The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells.

Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen-associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro-inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient-based clinical research in this area of human and veterinary medicine.

Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer.

A phase-I trial to assess the safety and tolerability of human interleukin-12 (IL-12) plasmid (phIL-12) formulated with a synthetic lipopolymer, polyethyleneglycol-polyethyleneimine-cholesterol (PPC), was conducted on women with chemotherapy-resistant recurrent ovarian cancer. A total of 13 patients were enrolled in four dose-escalating cohorts and treated with 0.6, 3, 12 or 24 mg m(-2) of the formulated plasmid once every week for 4 weeks. Administration of phIL-12/PPC was generally safe and well-tolerated. Common side effects included low-grade fever and abdominal pain. Stable disease and reduction in serum CA-125 levels were clinically observed in some patients. Measurable levels of IL-12 plasmid were detectable in PF samples collected throughout the course of phIL-12/PPC treatment. In comparison, serum samples either did not contain detectable amounts of plasmid DNA or contained <1% of the amount found in the corresponding PF samples. Treatment-related increases in IFN-gamma levels were observed in PF but not in serum. These data demonstrate that IL-12 gene delivery with a synthetic delivery system is feasible for ovarian cancer patients.

The role of arterial stimulation and simultaneous venous sampling in addition to cross-sectional imaging for localisation of biochemically proven insulinoma.

Insulinomas, although rare, cause considerable morbidity but are frequently amenable to surgical cure. Laparoscopic surgery can now be considered if the tumour is localised pre-operatively, but the optimal imaging approach has not been determined. The objective of this study was to evaluate the ability of different imaging investigations, including CT, MRI, endoscopic ultrasound, octreotide scintigraphy and arterial stimulation with simultaneous venous sampling (ASVS), to localise insulinomas. All patients with biochemically proven insulinoma at our institution underwent ASVS along with other imaging investigations as part of their routine investigation. The results of these investigations were compared with histological findings. Twenty-eight patients with biochemically proven insulinoma confirmed by histology were identified. Ultimately ASVS localised a lesion in all patients. Seventeen patients (61%) had laparoscopic surgery. Tumor-detection rates for other imaging investigations included 43.5% of cases using CT, 71% using MRI, 86% using endoscopic ultrasound and 33% using octreotide scintigraphy. In four patients, the ASVS was the only test to correctly localise the lesion. ASVS should be considered routinely before surgery to ensure accurate localisation of insulinomas.

Brainstem hypoperfusion in severe symptomatic vasospasm following aneurysmal subarachnoid hemorrhage: role of basilar artery vasospasm.

BACKGROUND: The hemodynamic effects of vertebrobasilar vasospasm are ill defined. The purpose of this study was to determine the effects of basilar artery (BA) vasospasm on brainstem (BS) perfusion. METHODS: Forty-five patients with delayed ischemic neurological deficits (DIND) following aneurysmal subarachnoid hemorrhage (SAH) underwent cerebral angiography prior to decision-making concerning endovascular treatment. BA diameter was compared with baseline angiogram. Regional brainstem (BS) cerebral blood flow (CBF) was qualitatively estimated by (99m)Tc ethyl cysteinate dimer single photon emission computed tomography (ECD-SPECT). FINDINGS: Delayed BS hypoperfusion was found in 22 (48.9%) of 45 patients and BA narrowing of more than 20% was found in 23 (51.1%). Seventeen of 23 (73.9%) patients with BA narrowing of more than 20% experienced BS hypoperfusion compared to 6 of 22 (27.3%) patients with minimal or no narrowing (p = 0.0072). Patients with severe and moderate BS hypoperfusion had higher degree of BA narrowing compared to patients with normal BS perfusion and mild BS hypoperfusion (p < 0.001). The three-month outcome of patients n-22) with BS hypoperfusion was significantly worse compared to patients (n-23) with unimpaired (p = 0.0377, odd ratio for poor outcome 4, 1.15-13.9 95% confidence interval). INTERPRETATION: These findings suggest that the incidence of BA vasospasm in patients with severe symptomatic vasospasm is high and patients with significant BA vasospasm are at higher risk to experience BS ischemia. Further studies should be done to evaluate the effects of endovascular therapy on BS perfusion and the impact of BS ischemia on morbidity and mortality of patients with severe symptomatic vasospasm.

