Influence of oxygen therapy on glucose-lactate metabolism after diffuse brain injury

OBJECT: Severe traumatic brain injury (TBI) imposes a huge metabolic load on brain tissue, which can be summarized initially as a state of hypermetabolism and hyperglycolysis. In experiments O2 consumption has been shown to increase early after trauma, especially in the presence of high lactate levels and forced O2 availability. In recent clinical studies the effect of increasing O2 availability on brain metabolism has been analyzed. By their nature, however, clinical trauma models suffer from a heterogeneous injury distribution. The aim of this study was to analyze, in a standardized diffuse brain injury model, the effect of increasing the fraction of inspired O2 on brain glucose and lactate levels, and to compare this effect with the metabolism of the noninjured sham-operated brain. METHODS: A diffuse severe TBI model developed by Foda and Maramarou, et al., in which a 420-g weight is dropped from a height of 2 m was used in this study. Forty-one male Wistar rats each weighing approximately 300 g were included. Anesthesized rats were monitored by placing a femoral arterial line for blood pressure and blood was drawn for a blood gas analysis. Two time periods were defined: Period A was defined as preinjury and Period B as postinjury. During Period B two levels of fraction of inspired oxygen (FiO2) were studied: air (FiO2 0.21) and oxygen (FiO2 1). Four groups were studied including sham-operated animals: air-air-sham (AAS); air-O2-sham (AOS); air-air-trauma (AAT); and air-O2-trauma (AOT). In six rats the effect of increasing the FiO2 on serum glucose and lactate was analyzed. During Period B lactate values in the brain determined using microdialysis were significantly lower (p < 0.05) in the AOT group than in the AAT group and glucose values in the brain determined using microdialysis were significantly higher (p < 0.04). No differences were demonstrated in the other groups. Increasing the FiO2 had no significant effect on the serum levels of glucose and lactate. CONCLUSIONS: Increasing the FiO2 influences dialysate glucose and lactate levels in injured brain tissue. Using an FiO2 of 1 influences brain metabolism in such a way that lactate is significantly reduced and glucose significantly increased. No changes in dialysate glucose and lactate values were found in the noninjured brain.

Progress on BIG 1-02/IBCSG 27-02/NSABP B-37, a prospective randomized trial evaluating chemotherapy after local therapy for isolated locoregional recurrences of breast cancer

BACKGROUND: The utility of chemotherapy for women who experience a locoregional recurrence after primary treatment of early breast cancer remains an open question. An international collaborative trial is being conducted by the Breast International Group (BIG), the International Breast Cancer Study Group (IBCSG), and the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine the effectiveness of cytotoxic therapy for these patients, either alone or in addition to selective use of hormonal therapy and trastuzumab. METHODS: The trial population includes women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery, but subsequently develop an isolated local and/or regional ipsilateral invasive recurrence. Excision of all macroscopic tumor without evidence of systemic disease is required for study entry. Patients are randomized to receive chemotherapy or no chemotherapy; type of chemotherapy is not protocol-specified. Radiation, hormonal therapy, and trastuzumab are given as appropriate. The primary endpoint is disease-free survival (DFS). Quality-of-life measurements are collected at baseline, and then at 9 and 12 months. The accrual goal is 977 patients. RESULTS: This report describes the characteristics of the first 99 patients. Sites of recurrence at study entry were: breast (56%), mastectomy scar/chest wall (35%), and regional lymph nodes (9%). Two-thirds of patients have estrogen-receptor-positive recurrences. CONCLUSION: This is the only trial actively investigating the question of "adjuvant" chemotherapy in locally recurrent breast cancer. The case mix of accrual to date indicates a broad representation of this patient population.

Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

Dual induction of PKR with E2F-1 and IFN-alpha to enhance gene therapy against hepatocellular carcinoma

Overexpression of the transcription factor E2F-1 induces apoptosis in tumor cells. This apoptotic effect is partly mediated through the induction of the double-stranded RNA-activated protein kinase (PKR). Here, we investigate if agents that upregulate PKR could enhance the apoptotic effect of E2F-1 overexpression in liver tumors. In human hepatocellular carcinoma (HCC) cells (Hep3B, HepG2, Huh7), adenovirus-mediated overexpression of E2F-1 (AdCMV-E2F) transcriptionally increased PKR mRNA. The subsequent increase of total and phosphorylated PKR protein was followed by induction of apoptosis. When AdCMV-E2F was combined with the PKR modifier interferon alpha (IFNalpha), PKR was additionally upregulated and both PKR activation and apoptosis were increased. Subcutaneous xenograft tumors were selectively targeted using an adenoviral vector expressing E2F-1 under the control of the human telomerase reverse transcriptase (hTERT) promoter (AdhTERT-E2F). Weekly systemic administration of AdhTERT-E2F inhibited tumor growth. The tumor suppressive effect of AdhTERT-E2F therapy was further enhanced in combination with IFNalpha.Our results demonstrate that PKR activating agents enhance the anti-tumor effect of E2F-1 overexpression in HCC in-vitro and in-vivo. Hence, modulation of PKR is a potential strategy to increase the efficacy of PKR-dependent anti-tumor therapies.

