SH2 domains are integral to many animal signaling pathways. By interacting with specific phosphotyrosine residues, they provide regulatable protein-protein interaction domains. Dictyostelium is the only nonmetazoan with functionally characterized SH2 domains, but the cognate tyrosine kinases are unknown. There are no orthologs of the animal tyrosine kinases, but there are very many tyrosine kinase-like kinases (TKLs), a group of kinases which, despite their family name, are classified mainly as serine-threonine kinases. STATs are transcription factors that dimerize via phosphotyrosine-SH2 domain interactions. STATc is activated by phosphorylation on Tyr922 when cells are exposed to the prestalk inducer differentiation inducing factor (DIF-1), a chlorinated hexaphenone. We show that in a null mutant for Pyk2, a tyrosine-specific TKL, exposure to DIF-1 does not activate STATc. Conversely, overexpression of Pyk2 causes constitutive STATc activation. Pyk2 phosphorylates STATc on Tyr922 in vitro and complexes with STATc both in vitro and in vivo. This demonstration that a TKL directly activates a STAT has significant implications for understanding the evolutionary origins of SH2 domain-phosphotyrosine signaling. It also has mechanistic implications. Our previous work suggested that a predicted constitutive STATc tyrosine kinase activity is counterbalanced in vivo by the DIF-1-regulated activity of PTP3, a Tyr922 phosphatase. Here we show that the STATc-Pyk2 complex is formed constitutively by an interaction between the STATc SH2 domain and phosphotyrosine residues on Pyk2 that are generated by autophosphorylation. Also, as predicted, Pyk2 is constitutively active as a STATc kinase. This observation provides further evidence for this highly atypical, possibly ancestral, STAT regulation mechanism.

Two conditional mutants of Chlamydomonas reinhardtii, dif-1 and dif-2, affecting gametic differentiation under conditions of nitrogen (N)-starvation, have been isolated. These mutant cell remain "vegetative" at the restrictive temperature (35 degrees C) in -N medium, as defined by assays of cell body-agglutinin and cell wall lytic enzyme activities in the soluble fractions of cell homogenates. Moreover, the mutants fail to form mating structures at the restrictive temperature, but do so at the permissive temperature (25 degrees C). Temperature-shift experiments show that mutant cells which have differentiated into gametes at 25 degrees C dedifferentiate into "vegetative" cells under N-starvation conditions after transfer to 35 degrees C, but differentiate again into gametes at 25 degrees C. Genetic analyses indicate that the dif-1 and dif-2 genes are recessive and unlinked to each other or to the mating-type locus; the dif-1 phenotype cosegregates with a conditional flagellaless phenotype expressed in both +N and -N medium at the restrictive temperature.

The differentiation-inducing factor-1 (DIF-1) is a putative morphogen that induces stalk-cell formation in the lower eukaryote Dictyostelium discoideum. This molecule has been shown to inhibit cell growth and induce erythroid differentiation in human leukemia K562 cells. In the present study, to clarify the mechanism of the actions of DIF-1, we examined the effect of DIF-1 on Akt/protein kinase B (PKB) in K562 cells. Akt/PKB is a serine/threonine kinase that plays a pivotal role in the regulation of cell survival and differentiation in a variety of cells. A nonphosphorylated (inactive) form of Akt/PKB was ordinarily expressed in K562 cells. However, Akt/PKB was phosphorylated and potently activated within several hours of incubation with 5-30 microM DIF-1, and this activation was inhibited by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase). Calcium-increasing agents thapsigargin and A23187 also activated Akt/PKB slightly, which was inhibited by wortmannin. By contrast, calcium-reducing agents TMB-8 and EGTA together with A23187 inhibited the DIF-1-induced activation of Akt/PKB. PMA (PKC activator) also activated Akt/PKB but this activation was not inhibited by wortmannin. DIF-1 exhibited no marked effect on the activation of PKCalpha, beta, and gamma, which were activated by PMA. These results indicate that DIF-1 activates Akt/PKB possibly via cytosolic calcium and subsequent activation of PI3-kinase and also that PMA activates Akt/PKB in a PI3-kinase-independent manner.

