Ismene Dontas

Pharmacological Aspects and Potential New Clinical Applications of Ketamine: Reevaluation of an Old Drug

Ketamine, the phencyclidine derivative described in 1965, is an intravenous anesthetic with a variety of applications. The enthusiasm following its initial release subsided due to side effects from the central nervous system. New anesthetics limited the role of ketamine in anesthetic practice. However, its hemodynamically stable profile, along with its beneficial respiratory properties and analgesic potency, rendered the drug invaluable in battlefield medicine, sedation of the uncooperative child, analgesia, and sedation in burn units. Reevaluation, though, of analgesic properties of ketamine resulted in new interest regarding its use in perioperative and chronic pain management. Moreover, recent studies in the effects of the substance on intracranial pressure and cerebral blood flow led to revising the recommendation against its use in brain injury. Furthermore, the bronchodilating effects of the substance led to increasing interest for potential use in asthma treatment. In addition, separation of the 2 enantiomers and subsequent separate studies indicated beneficial results of the S(+) one. Thus, new controlled multicentered clinical trials are to be conducted to justify approval for new uses of ketamine and take advantage of its unique range of applications.

Cardiac implications of Lyme disease, diagnosis and therapeutic approach

Lyme is a tick-borne disease. The genetic diversity of Borreliae its distribution worldwide and its epidemiology have been related to different clinical manifestations. Carditis is a rare manifestation of Lyme disease. The commonest abnormality is atrioventricular block of various degrees, though other rhythm abnormalities have been reported. Pericarditis, myocarditis, cardiomyopathy and degenerative valvular disease have been associated with B. burgdorferi. Temporary pacing might be required in unstable patients. The majority of the conduction disturbances have a benign prognosis, if the infectious agent is identified and treated appropriately.

Type 2 diabetes mellitus and fracture risk

Increased fracture risk, traditionally associated with type 1 diabetes, has lately been of great concern in patients with type 2 diabetes. A variable increase in fracture risk has been reported, ranging from 20% to 3-fold, depending on skeletal site, diabetes duration and study design. Longer disease duration, the presence of diabetic complications, inadequate glycemic control, insulin use and increased risk for falls are all reported to increase fracture risk. Patients with type 2 diabetes display a unique skeletal phenotype with either normal or more frequently increased, bone mineral density and impaired structural and geometric properties. Recently, alterations in bone material properties seem to be the predominant defect leading to increased bone fragility. Accumulation of advanced glycation end-products and changes in collagen cross-linking along with suppression of bone turnover seem to be significant factors impairing bone strength. FRAX score has been reported to underestimate fracture risk and lumbar spine BMD is inadequate in predicting vertebral fractures. Anti-diabetic medications, apart from thiazolidinediones, appear to be safe for the skeleton, although more data are needed. Optimal strategies to reduce skeletal fragility in type 2 diabetic patients are yet to be determined.

Combination pharmacotherapy in the treatment of experimental cardiac arrest

STUDY OBJECTIVES Full recovery after cardiopulmonary resuscitation (CPR) is poor. We hypothesized that the coadministration of epinephrine, a beta-blocker such as atenolol, and a calcium sensitizer such as levosimendan during CPR would improve survival and postresuscitation myocardial function. METHODS Ventricular fibrillation was induced in 60 piglets, which were left untreated for 8 minutes before attempted resuscitation. Animals were randomized into 4 groups (n = 15), to receive epinephrine (group E), epinephrine + atenolol (group E + A), epinephrine + levosimendan (group E + L) and epinephrine + atenolol + levosimendan (group E + A + L) during CPR. Electrical defibrillation was attempted 2 minutes after drug administration. RESULTS Five animals in group E survived for 48 hours in comparison to 8 animals in groups E + A and E + L and 12 animals in group E + A + L. Postresuscitation cardiac output was significantly better in the animals of group E + A + L. Troponin I remained significantly lower in groups E + A and E + A + L. Serum astroglial protein (S-100) and neuron-specific enolase values in group E + L and E + A + L were statistically lower than those measured in groups E and E + A during the entire observation period. The neurologic alertness score was higher in group E + A + L compared to groups E and E + A. CONCLUSIONS The administration of a drug combination of epinephrine + atenolol + levosimendan, when given during CPR, in a pig model of cardiac arrest, results in improved 48-hour survival and improves postresuscitation cardiac function.