Crystalloids versus colloids for goal-directed fluid therapy in major surgery

INTRODUCTION: Perioperative hypovolemia arises frequently and contributes to intestinal hypoperfusion and subsequent postoperative complications. Goal-directed fluid therapy might reduce these complications. The aim of this study was to compare the effects of goal-directed administration of crystalloids and colloids on the distribution of systemic, hepatosplanchnic, and microcirculatory (small intestine) blood flow after major abdominal surgery in a clinically relevant pig model. METHODS: Twenty-seven pigs were anesthetized and mechanically ventilated and underwent open laparotomy. They were randomly assigned to one of three treatment groups: the restricted Ringer lactate (R-RL) group (n = 9) received 3 mL/kg per hour of RL, the goal-directed RL (GD-RL) group (n = 9) received 3 mL/kg per hour of RL and intermittent boluses of 250 mL of RL, and the goal-directed colloid (GD-C) group (n = 9) received 3 mL/kg per hour of RL and boluses of 250 mL of 6% hydroxyethyl starch (130/0.4). The latter two groups received a bolus infusion when mixed venous oxygen saturation was below 60% ('lockout' time of 30 minutes). Regional blood flow was measured in the superior mesenteric artery and the celiac trunk. In the small bowel, microcirculatory blood flow was measured using laser Doppler flowmetry. Intestinal tissue oxygen tension was measured with intramural Clark-type electrodes. RESULTS: After 4 hours of treatment, arterial blood pressure, cardiac output, mesenteric artery flow, and mixed oxygen saturation were significantly higher in the GD-C and GD-RL groups than in the R-RL group. Microcirculatory flow in the intestinal mucosa increased by 50% in the GD-C group but remained unchanged in the other two groups. Likewise, tissue oxygen tension in the intestine increased by 30% in the GD-C group but remained unchanged in the GD-RL group and decreased by 18% in the R-RL group. Mesenteric venous glucose concentrations were higher and lactate levels were lower in the GD-C group compared with the two crystalloid groups. CONCLUSIONS: Goal-directed colloid administration markedly increased microcirculatory blood flow in the small intestine and intestinal tissue oxygen tension after abdominal surgery. In contrast, goal-directed crystalloid and restricted crystalloid administrations had no such effects. Additionally, mesenteric venous glucose and lactate concentrations suggest that intestinal cellular substrate levels were higher in the colloid-treated than in the crystalloid-treated animals. These results support the notion that perioperative goal-directed therapy with colloids might be beneficial during major abdominal surgery.

[Study protocol of the VISEP study. Response of the SepNet study group]

In the commentary by Zander et al. the authors appear concerned about the methods and results of our, at that time, unpublished sepsis trial evaluating hydroxyethyl starch (HES) and insulin therapy. Unfortunately, the authors' concerns are based on false assumptions about the design, conduct and modes of action of the compounds under investigation. For instance, in our study the HES solution was not used for maintenance of daily fluid requirements, so that the assumption of the authors that this colloid was used "exclusively" is wrong. Moreover, the manufacturer of Hemohes, the HES product we used, gives no cut-off value for creatinine, thus the assumption that this cut-off value was "doubled" in our study is also incorrect. Other claims by the authors such as that lactated solutions cause elevated lactate levels, iatrogenic hyperglycemia and increase O(2) consumption are unfounded. There is no randomized controlled trial supporting such a claim - this claim is neither consistent with our study data nor with any credible published sepsis guidelines or with routine practice worldwide. We fully support open scientific debate. Our study methods and results have now been published after a strict peer-reviewing process and this data is now open to critical and constructive reviewing. However, in our opinion this premature action based on wrong assumptions and containing comments by representatives of pharmaceutical companies does not contribute to a serious, unbiased scientific discourse.

