well as Heat-Glycated beta-lactoglobulin to Receptors for AGEs Is Determined by Charge and Hydrophobicity

Intake of dietary advanced glycation end products (AGEs) is associated with inflammation-related health problems. Nε-carboxymethyl lysine (CML) is one of the best characterised AGEs in processed food. AGEs have been described as ligands for receptors present on antigen presenting cells. However, changes in protein secondary and tertiary structure also induce binding to AGE receptors. We aimed to discriminate the role of different protein modifications in binding to AGE receptors. Therefore, β-lactoglobulin was chemically modified with glyoxylic acid to produce CML and compared to β-lactoglobulin glycated with lactose. Secondary structure was monitored with circular dichroism, while hydrophobicity and formation of β-sheet structures was measured with ANS-assay and ThT-assay, respectively. Aggregation was monitored using native-PAGE. Binding to sRAGE, CD36, and galectin-3 was measured using inhibition ELISA. Even though no changes in secondary structure were observed in all tested samples, binding to AGE receptors increased with CML concentration of CML-modified β-lactoglobulin. The negative charge of CML was a crucial determinant for the binding of protein bound CML, while binding of glycated BLG was determined by increasing hydrophobicity. This shows that sRAGE, galectin-3, and CD36 bind to protein bound CML and points out the role of negatively charged AGEs in binding to AGE receptors

The trauma of ongoing conflict and displacement in Chechnya: quantitative assessment of living conditions, and psychosocial and general health status among war displaced in Chechnya and Ingushetia

BACKGROUND: Conflict in Chechnya has resulted in over a decade of violence, human rights abuses, criminality and poverty, and a steady flow of displaced seeking refuge throughout the region. At the beginning of 2004 MSF undertook quantitative surveys among the displaced populations in Chechnya and neighbouring Ingushetia. METHODS: Surveys were carried out in Ingushetia (January 2004) and Chechnya (February 2004) through systematic sampling. Various conflict-related factors contributing to ill health were researched to obtain information on displacement history, living conditions, and psychosocial and general health status. RESULTS: The average length of displacement was five years. Conditions in both locations were poor, and people in both locations indicated food shortages (Chechnya (C): 13.3%, Ingushetia (I): 11.3%), and there was a high degree of dependency on outside help (C: 95.4%, I: 94.3%). Most people (C: 94%, I: 98%) were confronted with violence in the past. Many respondents had witnessed the killing of people (C: 22.7%, I: 24.1%) and nearly half of people interviewed witnessed arrests (C: 53.1%, I: 48.4%) and maltreatment (C: 56.2%, I: 44.5%). Approximately one third of those interviewed had directly experienced war-related violence. A substantial number of people interviewed – one third in Ingushetia (37.5%) and two-thirds in Chechnya (66.8%) – rarely felt safe. The violence was ongoing, with respondents reporting violence in the month before the survey (C: 12.5%, I: 4.6%). Results of the general health questionnaire (GHQ 28) showed that nearly all internally displaced persons interviewed were suffering from health complaints such as somatic complaints, anxiety/insomnia, depressive feelings or social dysfunction (C: 201, 78.5%, CI: 73.0% – 83.4%; I: 230, 81.3%, CI: 76.2% – 85.6%). Poor health status was reflected in other survey questions, but health services were difficult to access for around half the population (C: 54.3%, I: 46.6%). DISCUSSION: The study demonstrates that the health needs of internally displaced in both locations are similarly high and equally unaddressed. The high levels of past confrontation with violence and ongoing exposure in both locations is likely to contribute to a further deterioration of the health status of internally displaced. As of March 2007, concerns remain about how the return process is being managed by the authorities

Family history is neglected in the work-up of patients with colorectal cancer: a quality assessment using cancer registry data