Intramuscular administration of estrogen may promote angiogenesis and perfusion in a rabbit model of chronic limb ischemia

OBJECTIVE Promoting angiogenesis may be an effective treatment for patients with diffuse peripheral vascular disease. This study investigated whether estrogen can promote angiogenesis and perfusion in a rabbit model of chronic limb ischemia. METHODS AND RESULTS Ischemia was induced in one hindlimb of 24 oophorectomized New Zealand White rabbits. Ten days later (day 0), they were randomized into 4 groups for intramuscular treatment in the ischemic limb: controls receiving saline at day 0; Estrogen-1 group receiving estradiol valerate, modified release (EVMR), 1 mg/kg at day 0; Estrogen-2 group receiving EVMR 1 mg/kg at days 0 and 15; and Estrogen-3 group receiving EVMR 2 mg/kg at day 0. Revascularization was evaluated by clinical indexes, such as ischemic/normal limb systolic blood pressure (BPR), and capillary density/muscle fiber in the abductor muscle of the ischemic limb at the time of death (day 30). At day 30 the BPR was increased in all groups (0.39+/-0.08 in the controls, 0.52+/-0.11 in the Estrogen-1 group, 0.65+/-0.13 in the Estrogen-2 group and 0.61+/-0.16 in the Estrogen-3 group, F=2.39, P=0.04). The capillary/muscle fiber at day 30 was 0.87+/-0.09, 1.08+/-0.15, 1.01+/-0.14 and 1.10+/-0.9 (F=5.01, P=0.01), respectively, in the 4 groups. The capillary/muscle fiber was related to BPR (r=0.48, P<0.02) and to 17-beta estradiol plasma levels of day 15 (r=0.58, P=0.003) and of day 30 (r=0.46, P<0.02). CONCLUSION Administration of estrogen promotes angiogenesis and perfusion in ischemic rabbit hindlimbs. Thus, estrogen may represent a new therapeutic modality in the management of arterial insufficiency.

Cross-cultural validation of the Falls Efficacy Scale International (FES-I) in Greek community-dwelling older adults.

Purpose. The cross-cultural adaptation and validation of Falls Efficacy Scale-International (FES-I) in community-dwelling seniors in Greece. Method. For cross-cultural adaptation, the back-translation procedure was utilised by four bi-lingual translators. For validation, 89 community-dwellings (50 males, 39 females) aged 61–90 years old (mean: 72.87  ±  6.04) completed four questionnaires adapted into Greek; two instrument specific ones, FES-I and Confidence in Maintaining Balance (CONFbal), and two generic Questionnaires, Short-form Health Survey (SF-36v2) and General Health Questionnaire (GHQ30). Additionally, three functional/balance tests were compared against the FES-I. All questionnaires and measurements were repeated after 7–10 days to explore repeatability. Results. Content validity was achieved as all participants found the questionnaire appropriate and comprehensible. Validity of the FES-I yielded moderate to strong correlations with CONFbal (r  ==  0.694, p<0.01), three SF-36 subscales (r ranging between 0.560 and 6.55, p<0.01), GHQ30 (r  ==  0.584, p<0.01) and one functional test (r  ==  0.638, p<0.01 for Timed Up and Go test). FES-Is test–retest reliability (ICC:0.951, SEM: 1.79, SDD:20.44%%, r  ==  0.950) and internal consistency (Cronbachs α  ==  0.925) were excellent, and responsiveness across fallers and non-fallers yielded a large effect size (0.89), indicating good discriminant validity. Conclusions. The Greek FES-I was valid, reliable, comprehensible and acceptable for the sample tested and may thus, be used in cross-cultural rehabilitation research and practice.

Rodent models of hepatic ischemia–reperfusion injury: time and percentage-related pathophysiological mechanisms

Ischemia and reperfusion (IR) injury remains one of the major problems in liver surgery and transplantation, which determines the viability of the hepatic tissue after resection and of the grafted organ. This review aims to elucidate the mechanisms involved in IR injury of the liver in rodent experimental studies and the preventative methods and pharmacologic agents that have been applied. Many time- and percentage-related liver IR injury rodent models have been used to examine the pathophysiological mechanisms and the parameters implicated with different morbidity, mortality, and pathology findings. The most preferred experimental rodent model of liver IR is the induction of 70% IR for 45 min, which is associated with almost 100% survival. In this model, plasma levels of several parameters such as alanine transaminase, aspartate aminotransferase, gamma-glutamyltransferase, endothelin-1, malonodialdehyde, tumor necrosis factor α, interleukin 1b, inducible nitric oxide synthase, and caspases are increased. The increase of caspases is associated with the initiation of hepatic cellular apoptosis. The main injuries observed 24 h after reperfusion are nuclear pyknosis, cytoplasmic hypereosinophilia, severe necrosis, and loss of intercellular borders. Both ischemic pre- and post-conditioning preventative methods and pharmacologic agents are successfully applied to alleviate the IR injuries. The selection of the time- and percentage-related liver IR injury rodent model and the potential preventative method should be related to the clinical question being answered.

