Effect of dynamization on gap healing of diaphyseal fractures under external fixation

We asked whether dynamization of externally fixed diaphyseal fractures could improve bone healing in comparison to rigid fixation of fractures having similar remaining gap sizes. To answer this question we evaluated metatarsal osteotomies in 12 sheep. The osteotomy with a 0.6-mm gap was stabilized with a specially designed high bending and torsional stiffness external ring fixator. Osteotomies in six sheep were stabilized rigidly (axial movement < 0.06 mm) or dynamically (axial movement 0.15-0.34 mm). The cyclical axial interfragmentary movement was caused by the load-bearing of the operated limb. With increasing healing time, the initially allowed movement was decreased by callus formation around the osteotomy. The reduction in interfragmentary movement was measured and monitored by a linear variable displacement transducer at the external fixator and a telemetry system. After 9 weeks the sheep were sacrificed and the healed bones were investigated biomechanically and histomorphologically. Compared to the rigidly fixed osteotomies, the dynamized osteotomies showed significantly (P < 0.05) greater (+41%) callus formation and 45% greater tensile strength of the newly formed bone in the cortical osteotomy gap. Histological analysis indicated that the effect of dynamization occurred mainly after the 5th week. RELEVANCE: From these results we conclude that dynamic fixation of diaphyseal gaps is advantageous in comparison to stable external fixation.     

New derivatives of kanamycin B obtained by modifications and substitutions in position 6". 1. Synthesis and microbiological evaluation

The clinical use of the potent, wide-spectrum aminoglycoside antibiotics is limited by oto- and nephrotoxicities. The latter is related to the binding of these polycationic drugs to negatively charged phospholipids and to the subsequent inhibition of lysosomal phospholipases. In order to explore the influence of a modification of the hydrophobic/hydrophilic balance at a specific site of an aminoglycoside, kanamycin B has been chemically modified in position 6" by substitution of the hydroxyl group with a halogen atom (or a pseudohalogen group), or an amino, an amido, a thioalkyl, or an alkoxy group, each series containing increasingly bulkier chains. Examination of the antibacterial activity of the synthesized compounds revealed a negative correlation between the size of the 6"-substituent and the antibacterial activity against kanamycin B sensitive Gram-positive and -negative organisms. Only derivatives with small substituents in position 6", namely chloro, bromo, azido, amino, methylcarbamido, acetamido, methylthio, methylsulfinyl, O-methyl, O-ethyl, and O-isopropyl, showed acceptable activity (geometric mean of minimum inhibitory concentrations for Gram-negative strains less than or equal to 2.5 mg/L; value for kanamycin B, 0.5 mg/L). In vitro toxicological evaluation of all derivatives and computer-aided conformational analysis of selected compounds inserted in a phosphatidylinositol monolayer are presented in the following paper in this issue.     

New derivatives of kanamycin B obtained by combined modifications in positions 1 and 6". Synthesis, microbiological properties, and in vitro and computer-aided toxicological evaluation

Substitution of the C-1 atom in the 2-deoxystreptamine moiety of gentamicin C2, a broad-spectrum aminoglycoside antibiotic, by an axial hydroxymethyl group has been reported to confer protection against most clinically important bacterial enzymes inactivating aminoglycosides, while simultaneously reducing the nephrotoxic potential of this drug. We report here on a similar modification of kanamycin B. Microbiological evaluation, however, revealed no useful protection, as established by the almost complete lack of activity of 1-C-(hydroxymethyl)kanamycin B against an array of organisms producing defined types of aminoglycoside-inactivating enzymes and against which 1-C-(hydroxymethyl)gentamicin C2 and amikacin (1-N-[(S)-2-hydroxy-4-aminobutyryl]kanamycin A) are active. Moreover, toxicological evaluation, based on the in vitro measurement of the drug inhibitory potential toward lysosomal phospholipases, a predictive test of the intrinsic nephrotoxic potential of aminoglycosides, showed not decreased but rather increased toxicity. Comparative conformational analysis of the interactions of the drug with a phosphatidylinositol monolayer explained the lack of protective effect, since no significant change of the mode of insertion of the derivative in this monolayer was detected compared to that of kanamycin B. Combination of a 1-C-(hydroxymethyl) substituent with a 6"-chloro, 6"-acetamido substituent resulted in a partial improvement of the toxicological behavior with no loss of activity for the 6"-chloro and the 6"-azido derivatives, but not to the extent of obtaining better derivatives than kanamycin B itself. We, therefore, suggest that the advantages of an axial hydroxymethyl substituent at C-1 are probably restricted to the gentamicin family and do not extend to kanamycins. It might be concluded that the structural differences between gentamicins and kanamycins play an important, still undescribed role both in their effective recognition by aminoglycoside-inactivating enzymes, which are responsible for most of the clinically important cases of resistance to aminoglycosides, and also in the interactions with phospholipids, which in turn cause nephrotoxicity.     