In the diagnostic work-up of hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome), high-risk patients can be identified using information from the family history on cancer (‘Amsterdam criteria’ and ‘Bethesda guidelines’). To investigate to what extent the medical specialists apply these criteria to patients with colorectal carcinoma and a suspicion of HNPCC, we collected information on diagnostic work-up of 224 patients of seven hospitals in the region of the Comprehensive Cancer Centre West in Leiden, The Netherlands. These patients were diagnosed with colorectal cancer between 1999 and 2001 and satisfied at least one of the Bethesda guidelines. A complete family history was recorded for 38 of the 244 patients (16%). Patients with a complete family history were more likely to be referred to the Clinical Genetic Centre than those with an incomplete or absent family history (53% vs. 13% and 4%, respectively; P < 0.0001), and more likely to be analyzed for microsatellite instability (MSI), which is a characteristic of HNPCC (34% vs. 6% and 1%, respectively; P < 0.0001). We conclude that the family history is neglected in the majority of patients with colorectal cancer and MSI-analysis is only performed in a small proportion of the patients that meet the guidelines for this analysis

Cerebral activations related to ballistic, stepwise interrupted and gradually modulated movements in parkinson patients

Patients with Parkinson's disease (PD) experience impaired initiation and inhibition of movements such as difficulty to start/stop walking. At single-joint level this is accompanied by reduced inhibition of antagonist muscle activity. While normal basal ganglia (BG) contributions to motor control include selecting appropriate muscles by inhibiting others, it is unclear how PD-related changes in BG function cause impaired movement initiation and inhibition at single-joint level. To further elucidate these changes we studied 4 right-hand movement tasks with fMRI, by dissociating activations related to abrupt movement initiation, inhibition and gradual movement modulation. Initiation and inhibition were inferred from ballistic and stepwise interrupted movement, respectively, while smooth wrist circumduction enabled the assessment of gradually modulated movement. Task-related activations were compared between PD patients (N = 12) and healthy subjects (N = 18). In healthy subjects, movement initiation was characterized by antero-ventral striatum, substantia nigra (SN) and premotor activations while inhibition was dominated by subthalamic nucleus (STN) and pallidal activations, in line with the known role of these areas in simple movement. Gradual movement mainly involved antero-dorsal putamen and pallidum. Compared to healthy subjects, patients showed reduced striatal/SN and increased pallidal activation for initiation, whereas for inhibition STN activation was reduced and striatal-thalamo-cortical activation increased. For gradual movement patients showed reduced pallidal and increased thalamo-cortical activation. We conclude that PD-related changes during movement initiation fit the (rather static) model of alterations in direct and indirect BG pathways. Reduced STN activation and regional cortical increased activation in PD during inhibition and gradual movement modulation are better explained by a dynamic model that also takes into account enhanced responsiveness to external stimuli in this disease and the effects of hyper-fluctuating cortical inputs to the striatum and STN in particular

Oseltamivir Is Adequately Absorbed Following Nasogastric Administration to Adult Patients with Severe H5N1 Influenza

In the absence of a parenteral drug, oral oseltamivir is currently recommended by the WHO for treating H5N1 influenza. Whether oseltamivir absorption is adequate in severe influenza is unknown. We measured the steady state, plasma concentrations of nasogastrically administered oseltamivir 150 mg bid and its active metabolite, oseltamivir carboxylate (OC), in three, mechanically ventilated patients with severe H5N1 (male, 30 yrs; pregnant female, 22 yrs) and severe H3N2 (female, 76 yrs). Treatments were started 6, 7 and 8 days after illness onset, respectively. Both females were sampled while on continuous venovenous haemofiltration. Admission and follow up specimens (trachea, nose, throat, rectum, blood) were tested for RNA viral load by reverse transcriptase PCR. In vitro virus susceptibility to OC was measured by a neuraminidase inhibition assay. Admission creatinine clearances were 66 (male, H5N1), 82 (female, H5N1) and 6 (H3N2) ml/min. Corresponding AUC0–12 values (5932, 10,951 and 34,670 ng.h/ml) and trough OC concentrations (376, 575 and 2730 ng/ml) were higher than previously reported in healthy volunteers; the latter exceeded 545 to 3956 fold the H5N1 IC50 (0.69 ng/ml) isolated from the H5N1 infected female. Two patients with follow-up respiratory specimens cleared their viruses after 5 (H5N1 male) and 5 (H3N2 female) days of oseltamivir. Both female patients died of respiratory failure; the male survived. 150 mg bid of oseltamivir was well absorbed and converted extensively to OC. Virus was cleared in two patients but two patients died, suggesting viral efficacy but poor clinical efficacy