Potential Causative Factors Research Articles

Progress in xenotransplantation following the introduction of gene-knockout technology

The production of alpha1,3-galactosyltransferase gene-knockout (GT-KO) pigs has overcome the barrier of preformed anti-Galalpha1,3Gal (Gal) antibodies that has inhibited progress in pig-to-primate organ xenotransplantation for many years. Survival of GT-KO pig organs in nonhuman primates is currently limited by the development of a thrombotic microangiopathy that results in increasing ischemic injury of the transplanted organ over weeks or months. Potential causative factors include vascular endothelial activation from preformed anti-nonGal antibodies or cells of the innate immune system that recognize nonGal pig antigens directly, and coagulation dysregulation associated with molecular incompatibilities between pig and primate. Carefully isolated pancreatic islets from wild-type (genetically unmodified) adult pigs express minimal Gal epitopes, allowing survival sometimes for weeks or months after transplantation into nonhuman primates receiving immunosuppression directed only at T-cell function. However, there is a considerable immediate loss of islets, probably related to activation of coagulation and complement cascades. Further genetic manipulation of organ-source pigs is therefore required to overcome these problems. GT-KO pigs expressing a human complement-regulatory protein, e.g. decay-accelerating factor, and/or an 'anti-coagulant' gene, e.g. human tissue factor pathway inhibitor, might prevent the change in vascular endothelium from an anti-coagulant to a procoagulant phenotype, and protect the islets from early loss.

High incidence of myelodysplasia and secondary leukaemia in the UK Medical Research Council Pilot of autografting in chronic lymphocytic leukaemia

We report a high incidence of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) in patients entered into the preceding Medical Research Council Chronic Lymphocytic Leukaemia Pilot study of autografting [corrected] Of 115 newly diagnosed patients treated with fludarabine, 65 patients proceeded to autologous transplant. Conditioning was cyclophosphamide and total body irradiation in 49 (75%) patients and chemotherapy in 12 (18%). Ten patients have developed MDS/AML; eight had undergone an autograft. Five-year actuarial risk of developing MDS/AML postautograft was 12.4% (95% confidence interval, 2.5-24%). No analysed potential risk factor was predictive for MDS/AML development. We hypothesise that potential causative factors are fludarabine, low cell dose and transplant conditioning.

Assessment of changes in the seagrass-dominated submerged vegetation of tropical Chwaka Bay (Zanzibar) using satellite remote sensing

Spatial and temporal dynamics of submerged aquatic vegetation (SAV) cover were studied in the relatively pristine and seagrass-dominated area of Chwaka Bay, Zanzibar (Tanzania) by using satellite remote sensing. Through complementary field work the potential of the technique for change detection was verified. The general changes in SAV cover were examined using Landsat images from 1986, 1987, 1998, 2001 and 2003. Two of these images, from 1987 (Landsat TM) and 2003 (Landsat ETM+), were specifically analysed to create a map of the change in SAV cover. Overall, the general distribution of SAV stayed fairly stable over the period investigated, but the result also showed regions where significant alterations, both losses and gains, had occurred between the two years. Based on our findings and anecdotal information from local fishermen and seaweed farmers potential causative factors are discussed. It was concluded that a repeated mapping with satellite remote sensing is a suitable tool to monitor changes of seagrass and seaweed distribution in shallow tropical environments.

Psychiatric aspects of head injury management

Acute damage to the brain may lead to many changes in a patient's behaviour and some of these behavioural changes will lead to the involvement of a psychiatrist. This article emphasizes that the usual clinical psychiatric approach is still appropriate, within the constraints of the situation. The specific skill needed is to analyze the behaviour in terms of all the potential causative factors. This is best done within the illness model derived from the World Health Organization's International Classification of Functioning (outlined in this article). In essence, one needs to establish whether the person has any ‘hidden’ specific neurological impairments, and to consider their context (physical, social and personal). The main fact to bear in mind is that brain injury is rarely the specific direct cause of irrational or unacceptable behaviour. The important influences are usually the environment, the person's pre-existing behavioural patterns, drugs (licit and illicit), and less commonly perceptual or cognitive losses. Management of difficult behaviour occurring in the early stages after brain damage is largely one of preserving safety through providing a suitable environment, including one-to-one care if needed while recovery occurs. Later it is likely that the brain injury is a specific factor, and management will be as it would be for anyone else presenting with similar problems. Time spent understanding why a behaviour arises will usually ensure the optimal management.

