Clinical effect of bisphosphonate and vitamin D on osteoporosis: reappraisal of a multicenter double-blind clinical trial comparing etidronate and alfacalcidol

As inhibitors of bone resorption, bisphosphonates and vitamin D derivatives have been extensively used for the treatment of osteoporosis in various parts of the world, but the clinical effects of these two groups of agents have rarely been compared in detail. A multicenter, prospective, double-blind controlled study was started comparing the effects of etidronate and alfacalcidol (1-alpha-hydroxycholecalciferol) in 414 patients with established osteoporosis from 36 centers. Among these patients, 135 were given 400 mg etidronate daily at bedtime for 2 weeks followed by 10 weeks off treatment, and this cycle was repeated four times along with a placebo indistinguishable from the alfacalcidol capsule daily throughout the 48 weeks of study (Group A, High Dose Etidronate Group). In 133 patients, 200 mg etidronate was used instead of 400 mg (Group B, Low Dose Etidronate Group). In 138 patients, 1 μg alfacalcidol was given daily throughout the 48-week study period along with a placebo indistinguishable from the etidronate tablet in four separate periods of 2 weeks (Group C, Control Group). Dual-energy X-ray absorptiometry of the lumbar spine (L2–L4) was performed before the beginning of the study and every 12 weeks thereafter. Changes in spinal deformity were also assessed based on the lateral thoracic and lumbar spine X-ray films taken before and after the study. The lumbar spine bone mineral density (BMD) changes were +3.4% ± 0.6% (mean ± SEM) in Group A, +2.4% ± 0.5% in Group B, and −0.5% ± 0.4% in Group C, the former two being significantly higher than the last. New occurrence of spinal compression fracture was also significantly reduced in Group A compared to Group C. In patients without previous fracture at entry, incident fracture was 10.2% in Group C, but 0% in Groups A and B. In patients with prevalent fracture at entry, corresponding figures were 21.5% (Group C), 12.0% (Group A), and 13.2% (Group B), respectively. Alfacalcidol maintained lumbar spine BMD, preventing a decrease for 48 weeks, and etidronate significantly increased it further, demonstrating its usefulness in the treatment of established osteoporosis.     

The bisphosphonate ibandronate accelerates osseointegration of hydroxyapatite-coated cementless implants in an animal model

Background There is evidence that bisphosphonates can improve fixation of cementless metal implants by enhancing the extent of osseointegration. The current preclinical study examined whether the nitrogen-containing bisphosphonate ibandronate can accelerate this process, resulting in early achievement of secondary stability and sealing of the bone–implant interface to prevent wear debris migration. Methods The study was conducted on 88 female Sprague-Dawley rats in which uncoated titanium and hydroxyapatite-coated titanium implants were surgically inserted into the medullary canal of each femur. The animals were randomly assigned to receive subcutaneous treatment with 1.0, 2.5, or 5.0 μg/kg per day ibandronate or saline solution as a control. The extent of osseointegration expressed by the osseointegrated implant surface was quantified by histomorphometry at eleven time points during the study period. To determine the time course of osseointegration, the data were expressed using third-order polynomial regression analysis. Results For hydroxyapatite-coated implants, the highest dose of ibandronate (5 μg) reduced the time for a sufficient implant fixation of 60% osseointegrated implant surface to 18 days compared to 38 days in the control group. This reduction of 20 days (52.6%) represents a halving in the time required for sufficient osseointegration of the implant. For hydroxyapatite-coated implants and low-dose ibandronate application (1 μg, 2.5 μg) and for uncoated titanium implants, acceleration of osseointegration was not observed in any of the study arms. Conclusion Continuous treatment with 5 μg/kg per day ibandronate is potent in accelerating osseointegration of hydroxyapatite-coated implants. As a result, improved early secondary stability and prevention of wear debris migration by the sealing of the implant–bone interface can be expected, therefore prolonging the long-term survival of the implant.     