A randomised controlled trial of spinal manipulative therapy in acute low back pain

OBJECTIVE: To determine whether treatment with spinal manipulative therapy (SMT) administered in addition to standard care is associated with clinically relevant early reductions in pain and analgesic consumption. METHODS: 104 patients with acute low back pain were randomly assigned to SMT in addition to standard care (n = 52) or standard care alone (n = 52). Standard care consisted of general advice and paracetamol, diclofenac or dihydrocodeine as required. Other analgesic drugs or non-pharmacological treatments were not allowed. Primary outcomes were pain intensity assessed on the 11-point box scale (BS-11) and analgesic use based on diclofenac equivalence doses during days 1-14. An extended follow-up was performed at 6 months. RESULTS: Pain reductions were similar in experimental and control groups, with the lower limit of the 95% CI excluding a relevant benefit of SMT (difference 0.5 on the BS-11, 95% CI -0.2 to 1.2, p = 0.13). Analgesic consumptions were also similar (difference -18 mg diclofenac equivalents, 95% CI -43 mg to 7 mg, p = 0.17), with small initial differences diminishing over time. There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups. The extended follow-up showed similar patterns. CONCLUSIONS: SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain.

[Perianal erythema in a child--group A streptococci?!]

Perianal streptococcal dermatitis is a common disease. The typical clinical picture includes perianal erythema, pruritus, painful defaecation and bloody stools. The diagnosis is made by a swab taken from the affected skin with bacterial culture. Therapy consists of penicillin for 10 days. Screening for affected persons in contact with the patient is indicated because perianal streptococcal dermatitis is known to be highly contagious. Relapse is common and therefore follow-up visits are recommended. In case of relapse, a first or second generation cephalosporin may be considered.

Gene therapy with adenovirus-mediated VEGF enhances skin flap prefabrication

We investigated the feasibility in rats of enhancing skin-flap prefabrication with subdermal injections of adenovirus-encoding vascular endothelial growth factor (Ad-VEGF). The left saphenous vascular pedicle was used as a source for vascular induction. A peninsular abdominal flap (8 x 8 cm) was elevated as distally based, keeping the epigastric vessels intact on both sides. After the vascular pedicle was tacked underneath the abdominal flap, 34 rats were randomly divided into three groups according to treatment protocol. The implantation site around the pedicle was injected with Ad-VEGF in group I (n = 10), with adenovirus-encoding green fluorescent protein (Ad-GFP) in control group I (n = 14), and with saline in control group II (n = 10). All injections were given subdermally at four points around the implanted vessel by an individual blinded to the treatment protocol. The peninsular flap was sutured in its place, and 4 weeks later, an abdominal island flap based solely on the implanted vessels was elevated. The prefabricated island flap was sutured back, and flap viability was evaluated on day 7. Skin specimens were stained with hematoxylin and eosin for histological evaluation. In two rats from each group, microangiography was performed to visualize the vascularity of the prefabricated flaps. There was a significant increase in survival of prefabricated flaps in the Ad-VEGF group compared to the control groups: Ad-VEGF, 88.9 +/- 6.1% vs. Ad-GFP, 65.6 +/- 9.4% (P < 0.05) and saline, 56.0 +/- 3.4% (P < 0.05). Sections from four prefabricated flaps treated with Ad-GFP revealed multiple sites of shiny deposits of green fluorescent protein around the area of local administration 1 day and 3 weeks after gene therapy. Histological examination done under high-power magnification (x400) with a light microscope revealed increased vascularity and mild inflammation surrounding the implanted vessel in all groups. However, we were unable to demonstrate any significant quantitative difference with respect to vascularity and inflammatory infiltrates in prefabricated flaps treated with Ad-VEGF compared with controls. Microangiographic studies showed increased vascularity around the implanted pedicle, which was similar in all groups. However, vascularization was distributed in a larger area in the prefabricated flaps treated with Ad-VEGF. In this study, the authors demonstrated that adenovirus-mediated VEGF gene therapy increased the survival of prefabricated flaps, suggesting that it may allow prefabrication of larger flaps and have the potential to reduce the time required for flap maturation.

Comparison of oral antiviral therapy with valacyclovir or acyclovir after penetrating keratoplasty for herpetic keratitis

