Differential removal of thymidine nucleotide analogues from blocked DNA chains by human immunodeficiency virus reverse transcriptase in the presence of physiological concentrations of 2'-deoxynucleoside triphosphates.

Removal of 2',3'-didehydro-3'-deoxythymidine-5'-monophosphate (d4TMP) from a blocked DNA chain can occur through transfer of the chain-terminating residue to a nucleotide acceptor by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). ATP-dependent removal of either d4TMP or 3'-azido-3'-deoxythymidine-5'-monophosphate (AZTMP) is increased in AZT resistant HIV-1 RT (containing D67N/K70R/T215F/K219Q mutations). Removal of d4TMP is strongly inhibited by the next complementary deoxynucleoside triphosphate (50% inhibitory concentration [IC(50)] of approximately 0.5 microM), whereas removal of AZTMP is much less sensitive to this inhibition (IC(50) of >100 microM). This could explain the lack of cross-resistance by AZT-resistant HIV-1 to d4T in phenotypic drug susceptibility assays.

Emergency, acute, and surgical management of spine trauma.

OBJECTIVES: To assess trends in emergency, acute, and surgical management of spinal cord injury (SCI), and evaluate the relations between surgery and the occurrence of specific complications. SETTING: Model SCI Care Systems. DESIGN: Case series. PARTICIPANTS: Consecutive samples of 3,756 acute spinal injuries admitted to the Midwest Regional Spinal Cord Injury Care System between 1990 and 1999, 2,204 individuals admitted to a Model SCI System within 24 hours of injury before 1995, and 941 individuals who were injured between December 1995 and August 1998 and were admitted to a Model System within 24 hours of injury. MAIN OUTCOME MEASURES: Frequencies of injury types, nonoperative treatment and types of spine surgeries, and time sequence associated complications including postoperative wound infections, pressure ulcers, deep vein thrombophlebitis, pulmonary embolism, and pneumonia or atelectasis. RESULTS: Eighty-eight percent of cases entering a Model System through acute care were admitted within 72 hours of injury, 85% were admitted within 24 hours. Comparing 1990 with 1998, the number of persons admitted to Model Systems within 72 hours of injury declined 11%. Operative treatment within the Model Systems increased 5% (p < .01), with increases due to decompression surgeries. Complication rates of nonoperative and surgical cases were not different. CONCLUSIONS: The reduction in 72-hour admissions suggests an increasing percentage of admissions are directly to rehabilitation at a Model System after receiving acute care elsewhere. The increase in the use of surgical procedures involving surgical decompression of the spine is probably due to advances in surgical technology and increased experience and confidence in spine surgery. Surgery does not influence complication development beyond the usual expectations for those who sustain SCI.

A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase.

Mutations in HIV-1 reverse transcriptase (RT) give rise to 3'-azido-3'-deoxythymidine (AZT) resistance by a mechanism that has not been previously reproduced in vitro. We show that mutant RT has increased ability to remove AZTMP from blocked primers through a nucleotide-dependent reaction, producing dinucleoside polyphosphate and extendible primer. In the presence of physiological concentrations of ATP, mutant RT extended 12% to 15% of primers past multiple AZTMP termination sites versus less than 0.5% for wild type. Although mutant RT also unblocked ddAMP-terminated primers more efficiently than wild-type RT, the removal of ddAMP was effectively inhibited by the next complementary dNTP (IC50 approximately equal to 12 microM). In contrast, the removal of AZTMP was not inhibited by dNTPs except at nonphysiological concentrations (IC50 > 200 microM).

Management of an unstable lumbar fracture with a laminar split.

This is a case report describing the injury sustained by a 36-year-old man injured in a motorcycle crash who sustained a fracture dislocation of L2 upon L3, associated with a split in the lamina of L3. His neurologic lesion was T12 ASIA B: with a motor score of 52 but with preservation of sensory function (sensory score 96) in most parts of his lower extremities. He also suffered a lower extremity fracture. Imaging of the spine is presented showing a multiplanar fracture associated with translation and with a defect in the lamina that may be seen in certain AO type B or type C fractures, that may entrap the lumbar spinal nerve roots. Discussants of this case comment on the classification and clinical significance of this fracture pattern. and present their operative approaches, both for management of this particular fracture pattern and for any associated dural tear. The issues of steroid use and the place of rehabilitation are also discussed.

Diffuse idiopathic skeletal hyperostosis in the cervical spine.