Conservative outpatient renoprotective protocol in patients with low GFR undergoing contrast angiography: a case series

Background The correct strategy to prevent radiocontrast-induced nephropathy (CIN) in high-risk patients going for cardiac angiography is widely debated in the literature. It is well known that chronic kidney disease (CKD) patients with lower estimated glomerular filtration rates (eGFRs) at baseline are at the greatest risk for a significant loss in kidney function, or even dialysis after a contrast load. For this reason potentially life-saving procedures such as angiography are sometimes withheld or delayed. Methods We describe a case series of 31 well-characterized patients with CKD who underwent cardiac or peripheral vessel angiography, and patients with renal artery stenosis (RAS) who underwent angioplasty and stenting. All were treated with a standardized outpatient protocol of withholding their diuretics and angiotensin-converting enzyme (ACE) inhibitors (ACEs)/angiotensin receptor blockers (ARBs) the day prior to and 2 days after the procedure, restarting the diuretic the day after the procedure and the ACE inhibitor/ARB after 2 days. Calcium channel blockers were prescribed for the 2 days prior to and 2 days after the procedure. Patients had bloodwork on days 2–3 and days 7–10 post-procedure. Results The patients had a mean baseline creatinine of 214 μmol/l (SD = 123), ranging from 87 to 535 μmol/l. This corresponded to a mean baseline eGFR of 34 ml/min (SD = 15.8), ranging from a minimum of 12–59 ml/min. The mean age was 64 ± 13.8 years; 48% were male and 11 (35.5%) were diabetic. All patients enrolled had a baseline eGFR of less than 60 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) formula. Based on pre-procedure CKD stage, 21 (68%) were stage 3 (eGFR 30–60 ml/min), 5 (16%) were stage 4 (eGFR 15–30 ml/min), and 6 (19%) were stage 5 (eGFR < 15 ml/min). No patient required urgent hemodialysis following their angiography. All patients have had a longitudinal follow up of 26 months, and none developed any change in the rate of progression from prior to procedure. Conclusions This case series provides data in support of a conservative, outpatient-based approach for high-risk CKD patients going for cardiac angiography. This protocol warrants further study in randomized control trials.     

A Prospective Study of Bone Loss and Turnover after Cardiac Transplantation: Effect of Calcium Supplementation With or Without Calcitonin

Cardiac transplantation exposes recipients to osteoporosis and increased risk of consequent fractures. The purpose of the present study was to examine the magnitude, timing and mechanism of bone loss following cardiac transplantation, and to establish whether bone loss can be prevented by calcium with or without calcitonin. Thirty patients (29 men, 1 woman), aged 26 – 68 years (mean 48 years), were randomized into three groups of 10 to receive either no additional treatment, oral calcium 1 g twice daily for 12 months or the same dose of calcium plus intranasal calcitonin 400 IU/day for the first month and then 200 IU/day for 11 months. Bone mineral density (BMD) at the lumbar spine and three femoral sites (femoral neck, trochanter, Ward’s triangle) was measured by dual-energy X-ray absorptiometry (DXA) at the time of transplantation and 6 and 12 months later. Markers of bone formation [serum bone-specific alkaline phosphatase (B-ALP), type I procollagen carboxyterminal propeptide (PICP) and aminoterminal propeptide (PINP)] and resorption [serum type I collagen carboxyterminal telopeptide (ICTP)], as well as serum testosterone in men, were assayed before transplantation and at 1 week and 1, 3, 6 and 12 months after transplantation. During the first 6 post-transplant months BMD calculated as a percent change from baseline decreased in the control group by 6.4% (p= 0.014) in the lumbar spine, by 6.0% (p= 0.003) in the femoral neck, by 5.0% (p= 0.003) in the trochanter and by 5.5% (p= 0.130) in Ward’s triangle. Between 6 and 12 months a further decline in BMD occurred only at the three femoral sites, ranging from 2.2% to 9.8% (p= 0.004-0.079). In comparison with the control group, the group receiving calcium alone lost less bone in the trochanter between 0 and 6 months (p= 0.019), and the group receiving calcium together with calcitonin lost less bone in the femoral neck (p= 0.068) and Ward′s triangle (p= 0.076) between 0 and 12 months. Seven (28%) of 25 assessable patients experienced vertebral compression fractures. Calcium with or without calcitonin had no effect on changes in biochemical parameters; consequently, the three study groups were combined. The markers of bone formation increased, the elevations in mean values being 59% for B-ALP at 1 month (p= 0.009), 152% for PICP at 1 week (p < 0.0001) and 27% for PINP at 1 week (p= 0.021). After a temporary decline at 3 months B-ALP (p= 0.0002) and PINP (p < 0.0001) at 1 year were nearly doubled compared with baseline values. Throughout the study the marker of bone resorption, serum ICTP, was above normal, with a peak (mean values 67–69% above baseline) at 1 week (p= 0.0002) to 1 month (p < 0.0001). The mean concentration of total testosterone was decreased by 48% (p < 0.0001) 1 week and by 28% (p= 0.0005) 1 month after transplantation, but this was mainly explained by the concomitant drop in serum albumin. High bone turnover underlies bone loss after cardiac transplantation. Bone loss is most rapid during the first 6 post-transplant months. In the upper femur this bone loss may be reduced by treatment with calcium and calcitonin. Received: 5 May 1998 / Accepted: 12 January 1999     