Method for Dissection of Mesenteric Metastases in Mid-gut Carcinoid Tumors

With adequate medical management the midgut carcinoid tumor generally is an indolent malignancy associated with substantial life expectancy and appreciable life quality, even in the presence of liver metastases and significant tumor burden. Abdominal complications may occur in this entity of carcinoids owing to entrapment of intestines and encasement of mesenteric vessels by mesenteric metastases and associated marked mesenteric fibrosis. This may be the cause of abdominal pain, disabling diarrhea, weight loss to the extent of malnutrition, and eventually the risk of death with acute or chronic intestinal obstruction or intestinal gangrene. Operative removal of the mesentericointestinal lesion is often indicated to prevent or treat these complications but may be technically difficult when mesenteric metastases extend in the vicinity of major vessels in the mesenteric root. At laparotomy 56 patients with advanced midgut carcinoids underwent removal of the mesenteric tumor with a method for preserving the mesenteric vessels. This was feasible by mobilizing and releasing the right colon and mesenteric root from posterior adhesions, identifying the mesenteric artery below the pancreas, and free-dissecting this artery on the tumor capsule in the mobilized mesentery. Dissection was successful even with tumors initially judged inoperable unless tumor growth completely surrounded the mesenteric vessels or extended retroperitoneally. One patient was subjected to distal intestinal artery bypass. Symptom relief was been substantial and often of long duration after mesenteric tumor removal in patients who prior to surgery often had threatening intestinal ischemia. Patients with advanced midgut carcinoids may benefit markedly from dissectional removal of mesenteric tumors, which (conceivably better than conventional wedge resection) preserves the length of the remaining intestine.     

Effects of specimen length on the monosegmental motion behavior of the lumbar spine

STUDY DESIGN: An in vitro biomechanical analysis of the segmental motion behavior of the same segments in polysegmental (five segments), bisegmental, and monosegmental specimens using sheep lumbosacral spines. OBJECTIVES: To investigate the effect of specimen length on monosegmental motion behavior. These data may be helpful in planning in vitro tests and in comparing results of studies using specimens of different lengths. SUMMARY OF BACKGROUND DATA: The length of spinal specimens used for in vitro stability tests varies greatly, depending on the purpose of the study. Some investigators prefer testing specimens with one adjacent segment on either end of the region of interest. Others favor specimens as short as possible. METHODS: In a first step, seven sheep spine specimens, L3-S1 (note that sheep spines normally have seven lumbar vertebrae), each were tested without preload in a spine-loading apparatus. Alternating sequences of pure lateral bending, flexion/extension, and axial rotation moments (+/-3.75 Nm) were applied continuously. The motion in each single segment was measured simultaneously. Then, these polysegmental specimens were cut into two bisegmental specimens, L3-L5 and L6-S1, and tested in the same way. Finally, another vertebra was removed to obtain two monosegmental specimens, L3-L4 and L7-S1, and to test them as described. RESULTS: In general, the range of motion at L3-L4 and L7-S1 was smaller when tested in polysegmental than in monosegmental specimens. In polysegmental specimens (five segments), the range of motion at L3-L4 and L7-S1 was approximately 80% (range, 70.6-92.5%) and in bisegmental specimens approximately 95% (range, 66.7-100%) of their range of motion measured in monosegmental specimens. Neutral zone and coupled motions showed the inverse behavior. Significant differences were found. However, they were not consistent with either the loading direction or with the specimen length. CONCLUSIONS: For comparison of results, the specimen length should be kept constant within one experiment. Segmental motion behavior of specimens with different lengths should be compared only qualitatively.     

Subsidence resulting from simulated postoperative neck movements: an in vitro investigation with a new cervical fusion cage