We aimed to examine association between disordered eating attitudes (DEAs), alexithymia and suicide probability among adolescent females and to explore potential link between alexithymia and suicide probability in subjects with DEAs. 381 female students completed Eating Attitude Test (EAT-26), Toronto Alexithymia Scale (TAS-20) and Suicide Probability Scale (SPS). It was found that 13.2% (n=52) of the subjects have DEAs. Results indicated that total TAS-20 score and scores of Difficulty in Identifying Feelings (DIF) and Difficulty in Describing Feelings (DDF) subscales were significantly higher in DEAs group than in those non DEAs group (p<0.05). Additionally, total SPS score (p<0.001), Hopelessness (p=0.001), Suicide Ideation (p<0.001) and Hostility (p=0.003) subscales scores of SPS were significantly higher in the alexithymic DEAs than the non-alexithymic DEAs group. In order to control potential effect of depression, SPS subscales were used as covariate factors in ANCOVA. Negative Self-Evaluation subscale yielded a statistically significant difference between groups, other subscales did not. Results point out these; DEAs are relatively frequent phenomenon among female students in Turkey and presence of alexithymia was associated with an increased suicide probability in adolescents with DEAs. The results should be evaluated taking into account that depressive symptomatology was not assessed using a depression scale.

Differentiation-inducing factor-1 (DIF-1) produced by Dictyostelium discoideum strongly inhibits the proliferation of various types of cancer cells by suppression of the Wnt/β-catenin signal transduction pathway. In the present study, we examined the effect of differentiation-inducing factor-3 (DIF-3), a monochlorinated metabolite of DIF-1 that is also produced by D. discoideum, on human colon cancer cell lines HCT-116 and DLD-1. DIF-3 strongly inhibited cell proliferation by arresting the cell cycle at the G0/G1 phase. DIF-3 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via activation of GSK-3β in a time and dose-dependent manner. In addition, DIF-3 suppressed the expression of T-cell factor 7-like 2, a key transcription factor in the Wnt/β-catenin signaling pathway, thereby reducing the mRNA levels of cyclin D1 and c-Myc. Subsequently, we examined the in vivo effects of DIF-3 in Mutyh(-/-) mice with oxidative stress-induced intestinal cancers. Repeated oral administration of DIF-3 markedly reduced the number and size of cancers at a level comparable to that of DIF-1. These data suggest that DIF-3 inhibits intestinal cancer cell proliferation in vitro and in vivo, probably by mechanisms similar to those identified in DIF-1 actions, and that DIF-3 may be a potential novel anti-cancer agent.

YpfΦ is a filamentous phage that infected Yersinia pestis, the plague bacillus, during its emergence. Using an experimental transduction approach, we show here that this phage has the capacity to infect with variable efficiencies, all three pathogenic Yersinia species as well as Escherichia coli. Like other Inovirus phages, its genetic organization comprises three functional modules necessary for the production of infectious virions. Upon infection, YpfΦ integrates into the chromosomal dif site, but extrachromosomal forms are also frequently observed. Several pieces of evidence suggest that the absence of chromosomal YpfΦ in natural non-Orientalis Y. pestis isolates results from a higher chromosomal excision rate rather than from a defective integration machinery. A resident YpfΦ confers some protection against a superinfection. In contrast to other filamentous phages, the incoming YpfΦ genome inserts itself between two copies of the resident prophage. This analysis thus unravels infective properties specific to YpfΦ.