A comparison of intravenous-based and epidural-based techniques for anesthesia and postoperative analgesia in elderly patients undergoing laparoscopic cholecystectomy

Purpose We wished to compare the effectiveness of intravenous-based (IV) and epidural-based (EPI) techniques for anesthesia and postoperative analgesia in elderly patients undergoing laparoscopic cholecystectomy. Effectiveness was compared in terms of reduction of postoperative pain and adverse events, and achieving a high level of patient satisfaction. Methods Thirty American Society of Anesthesiologists (ASA) physical status I-II patients aged more than 65 years, scheduled for laparoscopic cholecystectomy, were enrolled in this study. The patients in the IV group (n = 15) received modified neurolept anesthesia with droperidol 0.2 mg·kg⁻¹ and pentazocine 0.15–0.3 mg·kg⁻¹ (maximum dose of 1.0 mg·kg⁻¹) and 60% nitrous oxide in oxygen, followed by postoperative intravenous infusion of 20 μg·ml⁻¹ buprenorphine, provided with a patient-controlled analgesia pump programmed to deliver a bolus of 0.5 ml with a lockout interval of 15 min and a background infusion of 0.5 ml·h⁻¹. The patients in the EPI group (n = 15) had combined epidural analgesia and general anesthesia with sevoflurane and 60% nitrous oxide in oxygen, followed by the epidural infusion of a 0.125% bupivacaine and 5 μg · ml⁻¹ buprenorphine mixture by means of an on-demand analgesic system (bolus of 2 ml, lockout interval of 60 min, and background infusion of 2 ml·h⁻¹). Results The quality of postoperative analgesia was similar in the two groups. The incidences of intraoperative hypotension and bradycardia and postoperative hypotension were significantly lower in the IV group than in the EPI group (P < 0.05). A significantly higher level of patient satisfaction was found in the IV group compared with that in the EPI group (P < 0.05). The major contributor to dissatisfaction in the EPI group was anxiety or discomfort associated with the epidural procedures. Conclusion Modified neurolept anesthesia with pentazocine and postoperative i.v. analgesia with buprenorphine were superior to epidural-based techniques, in terms of hemodynamic stability and patient satisfaction, in elderly patients undergoing laparoscopic cholecystectomy.     

Photodynamically induced changes of acetylcholinesterase activity from human erythrocytes

. The light and photodynamic actions on acetylcholinesterase activity from human erythrocytes were studied. After light irradiation (670 nm, semiconducting low power laser) the maximum reaction rate increased from 13.3 to 14.8 μmol per ml packed cells per min for an energy dose 9 J, and above that dose it decreased (10.8 μmol per ml packed cells per min for an energy dose of 15 J). The Michaelis–Menten constant changed in the opposite direction. After irradiation of erythrocyte suspension in the presence of zinc phthalocyanine the reaction rate increased, reaching the maximum for energy dose of 0.75 J (16.85 in comparison to the control value of 14.7 μmol per ml packed cells per min. Similarly, the Michaelis–Menten constant decreased reaching a minimum for an energy dose of 0.75 J (0.04 mm compared to 0.07 mm for control). Incubation of erythrocytes with the dye in the dark increased the reaction rate from 13.3 to 14.7 μmol per ml packed cells per min. Neither the incubation in the dark nor irradiation with laser light caused changes of enzyme activity in the presence of chloroaluminium or metal-free phthalocyanine. Paper received 25 December 1999; accepted after revision 7 June 2000.     

Intrapleural Hypotonic Cisplatin Treatment for Malignant Pleural Mesothelioma: In Vitro Experiments and Clinical Application

Purpose We studied the inhibitory effects of hypotonic cisplatin on the growth of malignant pleural mesothelioma (MPM) cell lines in vitro, and assessed the effectiveness of intraoperative intrapleural hypotonic cisplatin treatment combined with extrapleural pneumonectomy for patients with this tumor. Methods In the in vitro experiments, mesothelioma cell lines were exposed to various concentrations of cisplatin in either saline solution or distilled water for up to 5 min. After 48 h incubation, we calculated the inhibition of cell growth. In the clinical study, five patients with MPM underwent intraoperative intrapleural hypotonic cisplatin treatment combined with extrapleural pneumonectomy. Results The hypotonic cisplatin treatment inhibited cell growth at a significantly greater rate than the isotonic cisplatin treatment. Just 1–5 min exposure to 10 μg/ml of hypotonic cisplatin inhibited growth by more than 80%. Clinically, no recurrence was found in four of the five patients after a median follow-up period of 27 months (range: 16–36 months), although contralateral multiple pulmonary metastases were found in one patient 10 months after surgery. Conclusion Hypotonic cisplatin treatment is effective against MPM, and should be investigated further.     