The disease processes diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and ossification of the posterior longitudinal ligament are similar in pathology and can lead to unexpected but grossly unstable fractures that may not be diagnosed until neurologic change occurs in cases of trivial trauma. A retrospective study of 29 patients with cervical spinal fractures and diffuse idiopathic skeletal hyperostosis-like pathologies was done. Twenty patients with an average age of 62 years were treated surgically (six neurologically complete, five incomplete, nine intact). Three patients with an average age of 70 years died postoperatively (one complete, two incomplete). Nine patients with an average age of 65 years were treated conservatively (five neurologically complete, two incomplete, two intact). All patients with intact neurologic function survived. It is suggested, therefore, that all elderly patients with diffuse idiopathic skeletal hyperostosis-like pathology, history of trivial trauma, and complaint of neck pain be examined carefully for fractures, because mortality rates increase sharply in patients with decreased neurologic function.

Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism.

HIV-1 replication is inhibited by the incorporation of chain-terminating nucleotides at the 3' end of the growing DNA chain. Here we show a nucleotide-dependent reaction catalyzed by HIV-1 reverse transcriptase that can efficiently remove the chain-terminating residue, yielding an extendible primer terminus. Radioactively labeled 3'-terminal residue from the primer can be transferred into a product that is resistant to calf intestinal alkaline phosphatase and sensitive to cleavage by snake venom phosphodiesterase. The products formed from different nucleotide substrates have unique electrophoretic migrations and have been identified as dinucleoside tri- or tetraphosphates. The reaction is inhibited by dNTPs that are complementary to the next position on the template (Ki approximately 5 microM), suggesting competition between dinucleoside polyphosphate synthesis and DNA polymerization. Dinucleoside polyphosphate synthesis was inhibited by an HIV-1 specific non-nucleoside inhibitor and was absent in mutant HIV-1 reverse transcriptase deficient in polymerase activity, indicating that this activity requires a functional polymerase active site. We suggest that dinucleoside polyphosphate synthesis occurs by transfer of the 3' nucleotide from the primer to the pyrophosphate moiety in the nucleoside di- or triphosphate substrate through a mechanism analogous to pyrophosphorolysis. Unlike pyrophosphorolysis, however, the reaction is nucleotide-dependent, is resistant to pyrophosphatase, and produces dinucleoside polyphosphates. Because it occurs at physiological concentrations of ribonucleoside triphosphates, this reaction may determine the in vivo activity of many nucleoside antiretroviral drugs.

Postoperative drains at the donor sites of iliac-crest bone grafts. A prospective, randomized study of morbidity at the donor site in patients who had a traumatic injury of the spine.

A prospective, randomized study was performed to assess the effectiveness of postoperative closed suction drainage. One hundred and twelve consecutive procedures involving autologous iliac-crest bone graft were performed, from December 29, 1992, to July 1, 1993, following a traumatic injury of the spine in 108 patients. Sixty of the sites from which the bone graft had been obtained were drained with a single large Hemovac device. The drains were maintained for two to five days postoperatively. The remaining fifty-two incisions were closed without a drainage device. All patients were evaluated clinically for problems with wound-healing. The incisions were considered to be healed when they had been asymptomatic for one year. Of eleven patients who had problems with wound-healing, six had been managed with a drain and five had not. The findings of this study do not support the routine use of drainage at the donor sites of iliac-crest bone grafts.

Seat-belt use and relation to neurologic injury in motor vehicle crashes.

The relation between seat-belt use and neurologic injury was examined for the 1,352 patients who had spinal injuries as the result of motor vehicle crashes and were subsequently admitted to the Midwest Regional Spinal Cord Injury Center at Northwestern University between 1971 and 1993. Intact lesions were observed in 44% of patients (Frankel level E), complete lesions in 28% (Frankel A), sensory intact lesions in 8% (Frankel B), motor intact lesions in 5% (Frankel C), and functional motor lesions in 14% (Frankel D). Whereas only 14% of the sample were wearing seat belts, 60% of the belted and 41% of the unbelted vehicle occupants had intact lesions. The odds of surviving a motor vehicle crash with an intact injury were greater for patients who were wearing a lap or shoulder belt (odds = 1.57) for women (odds = 0.63) and for patients whose injury occurred more recently (odds = 1.05). The relation between position in the vehicle and extent of injury was strongest for rear passengers: intact lesions were sustained by 73% of belted and 35% of unbelted rear passengers, whereas complete lesions were sustained by 9% of the belted and 21% of the unbelted rear passengers. In conclusion, seat belts appear to be an effective means of decreasing the extent of neurologic deficit in those sustaining spinal injuries caused by motor vehicle crashes. The results of this study support injury-prevention efforts that emphasize lap- and shoulder-belt use.

