Comparative activity of the new lipoglycopeptide telavancin in the presence and absence of serum against 50 glycopeptide non-susceptible staphylococci and three vancomycin-resistant Staphylococcus aureus

BACKGROUND: Telavancin, a new multifunctional lipoglycopeptide antibiotic, exhibits broad-spectrum Gram-positive activity against a variety of pathogens. We examined the effects of human serum and antimicrobial concentrations on the activity of telavancin against glycopeptide-intermediate staphylococcal species (GISS), heteroresistant GISS (hGISS) and three vancomycin-resistant Staphylococcus aureus (VRSA) compared with vancomycin, quinupristin/dalfopristin, linezolid and daptomycin. METHODS: MIC and MBCs were performed against all antimicrobials. Time-kill experiments were performed using two strains of GISS (Mu50; NJ992) and VRSA (VRSAMI; VRSAPA) at 1, 2, 4, 8, 16 and 32x MIC. Telavancin and daptomycin were evaluated in the presence and absence of serum. RESULTS: All GISS and hGISS were susceptible to the tested agents with telavancin and quinupristin/dalfopristin demonstrating the lowest MIC, followed by daptomycin, linezolid and vancomycin. Against VRSA, daptomycin and quinupristin/dalfopristin had the lowest MIC, followed by linezolid, telavancin and vancomycin. In the presence of serum, telavancin and daptomycin MICs increased 1- to 4-fold. Concentration-dependent activity was demonstrated by telavancin and daptomycin, in the presence and absence of serum. Telavancin and daptomycin were bactericidal against GISS and performed similarly in the presence of serum. Quinupristin/dalfopristin demonstrated bactericidal activity at clinically achievable concentrations, whereas linezolid was bacteriostatic. CONCLUSIONS: Telavancin demonstrated concentration-dependent bactericidal activity against GISS, hGISS and VRSA at concentrations equal to or above 4x MIC, which corresponds to therapeutic levels against GISS and clinically achieved concentrations against the VRSA. Similar to daptomycin, telavancin activity was diminished in the presence of serum but bactericidal activity was maintained. Further investigation with telavancin against GISS, hGISS and VRSA is warranted.     

Stroke survivors' behavioral and psychologic symptoms are associated with informal caregivers' experiences of depression

OBJECTIVE: To determine the impact of stroke survivors' behavioral and psychologic symptoms (BPS) on informal caregivers' experience of depression in the context of the caregiving situation. DESIGN: Cross-sectional survey using a structured quantitative interview. SETTING: Rehabilitation facility outpatient clinic, tertiary care facility outpatient clinic, and community care organizations. PARTICIPANTS: Ninety-four informal caregivers to stroke survivors completed standardized measurement instruments. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Measurement instruments included the Center for Epidemiological Studies Depression Scale, Brain Impairment Behavior Inventory-Revised, Caregiver Assistance Scale, Caregiving Impact Scale, and Mastery scale. RESULTS: A substantial percentage (44.7%) of caregivers were at risk of clinical depression. Caregivers experienced more depression symptoms when they cared for stroke survivors exhibiting more BPS of memory and comprehension difficulties, provided less assistance, experienced more lifestyle interference, and had lower mastery (F(5,85)=26.02, P<.001, adjusted R(2)=.58). CONCLUSIONS: BPS exhibited by stroke survivors contribute to informal caregivers' experience of depression. These results can assist rehabilitation professionals to identify informal care providers who are at greater risk of experiencing emotional distress and, therefore, may benefit from intervention.     

Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis

Reductions in circulating estradiol concentrations could be implicated in the pathogenesis of steroid-induced osteoporosis (SIOP) in men. We assessed serum estradiol and adrenal androgens (dehydroepiandrosterone sulfate [DHEAS] and androstenedione) in 77 men (group A: idiopathic osteoporosis [IOP], n = 38, aged [mean +/- SD] 57.7 +/- 12.1 years; group B: SIOP, n = 39, aged 55.3 +/- 13.1 years). We also studied the relationship between bone mineral density (BMD) and serum estradiol in the group of men with SIOP. In group B, we observed a higher prevalence of low serum testosterone concentrations (<9.0 nmol/L) (P =.0052), which was significantly correlated with steroid dosage (r = -0.42, P =.0089) and estradiol concentrations (r = 0.42, P =.012). There was a significant positive association between BMD at the lumbar spine and serum estradiol (P =.004) in the men with SIOP (group B). A high proportion of subjects had low serum estradiol concentrations (<48 pmol/L) in both groups (group A: 44.7 %, group B: 36 %). Serum adrenal androgens concentrations were also significantly suppressed in group B (serum androstenedione-group A: 4.99 +/- 1.8; Group B: 2.1 +/- 1.6 nmol/L; P =.0001). Serum DHEAS was undetectable in 59% of patients in group B versus 6% in group A (P =.001). Reductions in androstenedione also correlated with steroid dosage (r = -0.35, P =.01). In conclusion, the data show that adrenal androgens synthesis is markedly suppressed in men with SIOP. The clinical relevance of this finding remains to be determined. This study also shows a positive association between serum estradiol and BMD and a high prevalence of low serum estradiol in men with SIOP. Low serum estradiol may contribute to bone loss in men with SIOP.     

Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized,double-blind,placebo-controlled,dose-escalation trial

OBJECTIVE: To investigate the safety and efficacy of MRA, a recombinant human anti-interleukin-6 (anti-IL-6) receptor monoclonal antibody of the IgG1 subclass that inhibits the function of IL-6, in patients with established rheumatoid arthritis (RA). METHODS: A randomized, double-blind, placebo-controlled, dose-escalation trial was conducted in 45 patients with active RA, as defined by the American College of Rheumatology (ACR) revised criteria. Patients were sequentially allocated to receive a single intravenous dose of either 0.1, 1, 5, or 10 mg/kg of MRA or placebo. The primary efficacy end point was meeting the ACR 20% response criteria at week 2 after treatment. RESULTS: Demographic features were similar between treatment groups. At week 2, a significant treatment difference was observed between the 5 mg/kg of MRA and placebo, with 5 patients (55.6%) in the MRA cohort and none in the placebo cohort achieving ACR 20% improvement. There was no statistically significant difference in the ACR 20% response between the other 3 MRA cohorts and placebo at week 2. The mean disease activity score at week 2 in those who received 5 mg/kg and 10 mg/kg of MRA was 4.8 and 4.7 (P < 0.001 and P < 0.001 by analysis of variance), respectively. These mean scores were statistically significantly lower than those in the 0.1- and 1-mg/kg MRA and the placebo cohorts (6.4, 6.2, and 7.0, respectively). The erythrocyte sedimentation rate and C-reactive protein values fell significantly in the 5- and 10-mg/kg MRA cohorts and normalized 2 weeks after treatment. Seventeen patients (5, 4, 6, 2, and 0 patients in the placebo, 0.1-, 1-, 5-, and 10-mg/kg MRA cohorts, respectively) required corticosteroid or disease-modifying antirheumatic drug treatment because of active disease before study end. They were regarded as nonresponders from the time they received these treatments. Diarrhea was the most common adverse event, occurring in 8% of patients. Seven patients (15.6%) reported a severe adverse event (3, 1, 2, and 2 patients in the placebo, 0.1-, 1-, and 10-mg/kg MRA cohorts). There were no serious adverse events that were thought to be related to the study drug. CONCLUSION: This is the first randomized controlled trial showing that inhibition of IL-6 significantly improved the signs and symptoms of RA and normalized the acute-phase reactants. Further research with multiple dosing is necessary to define the most appropriate therapeutic regimen of MRA in RA.     

Spontaneous rupture of the short gastric artery after vomiting

Spontaneous rupture of the short gastric artery is an extremely rare event that can cause abdominal apoplexy or spontaneous hemoperitoneum. For the emergency physician, simultaneous restoration of circulatory volume and a rapid diagnosis remain central to a successful outcome in such critical cases. We reported a 21-year-old man who initially presented with watery diarrhea and abdominal fullness followed by vomiting after the ingestion of alcohol but was later diagnosed with hemoperitoneum, resulting in hemorrhagic shock due to spontaneous rupture of the small branches of the short gastric artery. The patient underwent emergency exploratory laparotomy with a good outcome. Abdominal apoplexy should be considered in the differential diagnosis of unexplained hemorrhagic shock with an abrupt onset of severe abdominal pain associated with vomiting.     

What is the relationship between the Glasgow coma scale and airway protective reflexes in the Chinese population?

Aim

To describe the relationship of gag and cough reflexes to Glasgow coma score (GCS) in Chinese adults requiring critical care.

Method

Prospective observational study of adult patients requiring treatment in the trauma or resuscitation rooms of the Emergency Department, Prince of Wales Hospital, Hong Kong. A long cotton bud to stimulate the posterior pharyngeal wall (gag reflex) and a soft tracheal suction catheter were introduced through the mouth to stimulate the laryngopharynx and elicit the cough reflex. Reflexes were classified as normal, attenuated or absent.