Dexmedetomidine during local anesthesia

The objective of our study was to assess the efficacy and safety of dexmedetomidine given in a small dose for a 1-h infusion as an adjuvant to local analgesia in ophthalmic operations. The study was double-blind prospective, randomized, and placebo controlled. We studied the effects of a small dose of dexmedetomidine (0.5 μ·kg⁻¹·h⁻¹ for 10 min followed by 0.2 μ·kg⁻¹·h⁻¹ for 50 min. Patients were divided randomly into two groups with 20 patients in each: group A was the study group and group B was the placebo group. Heart rate, systolic blood pressure, and diastolic blood pressure were significantly lower in the dexmedetomidine group than the placebo group. Bispectral index values were significantly lower in the dexmedetomidine group than the placebo group. Also, intraocular pressure significantly decreased in the dexmedetomidine group compared to the placebo group. The study revealed that dexmedetomidine in the studied dose has a sedative effect, provides safe control of heart rate and blood pressure, and also decreases intraocular pressure during ophthalmic surgery under local anesthesia.     

Preoperative epidural fentanyl reduces postoperative pain after upper abdominal surgery

Forty patients, American Society of Anesthesiology (ASA) physical status 1–2, undergoing subtotal gastrectomy were enrolled in this study. The patients were allocated to two groups with or (group P) and without (group C) preoperative epidural fentanyl 100 μg. Postoperatively, all patients received continuous infusion of the study solution, containing fentanyl 30 μg·ml⁻¹ and 2 mg/ml bupivacaine, at a rate of 0.7 ml·h⁻¹ for 72 h. The scores on the Prince Henry Hospital self-assessed pain scale (PHPS) were recorded at 0, 4, 12, 24, 48, and 72 h after the surgery. We compared the total rescue doses of analgesics during each period of 24 h until 72 h postoperatively. Although the total rescue doses of analgesics were not different between the groups, the median PHPS score was lower in group P than in group C, except at 0 h after the surgery. Preoperative epidural fentanyl 100 μg may increase the analgesic potency of postoperative epidural low-dose infusion of bupivacaine with fentanyl.     

Cost-Effectiveness of Hormone Replacement Therapy for Fracture Prevention in Young Postmenopausal Women: An Economic Analysis Based on a Prospective Cohort Study

A recent systematic review of randomized controlled trials has shown that hormone replacement therapy (HRT) prevents fractures when taken soon after the menopause. HRT for treatment of menopausal symptoms is relatively cost-effective, but whether its use for prevention of perimenopausal fractures is economically efficient is unknown. We undertook a 6-year follow-up of 3645 perimenopausal women who had a bone mineral density (BMD) measurement with recommendation to use HRT if low BMD was present. Data were collected on incident fractures and costs. After an average of 6.2 years of follow-up HRT use significantly reduced incident fractures by 52% (95% CI: 67% to 18%). However, costs were increased by an average of ￡275 (95% CI: ￡228 to ￡330) for the group as a whole; for hysterectomized women costs were increased less (￡138), but this was still significantly greater than for non-HRT users (95% CI: ￡6 to ￡275). The cost per averted fracture was about ￡11 000 (95% CI: ￡8625 to ￡13 872) for the whole group and for hysterectomized women the corresponding figure was substantially less (￡1784; 95% CI: ￡59 to ￡3532). HRT given to women at or shortly after the menopause is therefore associated with a halving of fracture incidence. Such a policy for hysterectomized women without menopausal symptoms may be cost-effective as such women are at elevated risk of fracture and need cheaper, unopposed, estrogens. Received: 23 October 2001 / Accepted: 13 February 2002     

Epidural clonidine added to a bupivacaine infusion increases analgesic duration in labor without adverse maternal or fetal effects