Drug-induced Prolongation of the QT Interval: What’s the Point?

In his recent editorial,1Scuderi appropriately suggested that the action of the US Food and Drug Administration (FDA) in placing a “black box” on the use of low-dose droperidol for the treatment and prevention of postoperative nausea and vomiting “is clearly specious and does a tremendous disservice to the American public.”Although the editorial is excellent, it incorrectly stated that White et al. 2“demonstrated a prolongation of QTc when droperidol (either 0.625 or 1.25 mg) is administered intravenously” for antiemetic prophylaxis. In fact, the effect of low-dose droperidol was not found to be different from saline (placebo). Given the rigid position taken by the FDA decision makers in this matter, these findings clearly do not simply “restate the obvious” in their mind. In performing our recently published study,2we encountered a patient with sinus bradycardia and a corrected “baseline” QT interval of 419 ms on her 12-lead preoperative screening electrocardiographic tracing. According to Liu and Juurlink,3the corrected QT interval is considered to be prolonged if it is greater than 450 ms in men or greater than 460 ms in women. Although she was not entered into the study and did not receive any antiemetic or antibiotic drugs known to prolong the QT interval during surgery, we performed serial 12-lead electrocardiographic tracings after surgery. On arrival in the recovery room after the patient underwent a superficial operation for removal of a small mass in her neck with use of a propofol–remifentanil intravenous anesthetic technique, the QTc was found to be prolonged to 685 ms. Subsequent 12-lead electrocardiographic tracings at hourly intervals before discharge revealed QTc values of 720, 615, 742, and 641 ms at 1, 2, 3, and 4 h after surgery, respectively. The patient’s postoperative recovery was completely uneventful, and she was discharged home despite the persistently prolonged QTc interval. If this patient had received droperidol (or one of the 5-hydroxytryptamine type 3 antagonists4) for antiemetic prophylaxis, this otherwise “unexplained” prolongation of the QTc interval in the postoperative period would almost certainly have been incorrectly ascribed to the antiemetic drug.In a recent perspective on drugs and the QT interval, Liu and Juurlink3stated that “most of what is known about drug-induced QT-interval prolongation derives from spontaneous reporting mechanisms.” Unfortunately, these anecdotal reports are not subject to peer-review, and other potential causative factors for a resultant dysrhythmia are often overlooked. Analogous to the widely used antibiotic erythromycin, droperidol has been successfully used by anesthesiologists for the treatment and prevention of postoperative nausea and vomiting in millions of patients during the past 30+ years.5,6As a result of the FDA-imposed “black box” warning mandating additional electrocardiographic monitoring when this cost-effective antiemetic is administered, droperidol has been effectively eliminated from the anesthesiologist’s armamentarium at many medical centers in this country and abroad. As pointed out by Roden7in his recent review article on drug-induced prolongation of the QT interval, “since rare side effects occur with many otherwise highly-effective drugs, their withdrawal from the market probably harms more patients than it helps.”In the opinion of many clinicians around the world, the FDA’s recent obsession with drug-induced QT prolongation is an example of “making a mountain out of a molehill.”8Could someone please explain the basis for the FDA’s preoccupation with an apparent nonproblem of QT prolongation in the population at large?*University of Texas Southwestern Medical Center, Dallas, Texas. paul.white@utsouthwestern.edu

Transhepatic Catheter-directed Thrombectomy and Thrombolysis of Acute Superior Mesenteric Venous Thrombosis

To evaluate clinical outcomes after percutaneous treatment of superior mesenteric vein (SMV) thrombosis. A retrospective chart review was conducted of all patients with SMV thrombosis treated with percutaneous catheter-directed thrombectomy/thrombolysis. The demographics of the study population, potential causative factors contributing to SMV thrombosis, and morbidity and mortality associated with therapy were assessed. Eleven patients (mean age, 44.3 years +/- 12.8) with SMV thrombosis were treated with percutaneous transhepatic catheter-directed thrombectomy/thrombolysis. Potential causative factors included recent major abdominal surgery, thrombophilic conditions, pancreatitis, and repetitive abdominal trauma. The mean duration between the onset of symptoms and percutaneous treatment was 8.6 days +/- 6.5. Computed tomography confirmed the clinical diagnosis in nine patients (81.8%). One patient (9.1%) had a bleeding complication, which was treated by chest tube drainage without long-term sequelae. One patient (9.1%) with refractory SMV thrombosis died of sepsis and multiple organ failure. No recurrent episode of SMV thrombosis or mortality was documented during a mean follow-up of 42 months +/- 22.5. Percutaneous transhepatic catheter-directed thrombectomy/thrombolysis for SMV thrombosis is associated with a rapid improvement in symptoms and low incidences of long-term morbidity and mortality. Percutaneous thrombectomy and thrombolysis should be considered in all patients with acute SMV thrombosis without evidence of bowel necrosis.

