Aggressive management of dengue shock syndrome may decrease mortality rate: a suggested protocol.

OBJECTIVES: Dengue shock syndrome is a leading cause of mortality among Indian children. In January 2000, we instituted a protocol for aggressive management of children with dengue shock syndrome. The objective of this study was to compare outcomes (duration of ventilation, pediatric intensive care unit stay, incidence of acute respiratory distress syndrome, and intensive care unit and hospital mortality) before and after the protocol. DESIGN: Retrospective chart review. SETTING: Pediatric intensive care unit at a tertiary teaching hospital. PATIENTS: One hundred and fourteen patients admitted between July 1997 and December 1999 received standard therapy recommended by the World Health Organization (WHO) and were designated as the WHO guidelines group (W), whereas 96 patients admitted between January 2000 and December 2001 were treated by our protocol and designated as the protocol group (P). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The patients in each group were equally matched in terms of age, Pediatric Risk of Mortality, and number with dengue hemorrhage fever grade IV, although the platelet counts were higher in the W group compared with the P group (geometric mean 42.2, confidence interval 36.9, 48.4 vs. geometric mean 36.7, confidence interval 33.3, 40.5, p < .05). Patients in the W group received less fluids in the first hour compared with the P group (median and interquartile range 20 mL/kg, 15 and 20 vs. 30 mL/kg, 20 and 60). Fluid was actively removed less often in the W group than the P group (6 of 111 vs. 45 of 96, p < .05). There was no difference in the need for ventilation or incidence of acute respiratory distress syndrome between groups, although among dengue hemorrhage fever grade IV patients, the number requiring ventilation (17 of 30 vs. 20 of 23, p < .05) and the incidence of acute respiratory distress syndrome (9 of 30 vs. 17 of 23, p < .05) were significantly greater in the W group compared with the P group. The duration of ventilation (1.5 +/- 1.7 vs. 4.2 +/- 2.9 days, p < .05) and length of intensive care unit stay (3.0 +/- 2.8 vs. 3.4 +/- 2.9 days, p < .05) were significantly less in the W group. The pediatric intensive care unit mortality (16.6% vs. 6.3%, p < .05) was significantly higher in the W group than in the P group. CONCLUSIONS: Patients with dengue shock syndrome are at high risk of mortality due to refractory shock and multiple organ failure. Survival was better for patients in the P group. Aggressive shock management and possibly the use of judicious fluid removal may decrease mortality rates in the severest forms of dengue shock syndrome.     

Understanding the dose–response relationship of allopurinol: predicting the optimal dosage

Aims

The aim of the study was to identify and quantify factors that control the plasma concentrations of urate during allopurinol treatment and to predict optimal doses of allopurinol.

Methods

Plasma concentrations of urate and creatinine (112 samples, 46 patients) before and during treatment with various doses of allopurinol (50–600 mg daily) were monitored. Non-linear and multiple linear regression equations were used to examine the relationships between allopurinol dose (D), creatinine clearance (CL_cr) and plasma concentrations of urate before (U_P) and during treatment with allopurinol (U_T).

Results

Plasma concentrations of urate achieved during allopurinol therapy were dependent on the daily dose of allopurinol and the plasma concentration of urate pre-treatment. The non-linear equation: U_T = (1 – D/(ID₅₀ + D)) × (U_P – U_R) + U_R, fitted the data well (r² = 0.74, P < 0.0001). The parameters and their best fit values were: daily dose of allopurinol reducing the inhibitable plasma urate by 50% (ID₅₀ = 226 mg, 95% CI 167, 303 mg), apparent resistant plasma urate (U_R = 0.20 mmol l⁻¹, 95 % CI 0.14, 0.25 mmol l⁻¹). Incorporation of CL_cr did not significantly improve the fit (P = 0.09).

Conclusions

A high baseline plasma urate concentration requires a high dose of allopurinol to reduce plasma urate below recommended concentrations. This dose is dependent on only the pre-treatment plasma urate concentration and is not influenced by CL_cr.     

Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice

BACKGROUND AND PURPOSE

Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]_ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]_ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined.

EXPERIMENTAL APPROACH

This study examined the effects of escitalopram, on both [5-HT]_ext and [NA]_ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT^−/−) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]_ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]_ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]_ext and/or [NA]_ext affected the antidepressant-like activity of escitalopram.

KEY RESULTS

In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]_ext and [NA]_ext. As expected, escitalopram failed to increase cortical [5-HT]_ext in SERT^−/− mice, whereas its neurochemical effects on [NA]_ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters.

CONCLUSIONS AND IMPLICATIONS

These experiments suggest that escitalopram enhances, although moderately, cortical [NA]_extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET).     