Singing seizures.

Automatisms are commonly seen in epilepsy, either ictally or postictally. However, most automatisms are simple, with hand movements, mouth smacking, nose-rubbing, repetition of a single word, or coughing, grunting, or screeching. Complex automatisms are less common and striking. The authors report two cases of seizure-associated singing where song expression may be recognizable.

The role of removable appliances in contemporary orthodontics.

The contemporary uses of removable appliances are considerably more limited than in the past. This article discusses possible reasons for their declining use, including recognition of their limitations. It is possible to achieve adequate occlusal improvement with these appliances providing that suitable cases are chosen. Specific indications for their appropriate use on their own in the mixed dentition are presented. Removables can also be used as an adjunct to more complex treatments, to enhance the effect of fixed appliances, headgear or in preparation for functional appliances. Further research is required to confirm whether their use in conjunction with more complex treatments enhances the quality and efficiency of treatment or not.

Single-photon emission tomography imaging of the chest.

We review single-photon emission computed tomography (SPECT) of the chest for practical applications that may be used by pulmonary disease specialists. First, we cover SPECT uses in pulmonary thromboembolic disease. Second, SPECT's applications in quantitative evaluation of the lung are reviewed, with special emphasis on lung volume reduction surgery. Finally, we consider the use of SPECT to characterize somatostatin receptors in lung masses. The role of SPECT will always be compared to the ever-advancing place of positron emission tomography chest imaging for patients with pulmonary disease. We believe that SPECT will continue to help pulmonary specialists take care of their patients in the years to come.

A comparison of brain, core and skin temperature in children with complicated and uncomplicated malaria.

A prospective study was carried out in which brain, core and skin temperatures were studied in children with cerebral malaria (n = 23), uncomplicated malaria (n = 12) and normal children (n = 9) using the zero heat flow method. Patients with cerebral or uncomplicated malaria were admitted to the paediatric wards (mean age, 6 years 8 months +/- 2 years 8 months). Normal children, children of the investigators, of the same age group, served as controls. Parasitaemia levels were similar in the cerebral and uncomplicated malaria cases. Higher brain than core temperatures would have been expected in cerebral malaria but not in uncomplicated malaria but this was not the case in this study. There was no statistical difference in brain, core and skin temperature between cerebral and uncomplicated malaria patients. However, there was a highly significant difference between normal children and cerebral and uncomplicated malaria patients. Brain temperature was 0.02-0.2 degrees C below core temperature in all the groups with larger differences during the febrile period. Mean differences of brain minus core, brain minus skin and core minus skin between the two groups of patients were not statistically significant. There was no correlation between temperature and the level of coma or parasitaemia for cerebral and uncomplicated malaria patients. There was a positive correlation between brain and core temperature in both groups of patients during the febrile phase. Brain temperature remained lower than core temperature in cerebral and uncomplicated malaria as in normal children. Normal thermoregulation appears to be maintained in cerebral malaria.

Monozygotic twins discordant for chronic fatigue syndrome: regional cerebral blood flow SPECT.

PURPOSE: To evaluate the relationship between regional cerebral blood flow (rCBF) and chronic fatigue syndrome (CFS) in monozygotic twins discordant for CFS. MATERIALS AND METHODS: The authors conducted a co-twin control study of 22 monozygotic twins in which one twin met criteria for CFS and the other was healthy. Twins underwent a structured psychiatric interview and resting technetium 99m-hexamethyl-propyleneamine oxime single photon emission computed tomography of the brain. They also rated their mental status before the procedure. Scans were interpreted independently by two physicians blinded to illness status and then at a blinded consensus reading. Imaging fusion software with automated three-dimensional matching of rCBF images was used to coregister and quantify results. Outcomes were the number and distribution of abnormalities at both reader consensus and automated quantification. Mean rCBF levels were compared by using random effects regression models to account for the effects of twin matching and potential confounding factors. RESULTS: The twins with and those without CFS were similar in mean number of visually detected abnormalities and in mean differences quantified by using image registration software. These results were unaltered with adjustments for fitness level, depression, and mood before imaging. CONCLUSION: The study results did not provide evidence of a distinctive pattern of resting rCBF abnormalities associated with CFS. The described method highlights the importance of selecting well-matched control subjects.

