A systematic review of gut microbiota composition in observational studies of major depressive disorder, bipolar disorder and schizophrenia.

The emerging understanding of gut microbiota as 'metabolic machinery' influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to 'healthy' controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (ß-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.

Increasing Nrf2 Activity as a Treatment Approach in Neuropsychiatry.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor encoded by NFE2L2. Under oxidative stress, Nrf2 does not undergo its normal cytoplasmic degradation but instead travels to the nucleus, where it binds to a DNA promoter and initiates transcription of anti-oxidative genes. Nrf2 upregulation is associated with increased cellular levels of glutathione disulfide, glutathione peroxidase, glutathione transferases, thioredoxin and thioredoxin reductase. Given its key role in governing the cellular antioxidant response, upregulation of Nrf2 has been suggested as a common therapeutic target in neuropsychiatric illnesses such as major depressive disorder, bipolar disorder and schizophrenia, which are associated with chronic oxidative and nitrosative stress, characterised by elevated levels of reactive oxygen species, nitric oxide and peroxynitrite. These processes lead to extensive lipid peroxidation, protein oxidation and carbonylation, and oxidative damage to nuclear and mitochondrial DNA. Intake of N-acetylcysteine, coenzyme Q10 and melatonin is accompanied by increased Nrf2 activity. N-acetylcysteine intake is associated with improved cerebral mitochondrial function, decreased central oxidative and nitrosative stress, reduced neuroinflammation, alleviation of endoplasmic reticular stress and suppression of the unfolded protein response. Coenzyme Q10, which acts as a superoxide scavenger in neuroglial mitochondria, instigates mitohormesis, ameliorates lipid peroxidation in the inner mitochondrial membrane, activates uncoupling proteins, promotes mitochondrial biogenesis and has positive effects on the plasma membrane redox system. Melatonin, which scavenges mitochondrial free radicals, inhibits mitochondrial nitric oxide synthase, restores mitochondrial calcium homeostasis, deacetylates and activates mitochondrial SIRT3, ameliorates increased permeability of the blood-brain barrier and intestine and counters neuroinflammation and glutamate excitotoxicity.

An integrative collaborative care model for people with mental illness and physical comorbidities.

BACKGROUND: Many individuals with mental health problems have comorbid physical conditions, or may present with substance/alcohol misuse or abuse issues. This results in complex treatment challenges that may not be adequately addressed by a model of care that is solely delivered by an individual clinician using a sole intervention. Mainstream pharmacotherapeutic treatment of mental health problems often have limited effectiveness in completely resolving symptoms, and may cause adverse side effects. Adjunctive treatment approaches, including nutraceuticals, lifestyle and behaviour change interventions, are widely used to assist with treatment of mental health problems. However, whilst these can be generally safer with fewer side effects, they have varying levels of evidentiary support. These circumstances warrant reframing the current treatment approach towards a more evidence-based integrative model which may better address the real-world challenges of psychiatric disorders and comorbid physical conditions. In essence, this means developing an integrative model of care which embodies an evidence-informed, personalized stepwise approach using both conventional pharmacological treatments alongside novel adjunctive treatments (where applicable) via the application of a collaborative care approach. DISCUSSION: In order to inform this position, a brief review of findings on common patterns of comorbidity in mental illness is presented, followed by identification of limitations of conventional treatments, and potential applications of integrative medicine interventions. Advantages and challenges of integrative mental health care, collaborative models of care, review of research highlights of select integrative approaches, and comment on potential cost advantages are then discussed. We propose that a collaborative care model incorporating evidence-based integrative medicine interventions may more adequately address mental health problems with comorbid medical conditions. Robust research is now required of such a model, potentially within an integrative clinical practice.

The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.

Subsequent vertebral fractures after vertebroplasty: association with intraosseous clefts.

BACKGROUND AND PURPOSE: Patients with vertebral fractures containing intraosseous clefts may represent a distinct subgroup of vertebroplasty patients, yet the development of subsequent vertebral fractures in this population has not been explored. We tested the hypothesis that after vertebroplasty for intraosseous clefts, subsequent fractures would occur earlier and more frequently than after treatment of non-cleft-containing fractures. METHODS: We retrospectively reviewed 362 patients treated with vertebroplasty for osteoporotic fractures. The location, frequency, and timing of subsequent fractures were compared between 2 subgroups: group 1, patients treated at fractures containing clefts, and group 2, treated patients without clefts. A vertebra-by-vertebra analysis was used to compare the relative risk and timing of subsequent fractures adjacent to vertebrae with or without clefts. RESULTS: Group 1 included 63 patients treated at 65 vertebrae and group 2 included 250 patients treated at 399 vertebrae. Group 1 demonstrated a nearly twofold increased risk of subsequent fracture (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.04-3.49, P = .037). At the vertebral level, the relative risk of subsequent fracture was 2.02 (95% CI, 1.46-2.58; P = .013) times greater adjacent to a treated cleft. Fractures adjacent to any treated level occurred significantly sooner than nonadjacent fracture (P = .0004). The presence of a cleft was not significantly associated with the timing of subsequent fractures. CONCLUSIONS: Patients with osteoporotic vertebral fractures containing clefts are at increased risk for subsequent fractures and treatment of these clefts is associated with increased rates of adjacent fracture. There is no significant difference in the timing of subsequent fractures based on the presence of a cleft.