Purpose Many obstetric patients receiving epidural analgesia are encouraged to ambulate. This current study was designed to determine the potential for maximizing the time to first epidural supplement when adding clonidine to a 0.625 mg·ml⁻¹ bupivacaine continuous epidural infusion following epidural fentanyl bolus in early labor for patients allowed to ambulate. Maternal and fetal effects secondary to clonidine were also evaluated. Methods Sixty-eight laboring primigravid women received a 3-ml epidural test dose of lidocaine with epinephrine, followed by a fentanyl 100-μg bolus (in a 10 ml-volume). The patients then received a 0.625 mg·ml⁻¹ bupivacaine continuous epidural infusion, either with or without clonidine (5 μg·ml⁻¹), at a rate of 10 ml·h⁻¹. Pain scores and side effects were recorded for each patient. Results The overall quality of analgesia was similar in both groups. The mean duration prior to request for additional analgesia was significantly longer in the clonidine group (269 ± 160 min), compared to the control group (164 ± 64 min). No patient in either group experienced any detectable motor block; one patient (clonidine group) complained of mild thigh numbness and was not allowed to ambulate. While mean blood pressure was approximately 6 mmHg lower in the clonidine group at 1, 1.5, and 3.5 h, this was not clinically significant. No adverse effects on maternal heart rate or fetal heart rate were noted. Conclusion In early laboring patients, addition of clonidine prolongs the analgesia duration of a 0.625 mg·ml⁻¹ bupivacaine continuous epidural infusion following 100 μg epidural fentanyl (after a lidocaine-epinephrine test dose) without a clinically significant increase in side effects.     

Effect of clonidine premedication on postoperative sore throat and hoarseness after total intravenous anesthesia

To determine the effect of oral clonidine premedication on postoperative sore throat and hoarseness, we evaluated the incidence and severity of each of these complications in patients who underwent elective surgery in the supine position. The subjects were 82 patients, American Society of Anesthiologists (ASA) status I–III, aged 15–82 years. They were premedicated with either 150 μg oral clonidine and 20 mg raftidine (clonidine group; n = 41) or with 20 mg raftidine only (control group; n = 41) 2 h before anesthesia induction. General anesthesia was maintained with propofol, ketamine, fentanyl, and vecuronium, with or without epidural anesthesia. Postoperative sore throat and hoarseness were evaluated immediately after surgery and on the day after surgery. The incidences of sore throat and hoarseness tended to be higher in the clonidine group than in the control group; however, the difference did not reach statistical significance. There were no significant differences in the severity of these symptoms between the two groups. In conclusion, oral premedication with 150 μg clonidine did not prevent postoperative sore throat or hoarseness, and may have exacerbated these symptoms.     

Effects of Granulocyte-Colony Stimulating Factor on the Polymorphonuclear Leukocyte Activity and the Course of Sepsis in Rats with Experimental Peritonitis

Purpose Polymorphonuclear leucocytes (PML) play an essential role in the host immune response to severe infections. The effects of granulocyte-colony stimulating factor (G-CSF) on the PML immune functions during serious abdominal infection and course of sepsis, and on the survival in rats with peritonitis are the main subjects of this study. Methods The first phase of the study was carried out on 30 Wistar-albino rats equally divided into three groups; Group 1 (control) sham laparotomy; Group 2 (peritonitis); and Group 3 (peritonitis+G-CSF) with fecal peritonitis created by a cecal puncture. At postoperative hours 3, 12, and 24, 0.5 ml normal saline was injected subcutaneously in groups 1 and 2, and 0.5 ml solution containing 50 μg/kg of G-CSF in group 3. The phagocytic and chemotactic activities of neutrophils and monocytes were evaluated by a flow cytometry analysis. The plasma lactate concentrations were assessed as a marker of tissue perfusion during sepsis. The second phase was a survival analysis, which was observed during 10 days on 20 rats equally divided into two groups; group 1 (peritonitis) and group 2 (peritonitis+G-CSF). 0.5 ml normal saline in group 1 and 50 μg/kg of G-CSF in group 2 was injected subcutaneously at the 3rd hour and twice daily. Results Both the neutrophil- (1.636 vs 2.236) and monocyte-related (1.789 vs 2.465) phagocytic activities significantly (P < 0.001) improved after the G-CSF administration in the rats with peritonitis. In addition, the G-CSF treatment significantly (P < 0.0014) improved the chemotactic activity (1.18 vs 2.75) of neutrophils, and partly supported (P < 0.0952) the chemotactic activity (1.69 vs 2.37) of monocytes. The plasma lactate level (1.86 vs 4.9 mmol/l) was significantly (P < 0.0001) increased after septic changes due to experimental peritonitis. On the other hand, the lactate concentration was significantly (P < 0.001) decreased (4.9 vs 2.63 mmol/l) after the G-CSF administration. The survival was 20% at the 4th day and 0 at the 6th day in peritonitis, and 90% at the 4th day (P = 0.0055) and 80% at the 6th day (P = 0.0007) days in the peritonitis+G-CSF groups. Conclusion G-CSF enhances the immune functions of neutrophils and monocytes. The increased activities of these cells have a beneficial effect on the enhancement of the host immune response during severe infections. The improved immune function of PML due to the G-CSF treatment thus ameliorates the survival and the courses of sepsis, which is also defined by tissue perfusion and the cellular oxygen balance, which is affected by septic changes.     

