Radial extracorporeal shock wave therapy (rESWT) induces new bone formation in vivo: results of an animal study in rabbits

The aim of this study was to investigate if radial extracorporeal shock wave therapy (rESWT) induces new bone formation and to study the time course of ESWT-induced osteogenesis. A total of 4000 impulses of radial shock waves (0.16 mJ/mm²) were applied to one hind leg of 13 New Zealand white rabbits with the contralateral side used for control. Treatment was repeated after 7 days. Fluorochrome sequence labeling of new bone formation was performed by subcutaneous injection of tetracycline, calcein green, alizarin red and calcein blue. Animals were sacrificed 2 weeks (n = 4), 4 weeks (n = 4) and 6 weeks (n = 5) after the first rESWT and bone sections were analyzed by fluorescence microscopy. Deposits of fluorochromes were classified and analyzed for significance with the Fisher exact test. rESWT significantly increased new bone formation at all time points over the 6-week study period. Intensity of ossification reached a peak after 4 weeks and declined at the end of the study. New bone formation was significantly higher and persisted longer at the ventral cortex, which was located in the direction to the shock wave device, compared with the dorsal cortex, emphasizing the dose-dependent process of ESWT-induced osteogenesis. No traumata, such as hemorrhage, periosteal detachment or microfractures, were observed by histologic and radiologic assessment. This is the first study demonstrating low-energy radial shock waves to induce new bone formation in vivo. Based on our results, repetition of ESWT in 6-week intervals can be recommended. Application to bone regions at increased fracture risk (e.g., in osteoporosis) are possible clinical indications.

Evidence of prognostic relevant expression profiles of heat-shock proteins and glucose-regulated proteins in oesophageal adenocarcinomas

A high percentage of oesophageal adenocarcinomas show an aggressive clinical behaviour with a significant resistance to chemotherapy. Heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) are molecular chaperones that play an important role in tumour biology. Recently, novel therapeutic approaches targeting HSP90/GRP94 have been introduced for treating cancer. We performed a comprehensive investigation of HSP and GRP expression including HSP27, phosphorylated (p)-HSP27((Ser15)), p-HSP27((Ser78)), p-HSP27((Ser82)), HSP60, HSP70, HSP90, GRP78 and GRP94 in 92 primary resected oesophageal adenocarcinomas by using reverse phase protein arrays (RPPA), immunohistochemistry (IHC) and real-time quantitative RT-PCR (qPCR). Results were correlated with pathologic features and survival. HSP/GRP protein and mRNA expression was detected in all tumours at various levels. Unsupervised hierarchical clustering showed two distinct groups of tumours with specific protein expression patterns: The hallmark of the first group was a high expression of p-HSP27((Ser15, Ser78, Ser82)) and low expression of GRP78, GRP94 and HSP60. The second group showed the inverse pattern with low p-HSP27 and high GRP78, GRP94 and HSP60 expression. The clinical outcome for patients from the first group was significantly improved compared to patients from the second group, both in univariate analysis (p = 0.015) and multivariate analysis (p = 0.029). Interestingly, these two groups could not be distinguished by immunohistochemistry or qPCR analysis. In summary, two distinct and prognostic relevant HSP/GRP protein expression patterns in adenocarcinomas of the oesophagus were detected by RPPA. Our approach may be helpful for identifying candidates for specific HSP/GRP-targeted therapies.

Slow release antibiotics for treatment of septic arthritis in large animals

The search for an effective treatment for septic arthritis is ongoing. Current therapies are expensive since they require repeated joint lavage and long term antibiotic treatment. Local application of antimicrobial drugs is advantageous because high concentrations can be attained at the infection site, although repeated injections increase the risk of superinfection of the joint. Thus, slow release formulations, which have the advantage of local treatment yet single application of the drug, are appealing. Antibiotics used in slow release formulations are selected for tissue compatibility, an appropriate antibacterial spectrum, and stability both during the mixing procedure and within the carrier during the release period. Ideally the carriers should be bioresorbable. Promising reports on the clinical use of poly(methyl methacrylate) (PMMA) mixed with several different antibiotics, and of collagen sponges impregnated with gentamicin, should encourage the search for formulations optimally adapted to veterinary medical requirements.