A failure of matrix metalloproteinase inhibition in the prevention of rat intracranial aneurysm formation.

We tested the hypothesis that nonspecific matrix metalloproteinase (MMP) inhibition with doxycycline would decrease the incidence of intracranial aneurysm formation in a rat aneurysm model. We performed common carotid artery ligation on 96 Long-Evans rats. A treatment group of 48 animals was chosen at random to receive oral doxycycline (3 mg/kg) in addition to standard rat chow, and the control group of 48 animals received standard rat chow only. The major circle of Willis arteries was dissected at 1 year following carotid ligation, and the proportions of animals with aneurysms were compared between groups using Fisher's exact test. Four animals given oral doxycycline and ten control animals expired before 1 year. Of the examined animals, eight saccular intracranial aneurysms were found in 8 of 45 animals which had received doxycycline (17.8%) and seven saccular intracranial aneurysms were found in 7 of 37 control animals (18.9%). There was no significant difference in aneurysm formation between the doxycycline-treated and control groups (P=0.894). Nonspecific MMP inhibition with doxycycline is not effective in preventing intracranial aneurysm formation in a rat model.

Simultaneous bilateral laparoscopic adrenalectomy: a surgical option for multiple endocrine neoplasia (MEN 2) patients with bilateral pheochromocytomas.

Multiple endocrine neoplasia (MEN 2) is a rare disorder. Of this group, 42% develop a pheochromocytoma of which 60% will have bilateral involvement. Although the benefits of unilateral laparoscopic adrenalectomy have been well documented, fewer cases of simultaneous bilateral laparoscopic adrenalectomy have been reported. We present the cases of three patients with MEN 2 who underwent successful simultaneous bilateral laparoscopic adrenalectomy after their initial presentation with bilateral pheochromocytoma. Although the management of bilateral pheochromocytomas has traditionally been approached via open laparotomy or bilateral posterior incisions, the bilateral laparoscopic approach should be considered a viable alternative for patients requiring surgical intervention. Clinical outcomes and complications are similar to open laparotomy. Simultaneous bilateral laparoscopic adrenalectomy is a safe and effective procedure that results in a more rapid recovery and a shorter hospital stay for patients with bilateral pheochromocytomas originating from MEN 2.

Gastric bypass model in the obese rat to study metabolic mechanisms of weight loss.

A rat model replicating gastric bypass with Roux-en-Y (GB) as used in morbidly obese patients, evolved in our laboratory in stages, using the Zucker rat as an obese model (GB) is presented. In the final model, a 20% gastric fundic pouch to limit the gastric reservoir was created using two staple lines (Ethicon). A 4- to 5-mm end-to-side gastrojejunostomy and a 6- to 8-mm jejunojejunostomy, at 10 cm length of the Roux-en-Y limb, placed 16 cm below the ligament of Treitz, was hand sewn to create a limited area of nutrient digestion and absorption. Controls underwent sham operation. Rats were divided into: (i) sham-op ad lib-fed (Control); (ii) GB; and (iii) sham-op pair fed (PF) in two experiments. In Experiment 1, 24 Zuckers (control n = 8; GB n = 8; PF n = 8) were studied to assess the effectiveness of the model for weight loss. In Experiment 2, 24 Zuckers (8/group) were studied to confirm the effects of the operation on weight loss and on metabolic parameters. Boost was given for 4 days starting 24 h postop and then ground chow was given. Daily food intake (FI), meal size (MZ), meal number (MN), and body weight (BW) were measured. Rats were sacrificed on Day 20 in Experiment 1 and on Day 10 in Experiment 2. Serum metabolites and body fat weight were measured. Data were evaluated using Student's t test. Controls steadily gained BW (5.2-6.1 g/day), reaching approximately 500 g. In GB: FI, MZ, MN, BW, glucose, free fatty acids, insulin, and body fat decreased (P < 0.05). In PF: BW, insulin, triglycerides, and body fat decreased. A dependable, reproducible gastric bypass with Roux-en-Y obesity model was developed. This permits the study of biochemical and eventually molecular mechanism(s) of weight loss resulting from the operation.