Administration of human protein C improves survival in an experimental model of sepsis

Objective:Study the effect of human protein C (PC) concentrate administration on organ damage and survival in septic rats. Design:Animal study. Setting:University laboratory. Subjects:Male Wistar rats. Interventions:Cecal ligation and puncture (CLP) was performed in 210 rats. Rats were randomly assigned to receive either human protein C (PC) IV 1, 7, and 13 hrs after CLP (CLP+PC) or placebo (CLP). Septic animals were again randomized in a survival group (CLP: n = 50 and CLP+PC: n = 40) that was monitored for 60 hrs and time groups (CLP: n = 60 and CLP+PC: n = 60) that were killed at 6, 12, 24, 36, 48, and 60 hrs after CLP. Brain, heart, lung, liver, kidney, gastric, and colon tissue were removed and postfixed in paraffin sections. Measurements and Main Results:PC infusion increased PC serum levels in early sepsis (median 7.25) compared with late sepsis (median 2, p = .001). Activated protein C/a1-antitrypsin complex levels in the CLP+PC group were significantly increased in late sepsis (60 hrs after CLP) compared with early sepsis (6, 12, and 24 hrs after CLP, p = .009, p = .004, and p = .008, respectively) and to late septic CLP and normal rats (p = .005 and p = .007, respectively). Their IL-6 and tumor necrosis factor a plasma levels were decreased (by 27% and 25%, respectively) at 6 hrs compared with placebo (p = .008 and p = .016). Their serum PC levels were also decreased in CLP+PC survivors compared with nonsurvivors of the same group (median = 1.5 vs. median = 7, p = .001). Apoptosis was reduced in brain (10% vs. 77.8%, p < .001), stomach (66.7% vs. 100%, p < .002) and intestine (33.3% vs. 85.2%, p < .001) compared with placebo. Finally, the survival of septic rats treated with human PC was significantly increased compared with placebo (75% vs. 54%, p = .033). Conclusions:Human Protein C administration increased survival in septic rats, decreased plasma inflammatory cytokines levels and tissue injury in vital organs.

Volumetric bone mineral density and bone geometry assessed by peripheral quantitative computed tomography in women with differentiated thyroid cancer under TSH suppression

TSH suppression therapy in patients with differentiated thyroid cancer (DTC) has been associated with adverse effects on areal bone mineral density (aBMD) only in postmenopausal women. The purpose of study was to examine the effect of TSH suppression therapy on skeletal integrity using peripheral quantitative computed tomography (pQCT) at the radius and tibia in pre‐ and postmenopausal women with DTC and controls.

Effect of autologous platelet-rich plasma in combination with a biphasic synthetic graft material on bone healing in critical-size cranial defects.

Purpose The aim of the study was to investigate the effect of autologous platelet-rich plasma (PRP) on the osteogenic potential of a biphasic synthetic graft material composed of hydroxyapatite and beta-tricalcium phosphate (HA/&bgr;-TCP) in critical-size cranial defects in rabbits. Materials and Methods Three circular bicortical critical-size cranial defects were created in each of 18 rabbits. The first of the defects was grafted with autologous PRP and HA/&bgr;-TCP, the second was grafted with HA/&bgr;-TCP without PRP, and the third was left unfilled as a negative control. Animals were euthanized at 2, 4, and 6 weeks after surgery. Harvested tissue specimens were evaluated histologically and histomorphometrically. Several parameters associated with osteoclastic and osteoblastic activities were measured and calculated. The results were statistically analyzed using the 1-way analysis of variance statistical method. Results Histologic analysis of the samples showed bone tissue formation at all experimental sites including untreated control defects. A statistically significant difference in new bone formation between the defects treated with HA/&bgr;-TCP + PRP and defects treated with HA/&bgr;-TCP alone was not observed. Control untreated defects showed the greatest bone regeneration. Conclusions In this animal model, autologous PRP had no effect on bone healing in addition to a biphasic HA/&bgr;-TCP synthetic graft material after 2, 4, and 6 weeks of implantation.