Rehabilitation interventions after mild head injury

This review examines current management and rehabilitation strategies for mild traumatic brain injury, with emphasis on the need to address multiple potential causative factors in order to enhance outcomes and to conduct more controlled efficacy studies. Whilst most individuals who sustain mild traumatic brain injury make a good recovery, a proportion experience significant ongoing disability. In some cases this is due to diffuse axonal injury and cognitive impairment, but in others symptoms are exacerbated by factors such as pain, stress, personality issues or litigation, or in children, previous head injury, behavioural or learning difficulties. Provision of information early after injury results in reduced symptom reporting in adults and children. There is also a need, however, to address these other factors in treatment. Psychological therapy using a cognitive behavioural approach may be helpful, but controlled evaluations of such interventions have been lacking. Recent uncontrolled studies have examined the impact of computer-mediated interventions to remediate visual and verbal processing and oculomotor problems and the impact of quantitative electroencephalography. More rigorous efficacy studies of these approaches are needed. Guidelines for management of sports-related concussion and timing of return to play also require a more solid scientific basis. The evidence base for management of mild traumatic brain injury is still very limited. There is a need to conduct more carefully controlled prospective studies and examine the influence of factors not directly related to the brain injury as a basis for formulating more uniform management guidelines.

High Incidence of Myelodysplasia and Secondary Leukemia in the UK MRC Pilot Study of Autografting in Chronic Lymphocytic Leukemia.

In the MRC CLL Pilot Study of autografting conducted between 1996 and 2001 115 newly diagnosed patients were treated with a median of 6 cycles of fludarabine (range 3–8). In addition 26 patients received further treatment, mainly the addition of cyclophosphamide to fludarabine, CHOP or alemtuzumab, in order to achieve either CR, nPR or PR. Progenitor cells were mobilised with cyclophosphamide 2g/m2 and G-CSF. Sixty-five patients were autografted with cyclophosphamide and TBI conditioning or BEAM (20%). The median CD34 cell dose for transplanted patients was 2.6x106/Kg (range 0.75–3.9). Ten patients have subsequently developed AML/MDS at a median 3.5 years after starting treatment (range 2.5–7 years). Eight patients had undergone an autograft and 2 had received fludarabine alone and not proceeded to transplant. The actuarial risk of developing MDS/AML post autograft was 12.4% at 5 years (CI 0.7–24%). At the time of diagnosis of MDS/AML all the patients had either complex cytogenetics or/and deletion of chromosomes 5 or 7. These abnormalities were not detectable by FISH on the pre-transplant harvested material. Analysis of potential risk factors (age, stage of disease, previous treatment, cell dose, conditioning type) demonstrated only age as a possible factor (p<0.05). This frequency of post transplant MDS has been reported in low grade lymphomas but not previously in autografts for CLL. We hypothesise that this patient population may be particularly at risk of secondary MDS/AML and that potential causative factors are fludarabine, a low cell dose and transplant conditioning. [Display omitted]

An in vivo model to assess factors that may stimulate the generation of an immune reaction to erythropoietin

The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (s.c.) administration of epoetin alfa (EPREX®) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, in vivo models were developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). It was difficult to generate anti-EPO antibodies in mice. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to increase both the frequency of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some mice exhibited a reduction in hematocrit, suggesting neutralization of endogenous EPO by anti-EPO antibodies. To evaluate the primary lead identified in the technical investigation, leachates from the uncoated syringe stoppers of EPREX® syringes, a surrogate antigen (chicken egg albumin, OVA) was used to avoid possible interferences that could arise from the use of an endogenous protein like EPO. These leachates yielded a positive, concentration-dependent antibody response in the OVA animal model, demonstrating their adjuvant properties and providing support for the hypothesis generated through the technical investigation that leachates were capable of enhancing the immune response to rHuEPO.