Brain SPECT used to evaluate vasospasm after subarachnoid hemorrhage: correlation with angiography and transcranial Doppler.

PURPOSE: The primary objective of this study was to correlate Tc-99m HMPAO and ethyl cysteine dimer perfusion brain SPECT imaging with angiography and transcranial Doppler (TCD) to identify vasospasm after subarachnoid hemorrhage. METHODS: A retrospective analysis of consecutive patients who had cerebral blood flow SPECT imaging for subarachnoid hemorrhage and aneurysm clipping was made. Flow velocity measurements were correlated using TCD and cerebrovascular angiography. RESULTS: Of the 129 patients were included in this study, 84 were female and 45 were male, with a mean age of 51.9 years and a median age of 51 years (range, 9 to 84 years). Eighty-nine patients had brain SPECT evidence of hypoperfusion. Concordance was found between SPECT and TCD with vasospasm in 57 of 89 (64%) patients and nonconcordance was evident in 32 patients (36%). Eleven patients who had concordance between SPECT and TCD had nonconcordant results of angiography for vasospasm. CONCLUSIONS: These findings suggest that all three methods are complementary to each other in the evaluation of patients with vasospasm after subarachnoid hemorrhage. Concordance of 64% between SPECT and TCD is acceptable and explicable by the differences in technique and measurement of cerebral blood flow compared with vascular narrowing, respectively.

Clinical presentation and diagnosis of cerebral malaria in children in the highlands of western Kenya.

BACKGROUND: The clinical presentation of cerebral malaria in children in the highlands has not been documented. OBJECTIVE: To describe the presentation of cerebral malaria in the age group one to twelve years. DESIGN: Prospective study conducted from May to September 1997, the rainy season during which malaria occurs in epidemics in the highlands of Kenya. SETTING: Paediatric wards of the Moi Teaching and Referral Hospital, Eldoret which is the Teaching Hospital for Moi University and the referral centre for surrounding districts of Western Kenya, with an altitude of over 2000 metres above sea level. PATIENTS: Twenty three consecutive children aged one to twelve years with cerebral malaria as defined by the WHO were studied. All children were treated with the standard quinine regimen for cerebral malaria. RESULTS: Majority of the children were six to ten years of age with 95.7% having a normal weight for age. 91.3%, 89.5% and 72.2% had fever, headache and convulsions respectively. 68.1% had a short duration of illness (less than three days) with only 9.5% presenting with hypoglycaemia. Severe anaemia was not observed but 72% had mild to moderate anaemia. Hyperparasitaemia (parasite counts greater than 100,000 per microlitre) was found in majority of the cases. CONCLUSION: Cerebral malaria presentation in the highlands is similar to that among non-immune populations and is an acute fulminant illness presenting with coma, hyperparasitaemia, fever and convulsions in children with normal nutritional status.

An evaluation of the efficacy of injectable microencapsulated vitamin B12 in increasing and maintaining the serum and liver vitamin B12 concentrations of lambs.