Peripheral vascular disease in spinal cord injury patients: a difficult diagnosis.

The timely detection of peripheral vascular disease (PVD) in spinal cord injury (SCI) patients is difficult because the usual symptoms of claudication and rest pain are absent. In fact, the initial manifestation of PVD in SCI patients is often advanced gangrene, so that healing, primarily or following major amputation, is either difficult and prolonged or impossible. In addition, sacral and ischial pressure sores common among SCI patients may be exacerbated and reconstruction made more difficult by PVD. Five SCI patients presented with lower extremity gangrene as the initial recognized manifestation of PVD at our institution between January 1992 and January 1994. All 5 patients had risk factors for PVD. Four out of ten limbs in these patients required amputation, either above the knee or below the knee. Three patients required concurrent vascular reconstruction of the aortoiliac segments, including an aortobiprofunda femoral bypass, an iliac embolectomy with femoral-femoral bypass, and iliac angioplasty. Three patients had ischial and/or sacral pressure sores that had recurred following multiple musculocutaneous flap reconstructions before vascular disease was recognized. The timely diagnosis of PVD involving the iliac segment in the SCI patient is sometimes overlooked and is often necessary to optimize the treatment of both lower extremity ulcers and sacral/ ischial pressure sores common among these patients.

Towards a research agenda for pharmaceutical issues.

Currently, the most important issue in US pharmaceutical policy is probably cost containment. Research into pharmaceutical issues should therefore concentrate on this area. Analysis of changing trends in pharmaceutical expenditures, particularly during the early 1990s, would be a useful starting point. Research into the costs and returns associated with the development of pharmaceuticals, and into the levels, constituent parts, and impact on system costs of pharmaceutical expenditures would also be helpful. Cost-containment systems themselves should also be studied, particularly in terms of how they work, what they cost, what they save, their effects on patients, their effects on patterns of drug diffusion, and their impact on drug research and development as well as on international competitiveness.

Gastrointestinal tract complications after acute spine injury.

OBJECTIVES: To determine the incidence, risk factors, and mortality rate of gastrointestinal complications in patients with acute spine injury and to derive methods by which mortality can be reduced. DESIGN: Case series. SETTING: Regional tertiary care center. PATIENTS: Consecutive sample of 1952 patients with acute spine injury with complete medical records who were admitted from 1981 through 1990. MAIN OUTCOME MEASURES: Gastrointestinal tract complications, age, sex, time from injury to admission, cause of injury, level of spine injury, neurologic deficit, head injury, injury to other organ systems, incidence of surgical intervention for spine injury, length of hospital stay, and mortality rate. RESULTS: The incidence of gastrointestinal complications was 1.9%. Gastrointestinal hemorrhage was the most frequent complication. Risk factors for gastrointestinal complications were increasing age (P < .02), male sex (P < .01), injury to other organ systems (P < .02), head injury (P < .02), cervical spine injury (P < .02), and neurologic deficit (P < .005). The mortality rate was 19% in patients with gastrointestinal complications, significantly greater (P < .005) than the 2.9% rate in patients without gastrointestinal complications. CONCLUSIONS: Gastrointestinal complications after acute spine injury are uncommon but frequently lethal. Prophylaxis against hemorrhage and earlier diagnosis and surgical intervention are recommended.

Hyponatremia in acute spinal cord injury.

OBJECTIVE: To define the occurrence rate, time course, and potential etiologic factors of hyponatremia in patients with acute spinal cord injury. DESIGN: Analysis of data obtained from a retrospective review of medical records and from a systematized, prospective database pertaining to patients with spinal cord injury. SETTING: A university hospital with a federally funded regional spinal cord injury center and a dedicated spinal cord injury intensive care unit. PATIENTS: Two hundred eighty-two patients admitted between January 1, 1988 and December 31, 1989 with acute (< 24-hr duration) spinal cord or vertebral column injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean age of patients was 36.7 +/- 17.6 (SD) yrs; 225 (80%) of the patients were male and 57 (20%) were female. Hyponatremia, when it occurred, developed at a mean time of 6.4 +/- 6.7 days postadmission, reached its nadir at 8.7 +/- 8.8 days, and occurred in 28% of those patients with cervical injuries, 34% with thoracic injuries, and 27% with lumbar injuries (p = NS). Logistic regression analysis demonstrated that the type of spinal cord injury (Frankel class: range is A = complete neurologic lesion to E = no neurologic lesion) was the strongest predictor of hyponatremia. The occurrence rate of hyponatremia was as follows: Frankel class-A 62%; Frankel class-B 48%; Frankel class-C 41%; Frankel class-D 23%; Frankel class-E 16% (p < .0001). CONCLUSIONS: The prevalence of hyponatremia in acute spinal cord injury is much higher than in the general medical or surgical patient population. This abnormality usually occurs within the first week postinjury. The most significant predictor of hyponatremia is the type rather than the level of spinal cord injury. The potential etiological factors are many and these factors are probably interrelated. The pathophysiological mechanisms that result in hyponatremia must be explored so that this occurrence and its consequences can be prevented.