AIMS: To compare the outcome of prophylactic oral valacyclovir (VAL) or oral acyclovir treatment (ACV) in patients having undergone penetrating keratoplasty for herpetic keratitis (HK). METHODS: All patients having received a penetrating keratoplasty for HK and being treated postoperatively with either oral VAL or oral ACV (inclusion period from 12/97 to 3/06 and 5/92 to 9/96, respectively) were retrospectively evaluated. Records were analysed for postoperative reactivation of recurrent HK, graft rejection, endothelial cell loss, central corneal thickness and visual acuity after a follow-up of up to 5 years. RESULTS: Twenty patients received VAL and were compared with 19 patients being treated with ACV. Two patients developed clinical signs of recurrent herpetic disease in the VAL group compared with three patients in the ACV group. Two patients from both groups each developed an irreversible graft failure. Best corrected visual acuity improved in both treatment groups from baseline (logMAR) -1.97 (VAL), -1.47 (ACV) to -0.85, -0.72, respectively, at the 1-year follow-up and slightly deteriorated after 5 years in the ACV group (-0.71 VAL vs -1.14 ACV). CONCLUSION: Prophylactic oral VAL treatment is at least as effective as ACV in preventing recurrence in patients who underwent corneal transplantation for HK. The tolerability of the two drugs is similar, but the dosing for VAL might be more comfortable for patients.

Verteporfin therapy in occult with no classic CNV due to AMD: results of the Photodynamic Therapy in Occult-Only Lesions study

PURPOSE: To provide further information on verteporfin photodynamic therapy in occult with no classic choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). METHODS: Verteporfin therapy was administered at baseline and then at months 3, 6, and 9, if fluorescein leakage from CNV was evident on angiography. RESULTS: Of 202 patients enrolled, 184 completed 12 months. Each patient was treated in one eye only. All study eyes received verteporfin therapy at baseline, with a progressive decrease in the number treated at subsequent visits (mean 2.5 treatments during 12 months). The mean change in visual acuity letter score from baseline to month 12 was -11.9. At month 12, 164 eyes (82.4%) had lost <30 letters of visual acuity, 123 eyes (61.8%) had lost <15 letters, 78 eyes (39.2%) had lost <5 letters, 31 (15.6%) had >5-letter increase, and 7 (3.5%) had >15-letter improvement. The percentage of eyes with fluorescein leakage from CNV decreased from 75.5% at month 3 to 25.1% at month 12. Adverse events were documented for 54% patients. Few patients had treatment-associated adverse events (7%). Acute severe visual acuity decrease occurred in two eyes (1%), one of which had visual acuity that returned to baseline by the next follow-up visit. CONCLUSIONS: This study provides additional evidence that over 12 months, verteporfin is generally well tolerated and maintains or improves visual acuity in over one-third of eyes containing occult-only CNV. Verteporfin also improved anatomical outcomes by reducing leakage from CNV in at least two-thirds of eyes.

Use of fluorescein and indocyanine green angiography in polypoidal choroidal vasculopathy patients following photodynamic therapy

BACKGROUND: Exudative age-related macular degeneration (AMD) is a sight-threatening event in many elderly people. Some patients have a much better outcome in visual acuity (VA) than others after treatment with photodynamic therapy (PDT) with verteporfin. The combination of fluorescein angiography (FA) and indocyanine green (ICG) angiography using the Heidelberg Retina Angiograph II (HRA 2) should make a delineation of distinct pattern(s) possible in order to better select and assess therapy. METHODS: This is a retrospective, case-control, single-centre study. We identified a total of 168 eyes of 168 patients from July 2003 to June 2006, including 30 eyes of 30 patients with better visual outcome, defined in this study as VA < or = 0.48 logMAR (> or =20/60 Snellen chart) at the end of the study. Best-corrected VA, maximal central retinal thickness as measured by optical coherence tomography, and results of the FA/ICG angiography using the HRA 2 were analyzed. In this article, we discuss patients with polypoidal choroidal vasculopathy (PCV) and their characteristics. RESULTS: The average follow-up time was 15.3 months (range 4-28 months). Seventeen (57%) of the 30 patients with better visual outcome had PCV. All patients in the group with better visual outcome needed fewer PDT treatments compared with our control group of patients with an exudative AMD. INTERPRETATION: Simultaneous FA/ICG angiography using the HRA 2 allowed delineation of a subgroup of patients with PCV who showed a better visual outcome compared with those with other types of exudative AMD, after treatment with PDT.

Improvement in cardiac sympathetic nerve activity in responders to resynchronization therapy

AIMS: To assess changes in cardiac adrenergic activity with cardiac resynchronization therapy (CRT), and to investigate whether these changes are related to improvement in left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Sixteen patients (13 males, age 66 +/- 7 years) were studied at baseline and after > or =6 months of CRT (mean follow-up 9.2 +/- 3.2 months). LVEF was assessed by nuclear angiography. Responders were defined as patients showing > or =5% absolute increase in LVEF + improvement in > or =1 NYHA class + absence of heart failure hospitalization. Cardiac sympathetic nerve activity was studied by (123)I-metaiodobenzyl-guanidine ((123)I-MIBG) scintigraphy. Responders (n = 8) showed lower (123)I-MIBG washout at follow-up when compared with non-responders (P = 0.002), indicating lower cardiac sympathetic nerve activity. The decrease in (123)I-MIBG washout at follow-up when compared with baseline was only seen in the responder group (P = 0.036). There was a moderate correlation between increase in LVEF and decrease in (123)I-MIBG washout (r = 0.52, P = 0.04). CONCLUSION: CRT induces a reduction in cardiac sympathetic nerve activity in responders, that parallels an improvement in LVEF, whereas non-responders do not show any significant changes.