The aim of this study was to evaluate a physiologically based pharmacokinetic (PBPK) model for predicting PK profiles in humans based on a model refined in rats and humans in vitro uptake-transport data using valsartan as a probe substrate. Valsartan is eliminated unchanged, mostly through biliary excretion, both in humans and rats. It was, therefore, chosen as model compound to predict in vivo elimination based on in vitro hepatic uptake-transport data using a fully mechanistic PBPK model. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. A mechanistic two-compartment model was used to derive the active and passive transport parameters, namely uptake Michaelis-Menten parameters (V(max) and K(m,u)) together with passive diffusion (P(dif)). These transport parameters were then used as input in a whole body physiologically based pharmacokinetic (PBPK) model. The uptake rate of valsartan was higher for rat hepatocytes (K(m,u)=28.4+/-3.7 microM, V(max)=1320+/-180 pmol/mg/min, and P(dif) =1.21+/-0.42 microl/mg/min) compared to human hepatocytes (K(m,u)=44.4+/-14.6 microM, V(max)=304+/-85 pmol/mg/min, and P(dif)=0.724+/-0.271 microl/mg/min). OATP1B1 and -1B3 parameters were correlated to human hepatocyte data, using experimentally established relative activity factors (RAF). Resulting PBPK simulations were compared for plasma- (humans and rats) and bile- (rats) concentration-time profiles following iv bolus administration of valsartan. Plasma clearances (CL(P)) for rats and humans were predicted within twofold relative to predictions based on respective in vitro data. The simulations were extended to simulate the impact of either OATP1B1 or -1B3 inhibition on plasma profile. The limited data set indicates that the mechanistic model allowed for accurate evaluation of in vitro transport data; and the resulting hepatic uptake transport kinetic parameters enabled the prediction of in vivo PK profiles and plasma clearances, using PBPK modelling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro.

BACKGROUND

Immunofluorescence testing is an important tool for diagnosing blistering diseases.

OBJECTIVE

To characterize the immunofluorescence findings in patients diagnosed with autoimmune blistering skin diseases.

METHODS

We retrospectively analyzed immunofluorescence results encompassing a 10-year period.

RESULTS

421 patients were included and divided into 2 groups: group 1- intraepidermal blistering diseases (n=277) and 2- subepidermal blistering diseases (n=144). For group 1, positive DIF findings demonstrated: predominance of IgG intercellular staining (ICS) and C3 for pemphigus foliaceus-PF (94% and 73% respectively), pemphigus vulgaris-PV (91.5%-79.5%) and paraneoplastic pemphigus-PNP (66%-33%); ICS IgA in 100% of IgA pemphigus cases, and IgG deposits in the basement membrane zone (BMZ) along with ICS in one Hailey-Hailey patient. The IIF findings revealed mean titers of 1:2.560 for PV and 1:1.280 for PF. For paraneoplastic pemphigus, IIF was positive in 2 out of 3 cases with rat bladder substrate. In group 2, positive DIF findings included multiple deposits at basement membrane zone for epidermolysis bullosa acquisita-EBA (C3-89%,IgG-79%,IgA-47%,IgM-21%) mucous membrane pemphigoid-MMP (C3,IgG,IgA,IgM-80%) and bullous pemphigoid-BP (C3-91%,IgG-39%,IgA-11%,IgM-6%), and IgA at basement membrane zone for IgA linear disease (99%) and dermatitis herpetiformis-DH (dermal papillae in 84.6%). For lichen planus pemphigoides, there was C3 (100%) and IgG (50%) deposition at basement membrane zone. indirect immunofluorescence positive findings revealed basement membrane zone IgG deposits in 46% of BP patients, 50% for EBA, 15% for IgA linear dermatosis and 50% for LPP. Indirect immunofluorescence positive results were higher for BP and EBA with Salt-Split skin substrate.

CONCLUSIONS

Our results confirmed the importance of immunofluorescence assays in diagnosing autoimmune blistering diseases, and higher sensitivity for indirect immunofluorescence when Salt-split skin technique is performed.

OBJECTIVE

An endogenous digitalis-like factor (EDLF) has been implicated in the pathophysiology of preeclampsia (PE). This hypothesis is supported by two cases of preeclampsia in which administration of digoxin immune Fab (DIF) reduced mean arterial pressure (MAP).

METHODS

To study this observation further, we performed a double-blind, placebo-controlled, randomized clinical trial to examine the effects on MAP of intravenous DIF given after delivery in 26 subjects with severe preeclampsia. Treating obstetricians were blinded to subject assignment and were allowed to use standard antihypertensive drugs during the trial.

RESULTS

The primary outcome, a significant difference in blood pressure between the two groups over the 24-h period of observation after the intervention, was not supported. However, mean MAP was significantly lower in the DIF-treated subjects for the first 4 h after therapy as compared with controls (P=0.05). Six subjects (46.2%) in the placebo arm were given conventional antihypertensive medications by their obstetrician for blood pressure >160 mm Hg systolic or >110 mm Hg diastolic, compared with zero subjects in the treatment arm (P=0.01). A trend towards increased creatinine clearance was observed in DIF-treated subjects (137.6+/-42.6 versus 104.1+/-43.4, P=0.07).