Elastase-induced saccular aneurysms in rabbits: comparison of geometric features with those of human aneurysms.

BACKGROUND AND PURPOSE: The development of more effective intracranial aneurysm therapy depends on the ability to test various intravascular occlusion devices and techniques in preclinical animal models. This requires the creation of experimental aneurysms, which, ideally, should mimic the size and geometric features of human intracranial aneurysms. The purpose of this study was to characterize the morphologic features of elastase-induced saccular aneurysms in rabbits to determine whether the morphology of such aneurysms mimics that of human intracranial aneurysms. METHODS: Elastase-induced saccular aneurysms were created in 40 New Zealand white rabbits. Intravenous digital subtraction angiography was performed 14 days after surgery. Relative to an external sizing device, the following dimensions were determined: aneurysm dome (height and width), aneurysm neck diameter, and parent artery diameter. Based on maximal diameter, aneurysms were categorized as small (2.0-4.9 mm), medium-sized (5.0-9.9 mm), or large (10-16 mm), and as narrow-necked (<4.0 mm neck width) or wide-necked (>4.0 mm neck width). Mean dome-neck ratio was calculated and compared with that of human aneurysms. RESULTS: All aneurysm cavities were angiographically patent. Widths of the cavities ranged from 2.5 to 7.1 mm (mean, 4.1 +/- 1.2 mm); heights ranged from 3.0 to 15.6 mm (mean, 8.8 +/- 2.6 mm). Three (7.5%) of 40 aneurysms were small, 20 (50%) were medium-sized, and 17 (42.5%) were large. Twenty-two (55%) of 40 aneurysms were small-necked, and 18 (45%) were wide-necked. Mean dome-neck ratio was 1.13 +/- 0.54. Mean parent artery diameter was 4.3 +/- 1.4 mm. CONCLUSION: Saccular aneurysms of sizes similar to that of human intracranial aneurysms were reliably created using a simple method of vessel ligation and elastase injury. Neck sizes varied with both large and small-necked aneurysms created.

Age of fracture and clinical outcomes of percutaneous vertebroplasty.

BACKGROUND AND PURPOSE: The patient populations that are most likely to benefit from percutaneous vertebroplasty (PVP) are uncertain. Our purpose was to evaluate the effect of the age of vertebral compression fracture (VCF) on clinical improvement after PVP. METHODS: We performed a retrospective review of charts of patients who had undergone PVP for painful osteoporotic VCFs at our institution. The preprocedural and postprocedural outcome measurements of pain, mobility, and analgesic use were compared for 80 treatment sessions in 75 patients (122 total vertebrae treated). We assessed the association between the duration of pain before PVP and postprocedural outcomes by using multivariable analysis. RESULTS: Age of fracture at time of PVP was not independently associated with postprocedural pain or activity. Increasing age of fracture was independently associated with slightly greater postprocedural analgesic requirement, at least for patients who required narcotics at baseline before PVP. Greater preprocedural analgesic requirement was independently associated with greater postprocedural analgesic requirement. Reduced preprocedural mobility was independently associated with reduced postprocedural mobility. CONCLUSION: PVP is a highly efficacious therapy for relief of pain and improvement in mobility, regardless of fracture age. PVP also is efficacious in reducing analgesic requirement, although this effect may be slightly blunted in patients who require narcotics before the procedure and in those who have older fractures.

Improved objectivity of grading of T(A,1) transitional cell carcinomas of the urinary bladder by quantitative nuclear and proliferation related features.