CD4+ T cell count recovery in HIV type 1-infected patients is independent of class of antiretroviral therapy

BACKGROUND: In recent years, treatment options for human immunodeficiency virus type 1 (HIV-1) infection have changed from nonboosted protease inhibitors (PIs) to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and boosted PI-based antiretroviral drug regimens, but the impact on immunological recovery remains uncertain. METHODS: During January 1996 through December 2004 [corrected] all patients in the Swiss HIV Cohort were included if they received the first combination antiretroviral therapy (cART) and had known baseline CD4(+) T cell counts and HIV-1 RNA values (n = 3293). For follow-up, we used the Swiss HIV Cohort Study database update of May 2007 [corrected] The mean (+/-SD) duration of follow-up was 26.8 +/- 20.5 months. The follow-up time was limited to the duration of the first cART. CD4(+) T cell recovery was analyzed in 3 different treatment groups: nonboosted PI, NNRTI, or boosted PI. The end point was the absolute increase of CD4(+) T cell count in the 3 treatment groups after the initiation of cART. RESULTS: Two thousand five hundred ninety individuals (78.7%) initiated a nonboosted-PI regimen, 452 (13.7%) initiated an NNRTI regimen, and 251 (7.6%) initiated a boosted-PI regimen. Absolute CD4(+) T cell count increases at 48 months were as follows: in the nonboosted-PI group, from 210 to 520 cells/muL; in the NNRTI group, from 220 to 475 cells/muL; and in the boosted-PI group, from 168 to 511 cells/muL. In a multivariate analysis, the treatment group did not affect the response of CD4(+) T cells; however, increased age, pretreatment with nucleoside reverse-transcriptase inhibitors, serological tests positive for hepatitis C virus, Centers for Disease Control and Prevention stage C infection, lower baseline CD4(+) T cell count, and lower baseline HIV-1 RNA level were risk factors for smaller increases in CD4(+) T cell count. CONCLUSION: CD4(+) T cell recovery was similar in patients receiving nonboosted PI-, NNRTI-, and boosted PI-based cART.

Factors associated with the emergence of K65R in patients with HIV-1 infection treated with combination antiretroviral therapy containing tenofovir

BACKGROUND: The human immunodeficiency virus type 1 reverse-transcriptase mutation K65R is a single-point mutation that has become more frequent after increased use of tenofovir disoproxil fumarate (TDF). We aimed to identify predictors for the emergence of K65R, using clinical data and genotypic resistance tests from the Swiss HIV Cohort Study. METHODS: A total of 222 patients with genotypic resistance tests performed while receiving treatment with TDF-containing regimens were stratified by detectability of K65R (K65R group, 42 patients; undetected K65R group, 180 patients). Patient characteristics at start of that treatment were analyzed. RESULTS: In an adjusted logistic regression, TDF treatment with nonnucleoside reverse-transcriptase inhibitors and/or didanosine was associated with the emergence of K65R, whereas the presence of any of the thymidine analogue mutations D67N, K70R, T215F, or K219E/Q was protective. The previously undescribed mutational pattern K65R/G190S/Y181C was observed in 6 of 21 patients treated with efavirenz and TDF. Salvage therapy after TDF treatment was started for 36 patients with K65R and for 118 patients from the wild-type group. Proportions of patients attaining human immunodeficiency virus type 1 loads <50 copies/mL after 24 weeks of continuous treatment were similar for the K65R group (44.1%; 95% confidence interval, 27.2%-62.1%) and the wild-type group (51.9%; 95% confidence interval, 42.0%-61.6%). CONCLUSIONS: In settings where thymidine analogue mutations are less likely to be present, such as at start of first-line therapy or after extended treatment interruptions, combinations of TDF with other K65R-inducing components or with efavirenz or nevirapine may carry an enhanced risk of the emergence of K65R. The finding of a distinct mutational pattern selected by treatment with TDF and efavirenz suggests a potential fitness interaction between K65R and nonnucleoside reverse-transcriptase inhibitor-induced mutations.