CONCLUSIONS

These results support the hypothesis that EDLF contributes to the elevated blood pressure in preeclampsia and suggests a possible role for DIF as a treatment for this condition.

We reported that differentiation-inducing factor-1 (DIF-1), synthesized by Dictyostelium discoideum, inhibited proliferation of various tumor cell lines in vitro by suppressing the Wnt/β-catenin signaling pathway. However, it remained unexplored whether DIF-1 also inhibits tumor growth in vivo. In the present study, therefore, we examined in-vivo effects of DIF-1 using three cancer models: Mutyh-deficient mice with oxidative stress-induced intestinal tumors and nude mice xenografted with the human colon cancer cell line HCT-116 and cervical cancer cell line HeLa. In exploration for an appropriate route of administration, we found that orally administered DIF-1 was absorbed through the digestive tract to elevate its blood concentration to levels enough to suppress tumor cell proliferation. Repeated oral administration of DIF-1 markedly reduced the number and size of intestinal tumors that developed in Mutyh-deficient mice, reducing the phosphorylation level of GSK-3β Ser(9) and the expression levels of early growth response-1 (Egr-1), transcription factor 7-like 2 (TCF7L2) and cyclin D1. DIF-1 also inhibited the growth of HCT-116- and HeLa-xenograft tumors together with decreasing phosphorylation level of GSK-3β Ser(9), although it was not statistically significant in HeLa-xenograft tumors. DIF-1 also suppressed the expressions of Egr-1, TCF7L2 and cyclin D1 in HCT-116-xenograft tumors and those of β-catenin, TCF7L2 and cyclin D1 in HeLa-xenograft tumors. This is the first report to show that DIF-1 inhibits tumor growth in vivo, consistent with its in-vitro action, suggesting that this compound may have potential as a novel anti-tumor agent.

OBJECTIVE

Differential item functioning (DIF) is said to exist in an item if a subject's response to the item is affected by other aspects than that which the test is intended to assess. DIF might affect the validity of a test. The aim of this study was thus to examine whether any of the items in the Epworth Sleepiness Scale (ESS) exhibits DIF regarding age or gender, and if so, to which degree.

METHODS

Using previously collected cross-sectional ESS data from 1,168 subjects with different clinical characteristics (61% males, mean age 67.8 year (SD 12.2 year)), ordinal regression as well as Rasch-based DIF analyses were performed.

RESULTS

Concerning age, both DIF analyses showed DIF for age in items 3 (inactive in a public place), 4 (passenger in a car), and 8 (in a car that has stopped in traffic). The Rasch model also showed DIF for gender in item 3. The DIF magnitudes as judged by McFadden pseudo-R (2) changes were, however, only minor.

CONCLUSIONS

ESS has small but reproducible DIF for age in items 3, 4, and 8. The detected DIF might be worth to consider in large-sample studies, although it probably has no effect on an individual basis.

Previous studies indicate that residents may benefit from a "quiet side" to their dwellings. The influence of the level of road traffic noise exposure at the least exposed side on road traffic noise annoyance was studied in Amsterdam, The Netherlands. Road traffic noise exposure was assessed at the most and least exposed façade (Lden,most and Lden,least respectively) of dwellings for subjects in a population based survey (N = 1,967). It was investigated if and to what extent relative quietness at the least exposed façade affected the level of road traffic noise annoyance by comparing two groups: (1) The subgroup with a relatively quiet façade; (2) the subgroup without a relatively quiet façade (large versus small difference in exposure between most and least exposed façade; DIF ≥ 10 dB and DIF < 10 dB respectively). In addition, it was investigated if and to what extent Lden,least affected the level of road traffic noise annoyance. Results indicate a significantly lower road traffic noise annoyance score at a given Lden,most, in the subgroup with DIF ≥ 10 dB versus DIF < 10 dB. Furthermore, results suggest an effect of Lden,least independent of Lden,most. The estimated size of the effect expressed in an equivalent change in Lden,most approximated 5 dB for both the difference between the two subgroups (DIF ≥ 10 dB and DIF < 10 dB), and for a 10 dB change in Lden,least.