AIM: To analyse whether the mean nuclear area of the 10 largest nuclei (MNA-10), the mitotic activity index (MAI), and Ki-67 immunoquantitative features have additional value to discriminate different grades of T(A,1) transitional cell carcinoma (TCC) of the urinary bladder. MATERIALS/METHODS: One hundred and fifty of 200 consecutive cases (75%) showing interobserver agreement on duplicate blind grade assessment by independent pathologists were studied. Using random numbers, the 150 cases were divided into sets for learning (n = 75) and testing (n = 75). Single and multivariate analyses were applied to discriminate the different grades in the learning set. The multivariate classifier developed in this way was evaluated in the test set (n = 75). RESULTS: With the MNA-10 alone, using the classification MNA-10 < 80 microm(2) = grade 1, 80 microm(2) < MNA-10 < 130 microm(2) = grade 2, MNA-10 > 130 microm(2) = grade 3, 71% of all 150 cases were correctly classified (69% of grade 1 v grade 2 and 76% of grade 2 v grade 3). With multivariate analysis, the best discriminating features in the learning set (17 grade 1, 30 grade 2, and 28 grade 3) between grades 1 and 2 were MNA-10 and MAI, and between grades 2 and 3 MAI and Ki-67. With these features, 94% of grade 1 v grade 2 and 97% of grade 2 v grade 3 were correctly classified in the learning set (overall, 95% correct, none of the grade 3 cases misclassified). In the test set the classification results were similar. When the three grades were entered at the same time for discrimination, Ki-67 area % and MAI was the best discriminating combination, both in the sets for learning and testing. Overall correct classification results in the sets for learning and testing were slightly lower, but still 94% and 92%. Most importantly, none of the grade 3 cases was misclassified; the classification shifts all occurred between grades 1 and 2. CONCLUSIONS: The combination of MNA-10, MAI, and Ki-67 gives much better discrimination between grades 1, 2, and 3 in T(A,1) TCC of the urinary bladder than MNA-10 alone. The similarity of the classification results of the learning set and test set are encouraging and this quantitative pathological grading model should be applied in a prospective study.

Transforming growth factor beta-coated platinum coils for endovascular treatment of aneurysms: an animal study.

OBJECTIVE: To test the hypothesis that coating platinum coils with transforming growth factor beta (TGFbeta) would improve the cellular proliferation within experimental aneurysms relative to uncoated coils. MATERIALS AND METHODS: Elastase-induced saccular aneurysms were created in 12 New Zealand White rabbits. These aneurysms were embolized with platinum coils, either "control" (unmodified) coils or "test" (coated with TGFbeta) coils. Subjects were killed either 2 weeks (n = 3, control; n = 3, test) or 6 weeks (n = 3, control; n = 3, test) after embolization. Aneurysm tissue was embedded in plastic, sectioned, and stained with hematoxylin and eosin. The thickness of tissue covering the coils at the coil-lumen interface was measured by use of a digital microscope, and was compared between groups by use of the Student's t test (P < or = 0.05). RESULTS: Two-week implantation samples demonstrated mean thickness of tissue overlying TGFbeta-coated coils of 36+/-15 microm and mean thickness of overlying control coils of 3+/-5 microm, indicating significantly thicker tissue growth covering test versus control coils (P = 0.02). Six-week implantation samples demonstrated mean thickness of tissue overlying TGFbeta-coated coils of 86+/-74 microm versus mean thickness overlying control coils of 37+/-6 mu; this difference did not reach statistical significance (P = 0.30). Thickness of tissue covering TGFbeta-coated coils did not change significantly from 2 to 6 weeks (P = 0.31). Tissue thickness over control coils increased significantly between 2 and 6 weeks (P = 0.002). CONCLUSION: TGFbeta-coated platinum coils undergo earlier cellular coverage than standard platinum coils, but differences in coverage between coated and control coils are no longer present at later time points. These data suggest that improvements in intra-aneurysmal cellular proliferation resulting from coil modifications, although significant in the early postembolization phase, may dissipate over time.

Choroid plexus papilloma of the third ventricle: angiography, preoperative embolization, and histology.

We report a unique case of choroid plexus papilloma of the third ventricle in an 8-month-old girl in which preoperative embolization played a salient role in management. Initial surgery was aborted due to excessive bleeding. Cerebral angiography demonstrated enlarged posterior choroidal arteries feeding the tumor, and intense, persistent tumor staining. These vessels were effectively embolized to stasis with polyvinyl alcohol particles. The patient underwent a second craniotomy and complete resection of the tumor with minimal blood loss. Postsurgical histology showed postembolization iatrogenic intratumoral necrosis.

Preliminary reports and the rates of publication of follow-up reports in peer-reviewed, indexed journals.

PURPOSE: To test the hypothesis that articles published as "preliminary" or "pilot" reports are followed by more definitive publications in only a minority of cases. METHOD: A survey of Medline was performed for reports published in 1992 in journals listed in the Abridged Index Medicus that had the word "preliminary" or "pilot" in the title. For identified reports, a Medline search of publications in 1992 through 1999 was performed, using lead author's name, second author's name, and senior (last) author's name, and at least one keyword based on the publication title. Preliminary and pilot publications were subdivided by type of study (controlled clinical study, case series, laboratory or nonclinical) and by the report of either positive or negative results. Rates of publication based on study design and publication bias were compared using the chi-square test for statistical significance. RESULTS: The rate of publication of follow-up reports within seven years of the initial publication was 27%. Follow-up studies of controlled clinical studies (40%) were published more frequently than were those of laboratory or nonclinical studies (31%) or case series (22%), but these differences were not significant (p >.10). There was no statistically significant difference in follow-up publication rates based on publication bias. CONCLUSION: Only 27% of studies published as preliminary or pilot reports were subsequently followed by a more definitive publication. While the words preliminary and pilot suggest that publication of further, refined work is pending, this is often not the case.