Early hypocalcemia in severe trauma*

We tested the hypothesis that colloid-induced hemodilution can induce hypocalcemia in the early phase of severe trauma resuscitation and tried to assess other potential causative factors of that hypocalcemia. Prospective cohort. Level I academic trauma center. Consecutive severe trauma patients (n = 212, mean Injury Severity Score 34) resuscitated in the prehospital phase without any blood transfusion. At admission, ionized calcium (corrected to an arterial pH = 7.40) was measured. Hypocalcemia was defined as a value <1.15 mmol/L and severe hypocalcemia as a value <0.9 mmol/L. A normal ionized calcium concentration was observed in 56 (26%) patients, a mild ionized hypocalcemia (1.05 +/- 0.06 mmol/L) in 135 (64%) patients, and a severe ionized hypocalcemia (0.77 +/- 0.10 mmol/L) in 21 (10%) patients. There were significant correlations between ionized calcium concentration with the amount of infused colloid (R = .658, p < .001) and arterial pH (R = .760, p < 0.001) but not with the amount of infused crystalloid (R = .007, not significant). Despite taking into account hemodilution, arterial pH, binding of calcium to lactates, and colloids, some patients had marked differences (>15%) between calculated and observed ionized calcium, and these patients had more severe trauma and more frequently had acidosis and/or prehospital cardiac arrest. Using the TRISS methodology, survival was not significantly different from that expected in this trauma population. Hypocalcemia frequently occurs on arrival at the hospital in severe trauma patients, and colloid-induced hemodilution and severe shock and/or ischemia-reperfusion appear to be important causative factors.

A recent greening of the Sahel—trends, patterns and potential causes

For the last four decades there has been sustained scientific interest in contemporary environmental change in the Sahel (the southern fringe of the Sahara). It suffered several devastating droughts and famines between the late 1960s and early 1990s. Speculation about the climatology of these droughts is unresolved, as is speculation about the effects of land clearance on rainfall and about land degradation in this zone. However, recent findings suggest a consistent trend of increasing vegetation greenness in much of the region. Increasing rainfall over the last few years is certainly one reason, but does not fully explain the change. Other factors, such as land use change and migration, may also contribute. This study investigates the nature of a secular vegetation trend across the Sahel and discusses several potential causative factors.

Modeling the Role of Zebra Mussels in the Proliferation of Blue-green Algae in Saginaw Bay, Lake Huron

Between 1991 and 1993, Saginaw Bay experienced an invasion by zebra mussels, Dreissena polymorpha, which caused a significant perturbation to the ecosystem. Blooms of Microcystis, a toxin-producing blue-green alga, became re-established in the bay after the zebra mussel invasion. Microcystis blooms had all but been eliminated in the early 1980s with controls on external phosphorus loadings, but have re-occurred in the bay most summers since 1992. An apparent paradox is that these recent Microcystis blooms have not been accompanied by increases in external phosphorus loadings. An ecosystem model was used to investigate whether the re-occurrence of Microcystis could be due to changes caused by zebra mussels that impacted phytoplankton community structure and/or internal phosphorus dynamics. The model was first used to establish baseline conditions in Saginaw Bay for 1991, before zebra mussels significantly impacted the system. The baseline model was then used to investigate: (1) the composite impacts of zebra mussels with average 1991–1995 densities; (2) sensitivity to changes in zebra mussel densities and external phosphorus loadings; and (3) three hypotheses on potential causative factors for proliferation of blue-green algae. Under the model assumptions, selective rejection of blue-green algae by zebra mussels appears to be a necessary factor in the enhancement of blue-green production in the presence of zebra mussels. Enhancement also appears to depend on the increased sediment-water phosphorus flux associated with the presence of zebra mussels, the magnitude of zebra mussel densities, and the distribution of zebra mussel densities among different age groups.