Results

A total of 208 patients were recruited. Reduced gag and cough reflexes were found to be significantly related to reduced GCS (p = 0.014 and 0.002, respectively). Of 33 patients with a GCS ≤ 8, 12 (36.4%) had normal gag reflexes and 8 (24.2%) had normal cough reflexes. 23/62 (37.1%) patients with a GCS of 9-14 had absent gag reflexes, and 27 (43.5%) had absent cough reflexes. In patients with a normal GCS, 22.1% (25/113) had absent gag reflexes and 25.7% (29) had absent cough reflexes.

Conclusions

Our study has shown that in a Chinese population with a wide range of critical illness (but little trauma or intoxication), reduced GCS is significantly related to gag and cough reflexes. However, a considerable proportion of patients with a GCS ≤ 8 have intact airway reflexes and may be capable of maintaining their own airway, whilst many patients with a GCS > 8 have impaired airway reflexes and may be at risk of aspiration. This has important implications for airway management decisions.     

Mother to child transmission of diabetes mellitus: does gestational diabetes program Type 2 diabetes in the next generation?

AIM: Type 2 diabetes is frequently familial. Hyperglycaemia in pregnancy might act in addition to genetic factors to cause diabetes in the children of mothers with gestational diabetes mellitus (GDM). The first manifestation of this in female offspring is likely to be GDM in their own pregnancies. We compared the incidence of GDM in daughters of diabetic mothers and diabetic fathers to determine if in utero exposure to hyperglycaemia increased the risk of a diabetes-prone phenotype in offspring. METHODS: We analysed the outcome of a GDM screening programme in women with a family history of diabetes in their mother (n = 535), father (n = 566), both parents (n = 77) or neither (n = 4672). RESULTS: GDM was twice as common in the daughters of diabetic mothers (11%) than diabetic fathers (5%, P = 0.002). Women with two diabetic parents were no more likely to have GDM than women with only a diabetic mother. CONCLUSIONS: Genetic predisposition to GDM should be equally shared by daughters of diabetic mothers and fathers. An excess of maternal transmission of diabetes is consistent with an epigenetic effect of hyperglycaemia in pregnancy acting in addition to genetic factors to produce diabetes in the next generation.     

Ethnicity and risk factors in needle sharing among intravenous drug users in Sichuan Province, China

Combining survey and ethnographic data, this research examined differences in the risk factors associated with needle sharing amongst intravenous drug users (IDUs) in the Sichuan Province of China. A comparison was made between the province's majority Han population and its Yi minority. We developed a theoretical framework consisting of risk factors at the individual level (including risk factors such as lack of AIDS knowledge, low self-efficacy, and economic pressure), interpersonal level (having an IDU primary partner and lack of family support), and community level (social discrimination). The findings suggested that the Yi minority group was more socially disadvantaged and had a higher risk of contracting HIV than the Han group. Furthermore, the factors that put them at risk were different to those which affected the Han group. OLS regression results showed that, for Han IDUs, needle sharing was positively associated with having an IDU primary partner and with economic pressure. On the other hand, for the minority group, needle sharing was significantly associated with being male, AIDS knowledge, the lack of family support, and social discrimination. These findings highlight the need for HIV prevention work to target marginalized populations in China, such as ethnic minorities, and to tailor appropriate prevention strategies to meet the specific needs of different groups.     

Cross-talk between Chk1 and Chk2 in double-mutant thymocytes

Chk1 is a checkpoint kinase and an important regulator of mammalian cell division. Because null mutation of Chk1 in mice is embryonic lethal, we used the Cre-loxP system and the Lck promoter to generate conditional mutant mice in which Chk1 was deleted only in the T lineage. In the absence of Chk1, the transition of CD4(-)CD8(-) double-negative (DN) thymocytes to CD4(+)CD8(+) double-positive (DP) cells was blocked due to an increase in apoptosis at the DN2 and DN3 stages. Strikingly, loss of Chk1 activated the checkpoint kinase Chk2 as well as the tumor suppressor p53 in these thymocytes. However, the developmental defects caused by Chk1 deletion were not rescued by p53 inactivation. Significantly, even though Chk1 deletion is highly lethal in proliferating tissues, we succeeded in using in vivo methods to generate Chk1/Chk2 double-knockout T cells. Analysis of these T cells revealed an interesting interaction between Chk1 and Chk2 functions that partially rescued the apoptosis of the double-mutant cells. Thus, Chk1 is both critical for the survival of proliferating cells and engages in cross-talk with the Chk2 checkpoint kinase pathway. These factors have implications for the targeting of Chk1 as an anticancer therapy.