Alendronate treatment promotes bone formation with a less anisotropic microstructure during intramembranous ossification in rats

There are safety concerns regarding administration of bisphosphonates to children. Little is known about the effects of bisphosphonates on bone matrix organization during bone modeling. The present study examined the effects of alendronate (ALN) on bone matrices formed by intramembranous ossification in the appendicular growing skeleton. ALN was administered to 1-week-old Sprague–Dawley rats at a dose of 0, 35, or 350 μg/kg/week for 4 or 8 weeks. The position of femoral diaphysis formed exclusively by intramembranous ossification was identified, and cross sections of cortical bone at this position were analyzed. Bone mineral density (BMD) and geometric parameters were evaluated using peripheral quantitative computed tomography. The preferential orientation degree of biological apatite (BAp) crystals in the bone longitudinal direction, which shows the degree of bone matrix anisotropy, was evaluated using microbeam X-ray diffraction analysis. We analyzed bone histomorphometrical parameters and performed bone nanomechanical tests to examine the material properties of newly developing cortical bone. The preferential orientation degree of BAp crystals significantly decreased in 35 μg/kg/week ALN-treated groups compared with vehicle-treated groups, although there were no significant differences in BMD between the two groups. The periosteal mineral apposition rate significantly increased in the 35 μg/kg/week ALN-treated group. We found a high negative correlation between bone matrix anisotropy and the regional periosteal mineral apposition rate (r = −0.862, P < 0.001). Nanomechanical tests revealed that 35 μg/kg/week ALN administration caused deterioration of the material properties of the bone microstructure. These new findings suggest that alendronate affects bone matrix organization and promotes bone formation with a less anisotropic microstructure during intramembranous ossification.     

Cardioprotective effect and mechanism of action of landiolol on the ischemic reperfused heart

Purpose The authors examined the cardioprotective effect of landiolol, an ultra short-acting, highly selective β1-blocker, and its role in cardiac work, antioxidative effect, and sarcoplasmic reticulum (SR) function in hearts subjected to ischemia-reperfusion. Methods Isolated guinea pig hearts were subjected to ischemia-reperfusion by stopping the perfusion for 45 min and reperfusing. Before the ischemia, hearts were treated with landiolol (20, 100, or 500 μM) for 15 min (LAN group). In another set of experiments, before ischemia, hearts were washed out for 15 min after treatment with landiolol (WO group). In other hearts, the tissue concentration of malondialdehyde was measured after reperfusion. We also examined the phosphorylation of phospholamban at Ser¹⁶ and Thr¹⁷residues to evaluate the SR function. Results After 90 min of reperfusion, left ventricular pressure (LVP) was restored significantly in the LAN-500 μM group regardless of heart rate. However, the improvement in recovery in LVP disappeared in the WO group. The tissue malondialdehyde levels were decreased in the LAN group compared with those in the control group. In the control group, the phosphorylation of phospholamban at Ser¹⁶ and Thr¹⁷ residues was markedly increased after reperfusion. Landiolol at 500 μM suppressed the increase of phosphorylation at Ser¹⁶ residues. Conclusion The present study demonstrated that landiolol had a lipid peroxidation-reducing effect and suppressed the increase in phospholamban phosphorylation at the Ser¹⁶ residue in hearts subjected to ischemia-reperfusion. These findings indicate that landiolol may have an anti-ischemic effect, via an antioxidant effect and/or via preserving SR function during the ischemic period. Presented in part at the annual meeting of the American Society of Anesthesiologists, Las Vegas, Nevada, October 23–27, 2004.     