The Influence of Muscle Fatigue on Electromyogram and Plantar Pressure Patterns as an Explanation for the Incidence of Metatarsal Stress Fractures

Background Stress fractures are common overuse injuries in runners and appear most frequently in the metatarsals. Purpose To investigate fatigue-related changes in surface electromyographic activity patterns and plantar pressure patterns during treadmill running as potential causative factors for metatarsal stress fractures. Study Design Prospective cohort study with repeated measurements. Methods Thirty experienced runners volunteered to participate in a maximally exhaustive run above the anaerobic threshold. Surface electromyographic activity was monitored for 14 muscles, and plantar pressures were measured using an in-shoe monitoring system. Fatigue was documented with blood lactate measurements. Results The results demonstrated an increased maximal force (5%, P < .01), peak pressure (12%, P < .001), and impulse (9%, P < .01) under the second and third metatarsal head and under the medial midfoot (force = 7%, P < .05; pressure = 6%, P < .05; impulse = 17%, P < .01) toward the end of the fatiguing run. Contact area and contact time were only slightly affected. The mean electromyographic activity was significantly reduced in the medial gastrocnemius (-9%, P < .01), lateral gastrocnemius (-12%, P < .01), and soleus (-9%, P < .001) muscles. Conclusion The demonstrated alteration of the rollover process with an increased forefoot loading may help to explain the incidence of stress fractures of the metatarsals under fatiguing loading conditions.

Development of an In Vivo Model To Assess Factors That May Stimulate the Generation of an Immune Reaction to Epoetin Alfa.

The incidence of pure red cell aplasia (PRCA) in patients with chronic kidney disease associated with the subcutaneous (sc) administration of epoetin alfa (EPREX®) began to increase in 1998. As part of an intensive investigation into the reasons for this increase, an in vivo model was developed to assess the ability of potential causative factors to stimulate an immune response to recombinant human erythropoietin (rHuEPO). Due to species differences in protein sequence and as well as antigen processing and/or presentation, animal models cannot fully predict immunogenicity in humans. However, changes in relative immunogenicity have been readily detected in animal models. Moreover, transgenic animals have been utilized to negate the effects due to sequence differences between species. The EPO sequence is highly homologous between mouse and man. We found it difficult to generate anti-EPO antibodies in both human EPO transgenic mice and two normal mouse strains (Balb/c and BD-F1). To mitigate the complicating factors associated with the transgenic model (e.g. difficulty breeding, improper regulation of EPO production), normal mouse strains were selected for the development of animal models. Mice were injected sc with rHuEPO weekly for 4–6 weeks. Serum samples were analyzed 1–2 weeks following the last injection to ensure complete clearance of the injected protein. Serum samples were screened by an ELISA and/or by a surface plasmon resonance (BIAcore) method. In animals injected with rHuEPO alone, anti-EPO antibodies were either absent or present at very low levels. The addition of an adjuvant to the immunization protocol was able to boost both the rate of occurrence and titer of the immune response and resulted in the generation of anti-EPO antibodies that, in most cases, recognized both human and mouse EPO. Some of the mice exhibited a dramatic reduction in hematocrit, suggesting that the anti-EPO antibodies neutralized endogenous EPO. The development of an anti-EPO antibody response in humans is an extremely rare event that cannot be reproduced in an animal model without significant manipulation of the system (e.g. use of an adjuvant with doses of EPO considerably higher than therapeutic levels). Nevertheless, the fact that anti-EPO antibodies can develop with an appropriate immunization protocol allows for this model to be used to evaluate factors that may potentiate an immune response to rHuEPO.

The epidemiology of diffuse lamellar keratitis.

To report the incidence and outcomes of diffuse lamellar keratitis (DLK) after LASIK and to analyze potential causative factors. Retrospective review of 15,119 cases (11,232 primary procedures and 3887 enhancements) from 7168 patients undergoing LASIK from May 1995 through October 2002, comparing preoperative data and postoperative outcomes for each case developing DLK to patients in the study population and a control series of eyes that did not develop DLK. We identified 61 eyes (0.40%) that developed DLK after LASIK. Three study groups were identified based on sterilization protocols used: (1) steam autoclave without reservoir (8348 cases), (2) cassette autoclave with reservoir (6771 cases), (3) steam autoclave without reservoir and new instrument cleaner (1758 cases). Significantly more eyes developed DLK with Protocol 2 (47 cases, 0.94%) than with Protocol 1 (11 cases; 0.1%; P < 0.0001) or Protocol 3 (3 cases, 0.2%; P < 0.0005). There was no significant difference in the incidence of DLK in Protocol 1 versus Protocol 3. DLK was significantly more common after primary procedures than with enhancement procedures only under Protocol 2. No individual developed DLK after more than 1 procedure. Treatment protocols included frequent topical steroids only (24 cases, 39.3%), frequent topical steroids and oral steroids (19 cases, 31.2%), or topical and oral steroids combined with lifting and irrigating beneath the flap (18 cases, 29.5%). Final refractions and visual acuities were not significantly different in eyes that developed DLK and those that did not. DLK is a nonspecific inflammatory response to multiple stimuli that cannot be attributed solely to individual variation in the inflammatory response, the microkeratome, or material deposited by the microkeratome. Sterilizers with reservoirs may cause some cases of DLK. With appropriate diagnosis and treatment, DLK should resolve without sequelae, yielding visual outcomes comparable to cases with uneventful postoperative courses.