AIM: To develop a long-acting Vitamin B12 injection to prevent Co deficiency in sheep. METHODS: Formulations of microencapsulated Vitamin B12 in lactide-glycolide polymers were injected intramuscularly or subcutaneously into the anterior neck region of groups of 10 lambs and their efficacy determined from changes in serum and liver Vitamin B12 concentrations. RESULTS: The 95:5 lactide glycolide and the 100 lactide formulations containing more than 12.5% Vitamin B12 w/w significantly increased and maintained serum Vitamin B12 concentrations for at least 210 days as well as liver Vitamin B12 concentrations in treated lambs when compared with untreated controls. CONCLUSIONS: Injections of microencapsulated Vitamin B12 in lactide/glycolide copolymers are able to increase and maintain the Vitamin B12 status of lambs for at least 210 days. CLINICAL SIGNIFICANCE: Another option for the prevention of Co deficiency in sheep is now available using a long acting injectable Vitamin B12.

Interventional endovascular therapy: SPECT cerebral blood flow imaging compared with transcranial doppler monitoring of balloon angioplasty and intraarterial papaverine for cerebral vasospasm.

The effects of interventional endovascular treatment of cerebral vasospasm with balloon angioplasty or papaverine infusion were evaluated by single-photon emission computed tomography (SPECT) and transcranial Doppler (TCD) in 44 patients whose cerebral vasospasm was refractory to medical management. SPECT revealed blood flow improvements in 42% of patients with papaverine treated vessels and 70% of patients with balloon angioplasty (P=.037). TCD correlated with SPECT in 71% of patients in the papaverine group and 73% of patients in the balloon angioplasty group. TCD showed 93% of segments improved by angioplasty, whereas 43% of segments were improved with papaverine (P<.001). Disagreements were largely represented by patients with TCD velocity improvements in which SPECT blood flow imaging was, unchanged or worsened. Balloon angioplasty seems superior to papaverine infusion for treatment of vasospasm. SPECT and TCD are complementary tests in the evaluation of vasospasm and effect of interventional therapy.

High-resolution inter-ictal SPET and phased-array MRI in partial epilepsy: an imaging comparison with video/EEG and outcome correlation.

To assess the clinical utility of high-resolution inter-ictal single photon emission tomography (SPET) of regional cerebral perfusion and high-resolution magnetic resonance imaging (MRI) of the brain with a phased-array temporal lobe coil, 35 patients with presumed partial epilepsy were evaluated prospectively by these techniques in addition to prolonged video/electroencephalographic (EEG) monitoring. Twenty of these patients had surgical treatment of partial epilepsy with outcome determinations spanning from 12 months to 3 years at follow-up. There were four categories of imaging findings as compared to scalp/sphenoidal EEG localization. Category I included 12 patients (34% of total) in whom there was complete imaging and EEG concordance. Category II included 4 patients (11%) in whom MRI and EEG were concordant but SPET was divergent or normal. Category III included 13 patients (37%) in whom SPET and EEG were concordant but MRI was divergent or normal. Category IV included 4 patients (11%) in whom neither SPET nor MRI was concordant with EEG. In this study, the relative sensitivities of SPET and MRI for localization of partial epilepsy based on prolonged scalp/sphenoidal video/EEG recordings were 76% and 49%, respectively. We conclude that these neuroimaging techniques (phased-array MRI and inter-ictal cerebral perfusion SPET) are complementary and useful in the pre-operative evaluation of patients with partial epilepsy.

BUN/creatinine ratios: aid to decision making about delayed imaging in Tc-99m red blood cell scans for gastrointestinal hemorrhage.

In patients with gastrointestinal hemorrhage, delayed or late scans with Tc-99m labeled red blood cells are readily performed and have prognostic impact when early images are negative. Nevertheless, there have been no indicators for the likelihood of detecting bleeding on such images. In a review of all gastrointestinal bleeding scans over an 8-year period, 73 patients had delayed images (> 3 hours) following early negative exams. For these patients, determinations of serum blood urea nitrogen (BUN) and creatinine (Cr) were evaluated as the BUN/Cr ratio and were compared against delayed scan findings and confirmed diagnoses. Patients with significant renal failure were excluded from analysis. There were 34 late positive (46%) and 39 late negative (54%) studies. Mean BUN/Cr was 26.5 and 20.0 in patients with late positive and late negative scans, respectively (p < 0.05). Occurrence of late positive scans was 38% (19/50) for BUN/Cr < 25.0 vs. 65% (15/23) for BUN/Cr > 25.0 (p < 0.05). Patients with early negative images and a BUN/Cr ratio of 25 or greater have a greater likelihood of a positive delayed image. Late imaging should be encouraged in patients with elevated BUN/Cr and early negative scintigraphy.