The changing environment for US pharmaceuticals.

Health reform is currently the predominant health policy issue in the US. It carries profound implications for the pharmaceutical field, including the possibility of price controls that could stifle pharmaceutical research. While policy makers are contemplating alternative approaches to reform, the marketplace for pharmaceuticals has changed dramatically. For example, price increases have lessened, price discounting has increased, and new drugs are typically launched at prices lower than those of the leading product in the therapeutic class. These changes are driven in part by the growth of managed care. Further evidence of change in the industry is the number of job reductions announced and the decline in market valuation of pharmaceutical companies. Policy makers need to take the changed marketplace into consideration as they proceed with health reform, to avoid layering additional policy impediments on top of an increasingly harsh and unforgiving market. Such an approach could seriously compromise incentives for pharmaceutical research.

Complications in three-column cervical spine injuries requiring anterior-posterior stabilization.

A study was undertaken to elicit the hidden factors that, when identified, would signal the presence of cervical spine instability. Data were derived from the records and radiographs of 21 patients having sustained traumatic injury to the lower cervical spine (C3-C7) and who failed a single-stage posterior stabilization procedure necessitating a second (or combined) anterior-posterior arthrodesis. Mechanism of injury most frequently identified in this group was the distraction-flexion (locked facets) pattern (nine patients) and the "tear drop" compression-flexion injury pattern (seven patients). All 21 patients underwent a posterior wiring and bone graft stabilization procedure with persistent postoperative instability. Thus, failure to recognize the presence of "three-column" instability, the sine qua non of this group, resulted in the failure of posterior tension band stabilization as a means of gaining cervical spine stability. Three-column cervical spine instability is suspected in the presence of: 1) retrolisthesis and angulation of the superior vertebra on the next inferior vertebra; 2) distraction of the posterior interspinous ligaments sufficient to allow subluxation or dislocation of the facets; in conjunction with 3) a "shear" dislocation of one vertebra on another. Anterior shearing force through the disc space is capable of disrupting the intervertebral disc, along with disruption of the anterior and posterior longitudinal ligaments, each contributing to the presence of anterior and middle column cervical spine instability.

Traumatic spondylolisthesis of the lower cervical spine: case report.

A case of traumatic spondylolisthesis of C6 and C7 is presented. The mechanism of injury and the therapeutic implications are discussed.

The use of sublaminar cables to replace Luque wires.

Sublaminar wires have been used in conjunction with posterior instrumentation to stabilize the spine. Sublaminar wiring has fallen into disfavor because of an increase in neurologic complications with the Luque technique as well as wire breakage, dural tears, and difficulty of removal. A cable system consisting of two 49-stranded stainless steel cables connected to one malleable leader was designed to overcome these shortcomings. Biomechanical testing revealed that the maximum yield strength of a single stainless steel cable loop was 2.85-2.94 times greater than a double 0.05-in. stainless steel wire loop. The fatigue tests demonstrated that the stainless steel cables required 6-22 times more cycles to failure than the stainless steel wire. Many of the titanium cables failed immediately under higher loads (0-100 lb) because of slipping of the crimp. The preliminary clinical results after a mean of 19 months of follow-up of 245 cables are encouraging. There has been no breakage or loosening of the cables and no complications associated with the use of the cables. The stainless steel cables are very strong, but more important, the cable flexibility prevents repeated contusions to the spinal cord during insertion of the rods and tightening of wires. The cable conforms to the undersurface of the lamina. This may lead to a decrease in neurologic complications.

Spinal cord injury.

The evaluation and treatment of spinal cord injury continues to evolve, enhanced by new imaging modalities. Their application in reference to the cervical, thoracic, and lumbar spine is discussed. Treatment options, both conservative and surgical, are outlined.