Peri-operative glucocorticoid replacement therapy in transsphenoidal pituitary adenoma surgery: a prospective controlled study

Summary Background. We set out to prospectively study the peri-operative changes of the hypothalamic-pituitary-adrenal axis (HPA), and to test the hypothesis that the peri-operative corticoid replacement regimen used at the authors’ institution in patients with impaired HPA undergoing transsphenoidal pituitary adenoma surgery is adequate. Method. Thirty seven patients (21 females, 16 males, mean age 50.6 years) underwent transsphenoidal pituitary adenoma surgery (mean tumour diameter 20.6 mm, 13 tumours hormone-secreting). The HPA functions of these patients were classified as impaired (group A, n = 15) or preserved (group B, n = 22) according to the results of a pre-operative corticotrophin releasing-hormone test (CRHT). Eleven patients (9 female, 2 male, mean age 53.6 years) without pituitary adenomas and with a preserved HPA (as assessed by medical history and morning serum cortisol (MSC) measurements), undergoing decompressive surgery for degenerative lumbar disc disease, were also studied (group C). On the day of surgery, the patients of group A received 100 mg hydrocortisone (HC) replacement therapy, which was thereafter gradually tapered off in a standardised fashion. The patients of groups B and C were not treated with corticoids. Pre-operative, intra-operative and post-operative variables of these three patient groups were compared. Findings. The urinary free cortisol excretion (UFC) in group A declined from 6732 ± 7683 μg/d on the day of surgery to 305 ± 358 μg/d on the 10^th post-operative day. In group B, the respective UFC values were 12851 ± 16278 μg/d and 223 ± 235 μg/d. In both of these groups, the mean UFC did not fall into the normal range during the first ten post-operative days. On none of the post-operative days, was there a significant difference between the UFC of groups A and B. The UFC values of group C dropped from 177 ± 157 μg/d on the day of surgery to 87 ± 61 μg/d on post-operative day six, reaching the normal range from the 2^nd post-operative day onwards. All UFC values of group C were significantly lower than those of group A and B. None of the evaluated clinical, laboratory and MRI parameters, as disclosed by uni- and multivariate analysis, showed any significant influence on the peri-operative UFC values. Conclusions. The peri-operative UFC of pituitary adenoma patients with preserved HPA was very high, as compared to patients with degenerative lumbar disc disease. The present study showed for the first time, that the proposed regimen of peri-operative corticoid replacement therapy used in patients with pituitary adenomas and impaired HPA raised cortisol levels to match the physiological increase of UFC in patients with pituitary adenoma surgery and preserved HPA. However, although statistically not significant, the UFC of patients with pituitary adenomas and preserved HPA seemed considerably higher on the day of surgery than in patients with pituitary adenomas and HPA impairment. Although there is no evidence to make it mandatory, administration of 150 mg instead of 100 mg HC substitution on the day of pituitary adenoma surgery in patients with HPA impairment may be prudent. Correspondence: Rudolf A. Kristof, M.D., Universit?tsklinikum Bonn, Klinik und Poliklinik für Neurochirurgie, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany.     

Endogenous Porphyrin Production in Bacteria by δ-Aminolaevulinic Acid and Subsequent Bacterial Photoeradication

. In the present study we examined the effects of the accumulation of endogenous porphyrins on the microorganisms Staphylococcus aureus and Escherichia coli. δ-Aminolaevulinic acid (δ-ALA) 50 μg/ml can induce production of large amounts of porphyrins when incubated with the bacteria in the dark. This porphyrin production within the cells was examined directly by a fluorescence activated cell sorter (FACS) instrument and a significant increase in red fluorescence was observed. Incubation of δ-ALA with these microorganisms did not slow down their growth. δ-ALA or δ-ALA methyl ester induced accumulation of uroporphyrin in S. aureus cells and excretion of coproporphyrin into the growth medium. In E. coli, these inducers resulted in the accumulation of uroporphyrin and protoporphyrin within the cells and excretion of coproporphyrin and protoporphyrin from the cells. Photoinactivation of the porphyrin-loaded bacteria can be achieved by various light sources, depending on the dose. The most effective photokilling of S. aureus and of E. coli by its endogenic porphyrins was achieved by blue light (400–450 nm) at approximately 50 J/cm². With red light (600–700 nm), a 10-fold higher light dose was required to get a similar result for S. aureus killing. With a laser beam (632.8 nm), 50 J/cm² was necessary for 3 orders of decrease in the viability of S. aureus. With white light, 75 J/cm² was needed for 2–3 orders of decrease of S. aureus viability. With the last two light sources eradication of E. coli required at least 10 times higher doses of light. It seems that S. aureus is more susceptible than E. coli to photosensitisation when it is loaded with endogenous porphyrins. Ultrastructural alterations were observed in the bacteria incubated with δ-ALA in the dark and photosensitised by blue light (400–450 nm). Filamentous chromosomes were observed in E. coli, whereas honeycomb mesosomes were observed in S. aureus, with a destruction of the area around these mesosomes in the chromosomal area. The method described here is an additional approach to the photoinactivation of bacteria by porphyrins, with photoinactivation being accomplished by endogenous porphyrins. Paper received 6 October 1998; accepted after revision 12 April 1999.     