[A rare cause of cardiogenic shock with psychotic symptoms]

A 40-year-old man was admitted to the emergency department with psychotic symptoms and marked hypothermia. He was known to have had a macroadenoma of the pituitary gland which had been excised 10 years before. No information about his current medication was available. Several hours after admission the patient developed signs of acute cardiac failure and cardiogenic shock. He was admitted to the intensive care unit, intubated and treated with vasoactive drugs. Later investigations revealed that the patient had stopped his hormonal therapy (hydrocortisone and thyroxine) at least 3 months previously.

Histomorphologic evaluation of extracorporeal shock wave therapy of the fourth metatarsal bone and the origin of the suspensory ligament in horses without lameness

OBJECTIVE: To determine via histologic examination and scintigraphy the effect of focused extracorporeal shock wave therapy (ESWT) on normal bone and the bone-ligament interface in horses. ANIMALS: 6 horses without lameness. PROCEDURE: Origins of the suspensory ligament at the metacarpus (35-mm probe depth) and fourth metatarsal bone (5-mm probe depth) were treated twice (days 0 and 16) with 2,000 shocks (energy flux density, 0.15 mJ/mm2). One forelimb and 1 hind limb were randomly treated, and the contralateral limbs served as nontreated controls. Bone scans were performed on days -1 (before ESWT), 3, 16, and 19. Histomorphologic studies of control and treated tissues were performed on day 30. RESULTS: ESWT significantly increased the number of osteoblasts but caused no damage to associated soft tissue structures and did not induce cortical microfractures. A significant correlation between osteoblast numbers and radiopharmaceutical uptake was noticed on lateral views of the hind limb on days 3 and 16 and on caudal views of the forelimb on day 3. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that ESWT has the potential to increase osteoblast numbers in horses. The correlation between increased osteoblast numbers and radio-pharmaceutical uptake 3 days and 16 days after the first ESWT suggested that stimulation of osteogenesis occurred soon after ESWT. No damage to bone or the bone-ligament interface should occur at the settings used in this study, and ESWT can therefore be administered safely in horses.

Vasopressin in vasodilatory shock: ensure organ blood flow, but take care of the heart!

Supplementary arginine vasopressin infusion in advanced vasodilatory shock may be accompanied by a decrease in cardiac index and systemic oxygen transport capacity in approximately 40% of patients. While a reduction of cardiac output most frequently occurs in patients with hyperdynamic circulation, it is less often observed in patients with low cardiac index. Infusion of inotropes, such as dobutamine, may be an effective strategy to restore systemic blood flow. However, when administering inotropic drugs, systemic blood flow should be increased to adequately meet systemic demands (assessed by central or mixed venous oxygen saturation) without putting an excessive beta-adrenergic stress on the heart. Overcorrection of cardiac index to hyperdynamic values with inotropes places myocardial oxygen supply at significant risk.

Comparison of lactated Ringer's, gelatine and blood resuscitation on intestinal oxygen supply and mucosal tissue oxygen tension in haemorrhagic shock

OBJECTIVES: To evaluate the effects on intestinal oxygen supply, and mucosal tissue oxygen tension during haemorrhage and after fluid resuscitation with either blood (B; n=7), gelatine (G; n=8), or lactated Ringer's solution (R; n=8) in an autoperfused, innervated jejunal segment in anaesthetized pigs. METHODS: To induce haemorrhagic shock, 50% of calculated blood volume was withdrawn. Systemic haemodynamics, mesenteric venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. A flowmeter was used for measuring mesenteric arterial blood flow. Mucosal tissue oxygen tension (PO(2)muc), jejunal microvascular haemoglobin oxygen saturation (HbO(2)) and microvascular blood flow were measured. Measurements were performed at baseline, after haemorrhage and at four 20 min intervals after fluid resuscitation. After haemorrhage, animals were retransfused with blood, gelatine or lactated Ringer's solution until baseline pulmonary capillary wedge pressure was reached. RESULTS: After resuscitation, no significant differences in macrohaemodynamic parameters were observed between groups. Systemic and intestinal lactate concentration was significantly increased in animals receiving lactated Ringer's solution [5.6 (1.1) vs 3.3 (1.1) mmol litre(-1); 5.6 (1.1) vs 3.3 (1.2) mmol litre(-1)]. Oxygen supply to the intestine was impaired in animals receiving lactated Ringer's solution when compared with animals receiving blood. Blood and gelatine resuscitation resulted in higher HbO(2) than with lactated Ringer's resuscitation after haemorrhagic shock [B, 43.8 (10.4)%; G, 34.6 (9.4)%; R, 28.0 (9.3)%]. PO(2)muc was better preserved with gelatine resuscitation when compared with lactated Ringer's or blood resuscitation [20.0 (8.8) vs 13.8 (7.1) mm Hg, 15.2 (7.2) mm Hg, respectively]. CONCLUSION: Blood or gelatine infusion improves mucosal tissue oxygenation of the porcine jejunum after severe haemorrhage when compared with lactated Ringer's solution.