A model for the management of an atypical endophthalmitis outbreak.

To present a model for the assessment, investigation, and management of an atypical outbreak of infectious endophthalmitis of indeterminate aetiology. A published statistical model was used to determine when the case-load constituted an outbreak. Intraocular surgery was discontinued and a multidisciplinary infection control team was formed aimed at identifying potential causative factors among the following categories: environment around theatre, preoperative preparation, intraoperative theatre practices, intraoperative surgical practices, postoperative practices, equipment maintenance guidelines, cleaning/sterilization practices, and microbiological screening. Five cases of postoperative endophthalmitis developed following uncomplicated phacoemulsification cataract surgery by different surgeons over a 7-month period. Despite full investigation no single focus of infection could be determined. Four out of five cases were culture positive. Three grew Streptococcus viridans of different strains. The fourth culture grew Staphylococcus aureus. In the absence of a single causative factor, it was postulated the combined effect of multiple potential factors may have led to an increased bacterial load and subsequent infection rate. Improved practices were initiated including new cleaning protocols to combat the build-up of debris on phacoemulsification instruments. Cataract surgery was resumed with 3-monthly microbiological monitoring. There have been no further cases in the 12 months following the changes. Outbreaks of endophthalmitis typically present over a short time period and could often be attributed to a single infective cause. We present our experience of detecting and managing this cluster and recommend a 'ground-up' multidisciplinary model to manage future outbreaks of this devastating condition.

Occlusion of Internal Mammary Grafts: a review of the Potential Causative Factors

The outcome of patient undergoing CABG is largely dependant on the long-term patency of the conduit used. Internal mammary artery (IMA) is considered whenever possible due to its improved long-term functionality over saphenous vein graft. However, a 10% rate of late arterial closure is described without well-known predictors. Chronic competition induced by a moderate coronary lesion on the bypassed native vessel is thought to be a major factor of arterial graft shrinkage even if conflicting data are reported in the available literature. Therefore, the decision to use an IMA to bypass a moderate native coronary lesion should be carefully weighted. When angiography is doubtful, more accurate functional investigations should be considered. Among them, pressure-derived fractional flow reserve could give an immediate answer of whether an intermediate lesion should be bypassed.

Marked reduction in serum high-density lipoprotein cholesterol concentrations in a woman with acute inflammation due to diabetic gangrene

Background: C-reactive protein (CRP) is a well-established, sensitive marker of systemic inflammation and the risk of cardiovascular disease. High-density lipoprotein (HDL) is an anti-atherogenic lipoprotein known to be regulated by genetic and acquired factors. Methods: The patient was a 77-year-old Japanese woman, who was diagnosed with type 2 diabetes mellitus (DM), with a body height of 152 cm and a weight of 65 kg (body mass index 28.1 kg/m 2). She suffered from diabetic foot gangrene in her right foot with high-grade fever when she visited our hospital. Her plasma glucose (PG) concentration and serum CRP were markedly elevated being 21.6 mmol/l and 370 mg/l, respectively, while her serum HDL-C concentrations were markedly low being 0.13 mmol/l. She was immediately admitted to our hospital and received intensive insulin treatment, along with intravenous-administration of antibiotics. Her general conditions were gradually improved and the high-grade fever disappeared, with concentrations of plasma PG and serum CRP being reduced, and concurrent reciprocal increase in her serum HDL-C concentrations. Results: To determine the potential causative factors responsible for the drastic change in serum HDL-C concentrations, we investigated the relationship of serum HDL-C to serum CRP, serum total protein (TP) and PG. Serum CRP and PG showed inverse relationships with serum HDL-C, while serum TP concentrations showed a positive association with HDL-C. After multivariate analyses with CRP, TP and PG as independent variables and serum HDL-C as dependent variable, CRP maintained its independent association with serum HDL-C. CRP also showed inverse correlations with lipoprotein lipase (LPL) mass and cholesteryl ester transfer protein mass. Conclusions: In acute inflammation and poorly controlled diabetes, CRP is suggested to be inversely associated with serum HDL-C, independent of PG and TP.