Distal renal tubular acidosis with hereditary spherocytosis

Hereditary spherocytosis (HS) and distal renal tubular acidosis (dRTA), although distinct entities, share the same protein i.e. the anion exchanger1 (AE1) protein. Despite this, their coexistence has been rarely reported. We hereby describe the largest family to date with coexistence of dRTA and HS and discuss the molecular basis for the co-inheritance of these conditions.     

A predictive model for dysphagia following IMRT for head and neck cancer: Introduction of the EMLasso technique

Background and purpose

Design a model for prediction of acute dysphagia following intensity-modulated radiotherapy (IMRT) for head and neck cancer. Illustrate the use of the EMLasso technique for model selection.

Material and methods

Radiation-induced dysphagia was scored using CTCAE v.3.0 in 189 head and neck cancer patients. Clinical data (gender, age, nicotine and alcohol use, diabetes, tumor location), treatment parameters (chemotherapy, surgery involving the primary tumor, lymph node dissection, overall treatment time), dosimetric parameters (doses delivered to pharyngeal constrictor (PC) muscles and esophagus) and 19 genetic polymorphisms were used in model building. The predicting model was achieved by EMLasso, i.e. an EM algorithm to account for missing values, applied to penalized logistic regression, which allows for variable selection by tuning the penalization parameter through crossvalidation on AUC, thus avoiding overfitting.

Results

Fifty-three patients (28%) developed acute ? grade 3 dysphagia. The final model has an AUC of 0.71 and contains concurrent chemotherapy, D₂ to the superior PC and the rs3213245 (XRCC1) polymorphism. The model’s false negative rate and false positive rate in the optimal operation point on the ROC curve are 21% and 49%, respectively.

Conclusions

This study demonstrated the utility of the EMLasso technique for model selection in predictive radiogenetics.     

Hinge/floating craniotomy as an alternative technique for cerebral decompression: a scoping review

Neurosurgical Review - Hinge craniotomy (HC) is a technique that allows for a degree of decompression whilst retaining the bone flap in situ, in a ‘floating’ or ‘hinged’...     

Estrogenic Modulation of Uropathogenic Escherichia coli Infection Pathogenesis in a Murine Menopause Model

Recurrent urinary tract infections (UTIs), primarily caused by uropathogenic Escherichia coli (UPEC), annually affect over 13 million patients in the United States. Menopausal women are disproportionally susceptible, suggesting estrogen deficiency is a significant risk factor for chronic and recurrent UTI. How estrogen status governs susceptibility to UTIs remains unknown, and whether hormone therapy protects against UTIs remains controversial. Here, we used a mouse model of surgical menopause by ovariectomy and demonstrate a protective role for estrogen in UTI pathogenesis. We found that ovariectomized mice had significantly higher bacteriuria, a more robust inflammatory response, and increased production of the proinflammatory cytokine interleukin-6 (IL-6) upon UPEC infection compared to sham-operated controls. We further show that response of the urothelial stem cell niche to infection, normally activated to restore homeostasis after infection, was aberrant in ovariectomized mice with defective superficial urothelial cell differentiation. Finally, UPEC-infected ovariectomized mice showed a significant increase in quiescent intracellular bacterial reservoirs, which reside in the urothelium and can seed recurrent infections. Importantly, this and other ovariectomy-induced outcomes of UTI were reversible upon estrogen supplementation. Together, our findings establish ovariectomized mice as a model for UTIs in menopausal women and pinpoint specific events during course of infection that are most susceptible to estrogen deficiency. These findings have profound implications for the understanding of the role of estrogen and estrogen therapy in bladder health and pathogen defense mechanisms and open the door for prophylaxis for menopausal women with recurrent UTIs.     