A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis

BACKGROUND: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. METHODS: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. RESULTS: Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. CONCLUSIONS: Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.

Early resuscitation with polymerized bovine hemoglobin reverses acidosis, but not peripheral tissue oxygenation, in a severe hamster shock model

Awake hamsters equipped with the dorsal window chamber preparation were subjected to hemorrhage of 50% of the estimated blood volume. Initial resuscitation (25% of estimated blood volume) with polymerized bovine hemoglobin (PBH) or 10% hydroxyethyl starch (HES) occurred in concert with an equivolumetric bleeding to simulate the early, prehospital setting (exchange transfusion). Resuscitation (25% of estimated blood volume) without bleeding was performed with PBH, HES, or autologous red blood cells (HES-RBCs). Peripheral microcirculation, tissue oxygenation, and systemic hemodynamic and blood gas parameters were assessed. After exchange transfusion, base deficit was -8.6 +/- 3.7 mmol/L (PBH) and -5.1 +/- 5.3 mmol/L (HES) (not significant). Functional capillary density was 17% +/- 6% of baseline (PBH) and 31% +/- 11% (HES) (P < 0.05) and arteriolar diameter 73% +/- 3% of baseline (PBH) and 90% + 5% (HES) (P < 0.01). At the end, hemoglobin levels were 3.7 +/- 0.3 g/dL with HES, 8.2 +/- 0.6 g/dL with PBH, and 10.4 +/- 0.8 g/dL with HES-RBCs (P < 0.01 HES vs. PBH and HES-RBCs, P < 0.05 PBH vs. HES-RBCs). Base excess was restored to baseline with PBH and HES-RBCs, but not with HES (P < 0.05). Functional capillary density was 46% +/- 5% of baseline (PBH), 62% + 20% (HES-RBCs), and 36% +/- 19% (HES) (P < 0.01 HES-RBCs vs. HES). Peripheral oxygen delivery and consumption was highest with HES-RBCs, followed by PBH (P < 0.05 HES-RBCs vs. PBH, P < 0.01 HES-RBCs and PBH vs. HES). In conclusion, the PBH led to a correction of base deficit comparable to blood transfusion. However, oxygenation of the peripheral tissue was inferior with PBH. This was attributed to its negative impact on the peripheral microcirculation caused by arteriolar vasoconstriction.

Rapid restoration of microcirculatory blood flow with hyperviscous and hyperoncotic solutions lowers the transfusion trigger in resuscitation from hemorrhagic shock

Resuscitation from hemorrhagic shock relies on fluid retransfusion. However, the optimal properties of the fluid have not been established. The aim of the present study was to test the influence of the concentration of hydroxyethyl starch (HES) solution on plasma viscosity and colloid osmotic pressure (COP), systemic and microcirculatory recovery, and oxygen delivery and consumption after resuscitation, which were assessed in the hamster chamber window preparation by intravital microscopy. Awake hamsters were subjected to 50% hemorrhage and were resuscitated with 25% of the estimated blood volume with 5%, 10%, or 20% HES solution. The increase in concentration led to an increase in COP (from 20 to 70 and 194 mmHg) and viscosity (from 1.7 to 3.8 and 14.4 cP). Cardiac index and microcirculatory and metabolic recovery were improved with HES 10% and 20% when compared with 5% HES. Oxygen delivery and consumption in the dorsal skinfold chamber was more than doubled with HES 10% and 20% when compared with HES 5%. This was attributed to the beneficial effect of restored or increased plasma COP and plasma viscosity as obtained with HES 10% and 20%, leading to improved microcirculatory blood flow values early in the resuscitation period. The increase in COP led to an increase in blood volume as shown by a reduction in hematocrit. Mean arterial pressure was significantly improved in animals receiving 10% and 20% solutions. In conclusion, the present results show that the increase in the concentration of HES, leading to hyperoncotic and hyperviscous solutions, is beneficial for resuscitation from hemorrhagic shock because normalization of COP and viscosity led to a rapid recovery of microcirculatory parameters.