Snowmobile injuries and fatalities in children

Background/Purpose: Snowmobiling is a popular form of wintertime recreation but can be associated with significant morbidity and mortality. To better understand snowmobile trauma in children, medical records were reviewed, evaluating the relationships between demographic data, mechanisms, and resultant injuries. In addition, because prior studies of childhood snowmobile fatalities have reviewed only national databases, state and national data were combined to evaluate possible underreporting. Methods: Medical records were reviewed of children ≤17 years old admitted to one trauma center between 1991 and 2000 with snowmobile-related injuries. Demographics, helmet usage, driver versus passenger, mechanism, injuries, injury severity score (ISS), and outcome data were recorded. Statistical analyses were performed to identify relationships between potential causative factors and ISS. State mortality data were acquired from state agencies and 2 databases of the U.S. Consumer Product Safety Commission (CPSC). Data from the 3 sources were compared, and a single list of fatalities was compiled and evaluated. Results: Thirty-one children (65% boys; mean age, 12 years) were admitted with snowmobile-related injuries. Fifty-two percent were driving the snowmobile. Helmet usage was 68%. The most common mechanisms were collisions with a fixed object (42%) and with a motor vehicle (35%). The head was the most commonly injured site (71%) followed by the extremities (58%). ISS ranged from 1 to 38 (median, 10). Increased age and the child driving were the only factors associated with increased ISS (P <.05). One child died of a massive head injury. Twenty-two fatalities (70% boys; mean age, 14 years) statewide were identified from state and national databases, only 12 of which were identified by the CPSC Death Certificate file. Head injury was the most common cause of death. Conclusions: Reckless snowmobiling leads to significant morbidity and mortality among children. Prior reports based on CPSC data likely underestimated the number of snowmobile-related fatalities. Our findings support previous American Academy of Pediatrics recommendations, including the restriction of snowmobile driving by children under 16, graduated licensing for older children, and universal helmet usage. J Pediatr Surg 38:784-787. © 2003 Elsevier Inc. All rights reserved.

Radiofrequency therapy of the lower esophageal sphincter for treatment of GERD.

Recent years have witnessed the introduction of a multitude of novel therapies for GERD. Prominent among these is the Stretta procedure, an endoluminal therapy in which radiofrequency energy is delivered to the esophagogastric junction (EGJ). At first glance that may seem a strange way to treat what is generally thought to be either an oversensitive or overstimulated distal esophagus. However, in other organ systems radiofrequency energy has been shown capable of ablating aberrant nerve pathways as in Wolf-Parkinson-White syndrome,1 tightening lax tissue as in damaged joints,2 shrinking the prostate in benign prostatic hypertrophy,3 shrinking liver tumors,4 and volumetric reduction of the palate in snoring and sleep apnea.5 In each case, the mechanism of action targets the underlying pathophysiology of the disease process, be it neurolysis or tissue necrosis with subsequent scarring. Thus, the underlying hypothesis of the Stretta procedure is that one or both of these potential effects will prove beneficial in the treatment of GERD. If there is one true cliche of GERD it is that it is a heterogeneous clinical entity with a multitude of potential causative factors that has consistently defied all attempts at a simple definition. Consider for example the definition of GERD recently labored over by the Genval workshop, “...all individuals who are exposed to the risk of physical complications from gastrooesophageal reflux, or who experience clinically significant impairment of health related well being (quality of life) due to reflux related symptoms, after adequate assurance of the benign nature of their symptoms.”6 This definition was carefully crafted so as to encompass the multitude of GERD syndromes including the following: (1) esophagitis and its complications with or without corresponding esophageal symptoms, (2) esophageal symptoms without corresponding esophagitis or complications of esophagitis, or (3) extraesophageal reflux-related symptoms with or without accompanying esophageal manifestations. Clearly, if it is so difficult to define an entity, one can anticipate equal difficulty in finding a uniformly effective therapy. A corollary of that is that a multitude of potential therapies can be anticipated. One need spend little time on the Internet to appreciate that this prediction has been realized. It is from this perspective that the Stretta procedure will be analyzed. First, what is actually known about the physiologic effects of this intervention? Second, what are the resultant effects of this intervention on each potential manifestation of GERD?