B7h (ICOS-L) Maintains Tolerance at the Fetomaternal Interface

In a successful pregnancy, the semiallogeneic fetus is not rejected by the maternal immune system, which implies tolerance mechanisms protecting fetal tissues from maternal immune attack. Here we report that the ICOS-B7h costimulatory pathway plays a critical role in maintaining the equilibrium at the fetomaternal interface. Blockade of this pathway increased fetal resorption and decreased fetal survival in an allogeneic pregnancy model (CBA female × B6 male). Locally in the placenta, levels of regulatory markers such as IDO and TGF-β1 were reduced after anti-B7h monoclonal antibody treatment, whereas levels of effector cytokines (eg, IFN-γ) were significantly increased. In secondary lymphoid organs, enhanced IFN-γ and granzyme B production (predominantly by CD8⁺ T cells) was observed in the anti-B7h–treated group. The deleterious effect of B7h blockade in pregnancy was maintained only in CD4 knockout mice, not in CD8 knockout mice, which suggests a role for CD8⁺ T cells in immune regulation by the ICOS-B7h pathway. In accord, regulatory CD8⁺ T cells (in particular, CD8⁺CD103⁺ cells) were significantly decreased after anti-B7h monoclonal antibody treatment, and adoptive transfer of this subset abrogated the deleterious effect of B7h blockade in fetomaternal tolerance. Taken together, these data support the hypothesis that B7h blockade abrogates tolerance at the fetomaternal interface by enhancing CD8⁺ effector response and reducing local immunomodulation mediated by CD8⁺ regulatory T cells.More than 50 years ago, Medawar and colleagues¹ proposed that immunological tolerance should be present during pregnancy, to protect the fetus against an aggressive maternal alloimmune response directed at the paternal antigens expressed by the fetus. Since that initial hypothesis, several mechanisms have been proposed to function actively in the protection of the fetus from the maternal immune system.² Among them, the presence of regulatory T cells^3–7 and the expression of immune regulatory molecules in the fetal–maternal interface have been identified as crucial factors for fetomaternal tolerance.^8–12T cells play a major role in coordinating immune response. Although T-cell activation depends on the initial antigen-specific signal provided to T-cell receptors via the antigen-loaded major histocompatibility complex, additional signals provided by costimulatory molecules fine-tune this response, determining its strength, nature, and duration. Some costimulatory pathways activate effector T cells, but others inhibit T-cell activation and/or promote regulatory T cells. One of these inhibitory molecules is PD-L1, the expression of which is prevalent at the uteroplacental interface.¹¹ Moreover, placental PD-L1 has been shown to protect murine allogeneic conceptus from maternal T-cell–mediated attack.^11,13 Treatment of pregnant CBA mice with a blocking anti–PD-L1 monoclonal antibody (mAb) resulted in loss of allogeneic but not syngeneic conceptus. Similarly, PD-L1–deficient mice had a substantial increase in the rate of spontaneous fetal resorption and a decrease in fetal survival.¹¹ PD-L1 protective effect on fetomaternal tolerance was dependent on CD4+ regulatory T cells.¹⁴Inducible costimulatory molecule (ICOS) and its ligand (B7h; alias B7-H2, ICOS-L) are also considered important costimulatory molecules that influence T-cell activation and differentiation.¹⁵ In particular, ICOS–B7h interactions have been shown to promote regulation in a diabetes autoimmune model and to protect against atherosclerosis in a LDL receptor-deficient mice.^16,17 Whether ICOS-B7h is important for fetomaternal tolerance remains to be determined. In the present study, we investigated the role of the ICOS-B7h pathway in modulating the effector/regulatory balance at the fetomaternal interface and its role in preventing immune attack to the fetus.     

Acute kidney injury in scrub typhus

Background

We studied the urinary abnormalities and acute kidney injury (AKI) as per RIFLE criteria in scrub typhus.

Methods

A prospective case record-based study of scrub typhus was carried out from January 2009 to December 2010 in a tertiary hospital in South India. Patients were followed up until renal recovery or for at least 3 months after discharge. Univariate, chi-squared tests and multivariate logistic regression analyses were performed to identify the predictors of AKI.

Results

Scrub typhus was diagnosed in 259 patients. Urinary abnormalities were seen in 147 patients (56.7 %) with 60 patients (23.2 %) having AKI. All AKI patients had urinary abnormalities and 17 (28.3 %) were oliguric. Applying RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria, R, I, F were present in 23 (38.33 %), 13 (21.67 %), and 24 patients (40 %), respectively. Creatine phosphokinase (CPK) was raised in 33 patients (55 %) and hemodialysis was required in 6 patients (10 %). The case fatality rate in this study was 2 out of 259 (0.77 %), both having AKI and others recovering clinically. Significant predictors of AKI were tachycardia [odds ratio (OR) 2.28], breathlessness (OR 2.281), intensive care requirement (OR 2.43), mechanical ventilation (OR 3.33), thrombocytopenia (OR 2.90) and CPK >80 U/L (OR 1.76) by univariate analysis and intensive care requirement (adjusted OR 2.89) and thrombocytopenia (AOR 2.28) by multivariable logistic regression.

Conclusion

Scrub typhus should be part of the differential diagnosis of acute febrile illness with AKI. AKI in scrub typhus is usually mild, non-oliguric, and renal recovery occurs in most patients. Rhabdomyolysis may be contributory to AKI. Thrombocytopenia and intensive care requirement are significant predictors of AKI in scrub typhus.