STUDY DESIGN: A biomechanical in vitro subsidence test of different cervical interbody fusion devices was performed using a new testing protocol that simulates physiologic conditions. OBJECTIVES: To investigate the effect of simulated postoperative neck movements on the subsidence of the new WING cervical interbody fusion cage in comparison with two other cages and bone cement. SUMMARY OF BACKGROUND DATA: Cervical interbody fusion cages sometimes cause complications because of subsidence into the adjacent vertebrae with collapse of the intervertebral space. Complications such as cage dislocation or nonunion with instability also have been reported. To prevent such complications, the new WING cervical interbody fusion cage (Medinorm AG, Quierschied, Germany) has been developed. Its area of contact with the adjacent vertebrae is supposed to be large enough to resist excessive subsidence and small enough to prevent stress protection of the tissue growing in the cage. METHODS: In this study, 24 human cervical spine specimens were tested after stabilization with either a WING, BAK/C, AcroMed I/F cage or bone cement. Then, in a new testing protocol, 700 pure-moment loading cycles (+/-2 Nm) were applied in randomized directions (lateral bending, flexion-extension, and axial rotation alone or in combination with each other) to simulate the patient's neck movements during the first few postoperative days. Measurements of the subsidence depth (total height loss) in combination with flexibility tests (+/-2.5 Nm) were performed before cyclic loading and after 50, 100, 200, 300, 500, and 700 loading cycles. RESULTS: Cyclic loading caused subsidence in all four device groups, most distinct with BAK/C-cages (1.63 mm after 700 loading cycles) followed by the new WING (0.90 mm) and the AcroMed (0.82 mm) cages. No statistically significant difference could be found among the three cage designs. However, all three cage types showed a significantly higher subsidence depth than bone cement (0.48 mm;P = 0.023 between each of the three cage-types and bone cement). A moderate correlation between bone mineral density and subsidence depth could be found only in the BAK/C group (r2 = 0.495). A large subsidence depth after 700 loading cycles was associated with a large flexibility increase in the WING (r2 = 0.786) and AcroMed groups (r2 = 0.21), but with a small flexibility increase in the BAK/C group (r2 = 0.58). CONCLUSIONS: Postoperative neck movements caused subsidence in all cervical interbody implant types. The new WING cage and the AcroMed cage seemed to have a better resistance against subsidence than the BAK/C cage. However, all three cage types had a significantly higher subsidence tendency than bone cement.     

A Systematic Overview of Radiation Therapy Effects in Cervical Cancer (Cervix Uteri)

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for cervical cancer is based on data from 1 meta-analysis and 34 randomized trials. In total, 35 scientific articles are included, involving 7 952 patients. The results were compared with those of a similar overview from 1996 including 34 024 patients. The conclusions reached can be summarized in these points: There are limited scientific data supporting that postoperative pelvic radiotherapy improves disease-free survival in early cervical cancer. No firm conclusion can be drawn.There is moderate scientific evidence that external beam radiotherapy combined with brachytherapy gives a similar disease-free and overall survival rate as radical hysterectomy in early cervical cancer.There is strong scientific evidence that concomitant radiochemotherapy improves disease-free and overall survival compared to radiotherapy alone in early cervical cancer.The NCI has recently published an announcement stating that cisplantin-based chemotherapy should be used concomitantly with radiotherapy in cervical cancer. No solid documentation for this statement can be found concerning locally advanced stages (>IIB).There is a strong scientific evidence that cisplatin-based chemotherapy given concomitantly with radiotherapy is superior to concomitant chemotherapy with hydroxyurea.There is no scientific evidence to show that neoadjuvant chemotherapy followed by radiotherapy improves disease-free or overall survival compared to radiotherapy alone in patients with localized cervical cancer.There is moderate scientific evidence that high-dose-rate brachytherapy gives the same local control rate as low-dose-rate brachytherapy but with fewer rectal complications.     

In vitro cell behavior of human osteoblasts after physiological dynamic stretching

The cell activity of human bone derived cell cultures was studied after mechanical stimulation by cyclic strain at a magnitude occurring in physiologically loaded bone tissue. Monolayers of subconfluently grown human bone derived cells were stretched in rectangular silicone dishes with cyclic uniaxial movement along their longitudinal axes. Strain was applied over two days for 30 min per day with a frequency of 1 Hz and a strain magnitude of 1000 mustrain. Cyclic stretching of the cells resulted in an increased proliferation (10-48%) and carboxyterminal collagen type I propeptide release (7-49%) of human cancellous bone derived osteoblasts while alkaline phosphatase activity and osteocalcin release were significantly reduced by 9-25% and 5-32% respectively. These results demonstrate that cyclic strain at physiologic magnitude leads to an increase of osteoblast activities related to matrix production while those activities which are characteristic for the differentiated osteoblast and relevant for matrix mineralization are decreased.     

Validating the EQ-5D with time trade off for the German population

The aim of this survey study was to derive the societal values of the general public for the EuroQol EQ-5D. Using the same protocol as previously used in the United Kingdom, we compared the German values with the British. In face-to-face interviews a sample of 339 individuals in northern Germany valued 15 different health states from a sample of 36 states. Values were derived using the York MVH protocol for time trade-off (TTO) and a visual analogue scale (VAS). Values for all 243 health states of the EQ-5D were estimated by a regression model. The VAS values revealed close a resemblance to the British VAS results. German TTO values were higher than the British. This was especially the case for the worse health states. The results suggest that the TTO values are more related to national variables than values derived by VAS. The use of the TTO values of this investigation makes it possible to anticipate these cultural differences in studies carried out in Germany.