OBJECTIVE

To evaluate the psychometric properties of the Manual Ability Measure-36 (MAM-36), a new hand function outcome measure, and to examine differences in manual abilities and item parameters in patients with neurologic and musculoskeletal conditions.

METHODS

Convenience sample from 2 time periods, cross-sectional.

METHODS

Outpatient rehabilitation units and private hand clinics.

METHODS

Patients (N=337; mean age, 50.3+/-14.9y) with a variety of neurologic and musculoskeletal (orthopedic) diagnoses. Most of these individuals were community dwelling, and all had residual functional limitations in the hand(s).

METHODS

Not applicable.

METHODS

Rasch analysis was performed on MAM-36 data to evaluate both scale structure and psychometric properties, which include rating distribution, step measures, item fit, separation, and dimensionality. A t test was performed to examine the differences in manual abilities in patients with the 2 conditions. Uniform differential item functioning (DIF) between neurologic and musculoskeletal groups was examined. (DIF occurs when subgroup members within the sample with the same level of the underlying trait being measured respond differently to an individual item.) Manual ability estimates were recalibrated with step and common item anchoring; they were compared with those derived from the original analysis.

RESULTS

The 36 items measured a single construct with no misfitting items. The scale was used as intended. The items can reliably separate the participants into 5 ability strata. Neurologic patients had a significantly lower mean manual ability than musculoskeletal patients. Fourteen items exhibited DIF. However, DIF had no effect on either scale quality or calibration of manual ability. We decided that a single rating scale is appropriate for both groups.

CONCLUSIONS

This study showed that the MAM-36 has more than adequate psychometric properties and can be used as a generic outcome measure for patients with a wide variety of clinical diagnoses.

To assess the influence of morning rise of systolic blood pressure (SBP) as assessed by home blood pressure monitoring on the left ventricular mass index (LVMI) in relation to the blood pressure control status, we evaluated M-mode cardiac echocardiography in 626 hypertensive subjects (412 men and 214 women; mean age, 61.3+/-10.1 years) who were receiving antihypertensive medication. The subjects were requested to measure their blood pressure at home in the morning and evening over a 3-month period. They were distributed into the following four groups by the average (ME Ave) and the difference (ME Dif) of the morning and evening SBP. The well-controlled hypertensives with a morning rise of SBP (ME Ave<135 mmHg and ME Dif)or=10 mmHg; n=45; 7.2%) had a greater LVMI (122.9+/-22.7 vs. 92.7+/-15.6 g/m2, p<0.001) than the well-controlled hypertensives without a morning rise of SBP (ME Ave<135 mmHg and ME Dif<10 mmHg; n=367; 58.6%). The uncontrolled hypertensives with a morning rise of SBP (ME Ave>or=135 mmHg and ME Dif)or=10 mmHg; n=91; 14.5%) also had a greater LVMI (136.8+/-21.9 vs. 100.2+/-17.5 g/m2, p<0.001) than the uncontrolled hypertensives without a morning rise of SBP (ME Ave>or=135 mmHg and ME Dif<10 mmHg; n=123; 19.6%). A stepwise multivariate regression analysis revealed that the ME Dif was the most important factor related to the LVMI (r2=35.1% for all subjects, p<0001; r2=39.7% for men, p<0.001; and r2=18.7% for women, p<0.001). These results suggest that morning rise of blood pressure is an important factor influencing the development of left ventricular hypertrophy in hypertensive patients on antihypertensive medication.

OBJECTIVE

Instruments to assess functioning in patients with FM vary considerably in their content and are often symptom-specific. This study aimed to examine whether it is feasible to construct a psychometric-sound clinical instrument to measure functioning in FM based on the Brief ICF-Core-Set for chronic widespread pain (CWP).

METHODS

Two hundred and fifty six people with FM completed the Brief ICF-Core-Set. The Rasch model was used for analysis. Once ordering of response options of ICF categories was ensured, the following properties were studied: fit of the ICF categories to the Rasch model, the targeting between ICF categories and a person's abilities, unidimensionality, and reliability.