Balloon angioplasty for the treatment of vasospasm: results of first 50 cases.

OBJECTIVE: To report the results of the first 50 consecutive patients with vasospasm secondary to subarachnoid hemorrhage treated with balloon angioplasty after failure of medical management. METHODS: Retrospective uncontrolled study of 50 consecutive patients treated with balloon angioplasty between February 1988 and July 1992. Forty-six had objective clinical deterioration despite maximal medical therapy, whereas four were treated on the basis of rapidly accelerating transcranial Doppler velocities and decreased regional blood perfusion detected by technetium-99m-exametazime brain single photon emission computed tomography. All patients had evidence of marked vasospasm demonstrated by angiography. Thirty-two (64%) and 46 (92%) patients underwent angioplasty within 12 and 18 hours, respectively. RESULTS: Of the patients with clinical evidence of vasospasm-induced ischemia, 28 (61%) showed sustained neurological improvement within 72 hours of angioplasty. Three (6%) patients deteriorated within 72 hours after angioplasty, with two (4%) patients dying immediately after angioplasty as a result of vessel rupture and the other patient's Glasgow Coma Scale score decreasing by 2. Two additional patients in poor condition with Hunt and Hess Grade V at the time of angioplasty subsequently died during hospitalization. Two other patients died as a result of unclipped aneurysms that subsequently bled 4 and 12 days after angioplasty, respectively. The improvement demonstrated clinically, angiographically, and by transcranial Doppler after angioplasty was sustained, with only one patient requiring subsequent angioplasty of a previously dilated segment (total, 170 vessel segments dilated). Two patients developed vasospasm in previously undilated segments. CONCLUSION: Timely balloon angioplasty can reverse delayed ischemic deficit caused by vasospasm in patients for whom medical therapy has failed.

Comparison of balloon angioplasty and papaverine infusion for the treatment of vasospasm following aneurysmal subarachnoid hemorrhage.

OBJECT: The purpose of this study was to test the hypothesis that balloon angioplasty is superior to papaverine infusion for the treatment of proximal anterior circulation arterial vasospasm following subarachnoid hemorrhage (SAH). Between 1989 and 1995, 125 vasospastic distal internal carotid artery or proximal middle cerebral artery vessel segments were treated in 52 patients. METHODS: Blood flow velocities of the involved vessels were assessed by using transcranial Doppler (TCD) monitoring in relation to the day of treatment with balloon angioplasty or papaverine infusion. Balloon angioplasty and papaverine infusion cohorts were compared based on mean pre- and posttreatment velocity at 24 and 48 hours using the one-tailed, paired-samples t-test. Balloon angioplasty alone was performed in 101 vessel segments (81%) in 39 patients (75%), whereas papaverine infusion alone was used in 24 vessel segments (19%) in 13 patients (25%). Although repeated treatment after balloon angioplasty was needed in only one vessel segment, repeated treatment following papaverine infusion was required in 10 vessel segments (42%) in six patients because of recurrent vasospasm (p < 0.001). Seven vessel segments (29%) with recurrent spasm following papaverine infusion were treated with balloon angioplasty. Although vessel segments treated with papaverine demonstrated a 20% mean decrease in blood flow velocity (p < 0.009) on posttreatment Day 1, velocities were not significantly lower than pretreatment levels by posttreatment Day 2 (p = 0.133). Balloon angioplasty resulted in a 45% mean decrease in velocity to a normal level following treatment (p < 0.001), a decrease that was sustained. CONCLUSIONS: Balloon angioplasty is superior to papaverine infusion for the permanent treatment of proximal anterior circulation vasospasm following aneurysmal SAH.