High dosage treatment of nitrogen-containing bisphosphonate ibandronate is required for osseointegration of cementless metal implants

Background There is evidence that application of a bisphosphonate can improve fixation of cementless metal implants by enhancing the extent of osseointegration, but the required dose regimen is still under discussion. The current preclinical study was designed to determine the optimal treatment dose of the nitrogen-containing bisphosphonate ibandronate to improve osseointegration of cementless metal implants. Methods The study was conducted in 52 female Sprague-Dawley rats in which uncoated and hydroxyapatite-coated titanium implants were surgically inserted into the medullary canal of each femur. The animals were randomly assigned to receive subcutaneous treatment with ibandronate 1 μg/kg body weight (osteoporosis dose) or 25 μg/kg (tumor dose) per day or saline solution for control. Results Histomorphometric evaluation revealed a significant enhanced extent of osseointegrated implant surface in the high-dose treatment group for both implants compared to the low-dose group and the control group. No significant differences were observed between the two implants in any group. Conclusions The results of the present study indicate that improved osseointegration of hydroxyapatite-coated and uncoated titanium implants is dose-dependent and requires high-dose application of bisphosphonate ibandronate equivalent to that needed to treat patients with tumor disease. Lower doses equivalent to those for treatment of osteoporosis showed no beneficial effect.     

Bone Tissue Ablation with sub-µs Pulses of a Q-switch CO<Subscript>2</Subscript> Laser: Histological Examination of Thermal Side Effects

. The goal of this study is an in vitro evaluation of thermal side-effects by the application of short sub-μs CO₂ laser pulses in combination with an air–water spray on different types of bone tissue. A mechanically Q-switched CO₂ laser delivered 300 ns pulses at 9.6 μm wavelength, which were focused down to a spot size of 440 μm on the tissue (a corresponding energy density of 9 J/cm²). Bone samples (blocks from pig femur, rib, or cartilage) were moved through the beam repeatedly until 1–5 mm deep cuts were produced. An air driven water spray was applied to prevent the tissue dehydration. Subsequent visual and histological examinations revealed no carbonisation, melting traces or fissuring of the tissue. An extremely narrow, 2–6 μm thick thermally altered layer was observed at the cut border in compacta and cartilage. No accumulation of the thermal damage occurred with increasing cut depth. Laser incisions in trabecular tissue were accompanied with a 100–200 μm thick zone of thermal necrosis in bone marrow. The difference from compacta and cartilage can be explained considering the particular character of the spreading of the ablation products in the trabecular meshwork. Minor thermal side effects make the Q-switched and probably other short pulsed CO₂ laser systems interesting for hard tissue surgery. Paper received 16 November 2001; accepted after revision 23 April 2002. Correspondence to: M.M. Ivanenko, Centre of Advanced European Studies and Research, Friedensplatz 16, 53111 Bonn, Germany. Fax: +49 (0) 228/96 56-111; E-mail: ivanenko@caesar.de     

Landiolol attenuates the cardiovascular response to tracheal intubation

Purpose The objective of this prospective study was to compare the cardiovascular responses with or without landiolol to the induction of general anesthesia and tracheal intubation. Methods Twenty-two patients were randomly allocated to receive a loading dose of landiolol 125 μg kg⁻¹ min⁻¹ for 1 min followed by an infusion at 40 μg kg⁻¹ min⁻¹ for 4 min, or placebo. Four minutes after landiolol or placebo was started, propofol and succinylcholine were administered. Laryngoscopy and tracheal intubation were performed 1 min after the administration of succinylcholine. Heart rate and blood pressure were measured noninvasively every minute. Results A significant attenuation of the heart rate and blood pressure response were seen in the landiolol group for 3 min after intubation. Heart rate and systolic blood pressure in the landiolol group were decreased for 2 min before intubation and just before intubation compared with baseline, srespectively. Conclusion Continuous administration of landiolol before tracheal intubation results in the attenuation of cardiovascular response for tracheal intubation.