RESULTS

Six ICF categories were rescored due to disordered thresholds. Five ICF categories were removed due to high model-misfit and differential item functioning (DIF) for gender. Scores from 46 participants were excluded due to extreme scores. The ICF categories included display consistency with an underlying unidimensional construct, are free of DIF for age, disease duration and gender, display excellent overall reliability, and cover a range of functioning difficulties.

CONCLUSIONS

This study illustrates that it is possible to measure functioning as a unidimensional construct based on selected ICF categories from the components body functions, as well as activities and participation of the Brief ICF-Core-Set for CWP in patients with FM.

The psychometric properties of instruments used to measure self-reported experiences of discrimination in epidemiologic studies are rarely assessed, especially regarding construct validity. The authors used 2000-2001 data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study to examine differential item functioning (DIF) in 2 versions of the Experiences of Discrimination (EOD) Index, an index measuring self-reported experiences of racial/ethnic and gender discrimination. DIF may confound interpretation of subgroup differences. Large DIF was observed for 2 of 7 racial/ethnic discrimination items: White participants reported more racial/ethnic discrimination for the "at school" item, and black participants reported more racial/ethnic discrimination for the "getting housing" item. The large DIF by race/ethnicity in the index for racial/ethnic discrimination probably reflects item impact and is the result of valid group differences between blacks and whites regarding their respective experiences of discrimination. The authors also observed large DIF by race/ethnicity for 3 of 7 gender discrimination items. This is more likely to have been due to item bias. Users of the EOD Index must consider the advantages and disadvantages of DIF adjustment (omitting items, constructing separate measures, and retaining items). The EOD Index has substantial usefulness as an instrument that can assess self-reported experiences of discrimination.

The genome of Dictyostelium contains two novel hybrid-type polyketide synthases (PKSs) known as 'Steely'; the Steely enzyme is formed by the fusion of type I and type III PKSs. One of these enzymes, SteelyB, is known to be responsible for the production of the stalk cell-inducing factor DIF-1 in vivo. On the other hand, the product(s) and expression pattern of SteelyA are not clearly understood, because there are two different reports associated with the in vitro products of SteelyA and its expression pattern. To solve this problem, we first examined the expression pattern using two different primer sets and found that it was quite similar to that shown in the dictyExpress database. stlA expression peaked at approximately 3 h and declined, but showed a small peak around the end of development. Next, we examined the in vivo product of SteelyA using a stlA null mutant and found that the mutant lacked 4-methyl-5-pentylbenzene-1,3-diol (MPBD). This null mutant showed aberrant, glassy sori, and most of the cells in the sori remained amoeba-like without a cell wall. This defect was restored by adding 200 nM of MPBD to the agar. These results indicate that SteelyA produces MPBD in vivo and induces spore maturation.

OBJECTIVE

Increasingly, medical research involves patients who complete outcomes in different languages. This occurs in countries with more than one common language, such as Canada (French/English) or the United States (Spanish/English), as well as in international multi-centre collaborations, which are utilized frequently in rare diseases such as systemic sclerosis (SSc). In order to pool or compare outcomes, instruments should be measurement equivalent (invariant) across cultural or linguistic groups. This study provides an example of how to assess cross-language measurement equivalence by comparing the Center for Epidemiologic Studies Depression (CES-D) scale between English-speaking Canadian and Dutch SSc patients.

METHODS

The CES-D was completed by 922 English-speaking Canadian and 213 Dutch SSc patients. Confirmatory factor analysis (CFA) was used to assess the factor structure in both samples. The Multiple-Indicator Multiple-Cause (MIMIC) model was utilized to assess the amount of differential item functioning (DIF).

RESULTS

A two-factor model (positive and negative affect) showed excellent fit in both samples. Statistically significant, but small-magnitude, DIF was found for 3 of 20 items on the CES-D. The English-speaking Canadian sample endorsed more feeling-related symptoms, whereas the Dutch sample endorsed more somatic/retarded activity symptoms. The overall estimate in depression scores between English and Dutch was not influenced substantively by DIF.

CONCLUSIONS

CES-D scores from English-speaking Canadian and Dutch SSc patients can be compared and pooled without concern that measurement differences may substantively influence results. The importance of assessing cross-language measurement equivalence in rheumatology studies prior to pooling outcomes obtained in different languages should be emphasized.

BACKGROUND

Aquagenic pruritus is characterized by pruritus after contact with water; there are no objective cutaneous changes. Capsaicin, which induces the release of neuropeptides from A delta and C cutaneous nerve fibers, has been successfully used in the treatment of several dermatoses associated with pruritus. Among the many different neuropeptides present in human skin, the undecapeptide substance P has been shown to cause pruritus.

OBJECTIVE

We evaluated the clinical effect and searched for alterations in cutaneous neuropeptidergic fibers before and after treatment with capsaicin cream.

METHODS

Five patients with aquagenic pruritus were treated with capsaicin cream 0.025%, 0.5% or 1.0% three times daily for 4 weeks. Direct immunofluorescence (DIF) was performed before and after treatment to evaluate the storage of neuropeptides in the A delta and C type cutaneous nerve fibers.

RESULTS

Before treatment (when by DIF the neuropeptidergic fibers appeared filled with neuropeptides), contact with water consistently provoked itching. After capsaicin treatment (when by DIF the neuropeptidergic fibers were depleted of neuropeptides), contact with water did not evoke pruritus. Areas of skin treated with the vehicle alone showed no clinical improvement or change in neuropeptide content.

CONCLUSIONS

This study suggests that neuropeptides, including substance P, may contribute to mediating the itch in aquagenic pruritus.

BACKGROUND

Exercise capacity as measured by peak oxygen uptake (Vo₂(peak)) is low in hemodialysis patients. The present study assesses determinants of VO₂(peak) in patients with chronic kidney failure who either changed kidney replacement modality to frequent hemodialysis therapy or received a kidney transplant.

METHODS

Cohort study with assessment at baseline and 6 months after modality change.

METHODS

Participants included nondiabetic individuals receiving conventional hemodialysis who: (1) remained on conventional hemodialysis therapy (n = 13), (2) changed to short daily hemodialysis therapy (n = 10), or (3) received a transplant (n = 5) and (4) individuals who underwent a pre-emptive transplant (n = 15). Additionally, 34 healthy controls were assessed at baseline only.

METHODS

Modality change.

METHODS

Exercise capacity, assessed using the physiologic components of the Fick equation (Vo₂ = cardiac output × a-vo₂(dif), where a-vo₂(dif) is arterial to venous oxygen difference) was determined using measurement of Vo₂(peak) and cardiac output during symptom-limited exercise testing. Analysis of covariance was used to compare differences in changes in Vo₂(peak), cardiac output, heart rate, stroke volume, and a-vo₂(dif) at peak exercise between participants who remained on hemodialysis therapy and those who underwent transplant.

RESULTS

Transplant was the only modality change associated with a significant change in Vo₂(peak), occurring as a result of increased peak cardiac output and reflecting increased heart rate without a change in peak a-vo₂(dif) despite increased hemoglobin levels. There were no differences in participants who changed to daily hemodialysis therapy compared with those who remained on conventional hemodialysis therapy.

CONCLUSIONS

Small nonrandomized study.

CONCLUSIONS

Vo₂(peak) increases significantly after kidney transplant, but not with daily hemodialysis; this improvement reflects increased peak cardiac output through increased peak heart rate. Despite statistical significance, the increase in Vo₂(peak) was not clinically significant, suggesting the need for interventions such as exercise training to increase Vo₂(peak) in all patients regardless of treatment modality.

BACKGROUND

To assess the psychometric properties of the Thai version of the 15-item Geriatric Depression Scale (TGDS-15) when screening for major depression (MDD) among geriatric outpatients (GOs) and long-term care (LTC) home residents in Thailand.

METHODS

This was a cross-sectional study of 156 geriatric outpatients and 81 LTC home residents. All 237 participants were given a Mini-Mental State Examination, a MDD diagnosis according to the Mini-International Neuropsychiatric Interview, and completed a TGDS-15 questionnaire. Sensitivity, specificity, overall accuracy, and positive and negative predictive values were calculated. A comparison between the two groups was carried out. Differential Item Functioning (DIF) using logistic regression and factor analytic study were also applied.

RESULTS

Overall, 38.4% of the participants were found to have MDD. The TGDS-15 was found to perform better when used with the GOs than with the LTC home residents, revealing a sensitivity of 0.92 and a specificity of 0.87 in the GOs (cut-off score of ≥ 5), but a sensitivity of 100% and a specificity of 49% with the LTC home group (cut-off score of ≥ 8), when comparing only cognitively intact subjects. The negative predictive value (NPV) was very good for both groups, but the positive predictive value (PPV) for the GO group was much better than for those in the LTC group (83.3% vs. 31.2%). Seven uniform DIF items were found - 2 by gender and 4 by age. Cronbach's alpha was higher for the GO group than for the LTC home residents. Factor analysis supported a two-factor solution, using the 'depressed mood' and 'positive mood' factors, which accounted for 46.55% of the total variance.

CONCLUSIONS

The TGDS-15 scale was effective at screening for MDD in elderly cognitively intact Thais, those in both GO and LTC settings, as the sensitivity and NPV were shown to be very good in both groups. However, in the LTC setting, the low specificity and PPV found leads to the need for a further assessment to be carried among the potentially depressed individuals, based on the GDS results. Taking the factor analytic study into account, a more suitable version of the GDS should be developed.

The tet39 tetracycline resistance determinant and the macrolide resistance genes msrE and mphE were found in an 18.2-kb plasmid, pS30-1, recovered from a global clone 2 (GC2) Acinetobacter baumannii isolate from Singapore, that conferred resistance to tetracycline and erythromycin. pS30-1 also contains mobA and mobC genes encoding MOBQ family proteins, but attempts to mobilize pS30-1 utilizing a coresident conjugative repAci6 plasmid were unsuccessful. Eight pdif sites, consisting of inversely oriented binding sites for the XerC and XerD recombinases separated by 6 bp, were detected in pS30-1. The tet39 determinant and the msrE-mphE gene pair are each surrounded by two pdif sites in inverse orientation. Identical regions in different contexts and many previously unnoticed pdif sites were found in a number of different plasmids in GenBank, showing that the tet39 and msrE-mphE dif modules are mobile. A putative toxin/antitoxin system, a gene encoding a serine recombinase, and open reading frames of unknown function were also part of dif modules in pS30-1. In general, modules with internal XerC or XerD sites alternate. Two copies of ISAjo2-1 (94% identical to ISAjo2) in pS30-1 were inserted 5 bp from a XerC site, and this appears to be the preferred insertion site for this insertion sequence (IS) group. Apparently, Acinetobacter plasmids exploit the Acinetobacter XerC-XerD recombinases to mobilize DNA units containing resistance and other genes, via an uncharacterized mechanism. The tet39 and msrE-mphE dif modules add to the oxa24 module and the oxa58 module redefined here, bringing the total of resistance gene-containing dif modules in Acinetobacter plasmids to four.

In Western European countries, the prevalence of depressive symptoms is higher among ethnic minority groups, compared to the host population. We explored whether these inequalities reflect variance in the way depressive symptoms are measured, by investigating whether items of the PHQ-9 measure the same underlying construct in six ethnic groups in the Netherlands.

A total of 23,182 men and women aged 18-70 of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish or Moroccan origin were included in the HELIUS study and had answered to at least one of the PHQ-9 items. We conducted multiple group confirmatory factor analyses (MGCFA), with increasingly stringent model constraints (i.e. assessing Configural, Metric, Strong and Strict measurement invariance (MI)), and regression analysis, to confirm comparability of PHQ-9 items across ethnic groups.

A one-factor model, where all nine items reflect a single underlying construct, showed acceptable model fit and was used for MI testing. In each subsequent step, change in goodness-of-fit measures did not exceed 0.015 (RMSEA) or 0.01 (CFI). Moreover, strict invariance models showed good or acceptable model fit (Men: RMSEA = 0.050; CFI = 0.985; Women: RMSEA = 0.058; CFI = 0.979), indicating between-group equality of item clusters, factor loadings, item thresholds and residual variances. Finally, regression analysis did not indicate potential ethnicity-related differential item functioning (DIF) of the PHQ-9.

This study provides evidence of measurement invariance of the PHQ-9 regarding ethnicity, implying that the observed inequalities in depressive symptoms cannot be attributed to DIF.