Serial angiography in an elastase-induced aneurysm model in rabbits: evidence for progressive aneurysm enlargement after creation.

BACKGROUND AND PURPOSE: Among the several reports of elastase-induced aneurysm models, only the rabbit common carotid artery (CCA) model has been used for testing endovascular occlusion devices. Our purpose was to study the growth characteristics of an elastase-induced aneurysm model in rabbits for the purpose of determining whether delayed aneurysm enlargement occurs after creation. METHODS: Nine New Zealand White rabbits (3-4 kg) were used in this study. All study animals underwent surgery to isolate the right CCA. In three control animals, the lumen was incubated with saline and iodinated contrast material for 20 minutes. In six test animals, the lumen of the CCA was incubated with porcine elastase for 20 minutes. In all study animals, the distal right CCA was ligated. IV digital subtraction angiography was performed on postprocedural days 3, 5, 7, 14, 28, 35, 56, 84, and 112. Using an external sizing reference, the width and height of patent arterial segments at the right CCA origin were measured by two observers. For test animals, aneurysm dimensions were compared between early and late time points by using the Student's t test. RESULTS: In the control (no elastase) animals, slitlike cavities at the origin of the right CCA decreased in size over time to become nearly obliterated by 21 days. Conversely, a short segment of the proximal CCA remained widely patent in all six test animals. With the exception of a single time point in one test animal, all "aneurysm" cavities in the test animals were dilated as compared with the normal diameter of the CCA. On day 3 after surgery, the mean width and height of the aneurysm cavities in the test animals were 3.2 +/- 0.6 and 6.0 +/- 1.3 mm, respectively. Compared with dimensions at day 3, aneurysms in test animals were larger at day 14, with mean width and height of 4.1 +/- 1.7 and 8.3 +/- 1.9 mm, respectively (P =.02). Aneurysms in test animals had increased further at 21 days compared with 14 days (P =.01). Compared with measurements obtained at 21 days, dimensions remained essentially unchanged at 28 and 35 days. Thirty-five days after surgery, mean width and height were 5.0 +/- 0.9 and 10.0 +/- 2.2 mm, respectively. Follow-up imaging performed < or = 4 months after aneurysm creation showed no further change in aneurysm dimensions. CONCLUSION: Elastase incubation and vessel ligation results in patent aneurysmally dilated arterial segments at the origin of the right CCA in rabbits. These aneurysms show progressive increases in diameter over time, finally stabilizing at approximately 1 month. Our data, which show early progressive aneurysm enlargement, suggest that this model may be used for the study of systemic therapies aimed at diminishing aneurysm rest regrowth and also indicate that embolization of these model aneurysms should be delayed at least 21 days after aneurysm creation.

[Immunology-related chronic progressive cicatricial conjunctival diseases: diagnosis, therapy and prognosis]. / Immunologisch bedingte, chronisch-progressiv vernarbende Bindehauterkrankungen. Diagnose, Therapie und Prognose.

PURPOSE: We reviewed the records of patients with chronic cicatricial disease of the conjunctiva for differences in prognosis between clinical and histopathological subgroups of the disease and in therapeutic options. PATIENTS: In 30 patients (58 eyes) with an average age of 69 years (52-86) chronic cicatricial disease of the conjunctiva was diagnosed clinically. Only in 22/30 patients conjunctival biopsies could be performed. The correlation of histopathological and immunohistochemical diagnoses with clinical course under systemic immunosuppression was studied. RESULTS: 15/22 biopsies led to a classification into different subgroups. Under systemic immunosuppression disease ceased to progress for a mean time of 15 months in 13 of 15 patients with positive biopsies and in 9 of 15 without classification. The results after cyclosporine A therapy (4 of 5 patients stabilized after a mean of 27.5 months) and mycophenolate mofetil (8 of 11 patients stabilized at a mean of 7.8 months) were better than those after therapy with dapsone, azathioprine and cyclophosphamide. CONCLUSIONS: Histopathological and immunohistochemical examinations led to a classification in two-thirds of the patients with clinical aspects of chronic cicatricial disease of the conjunctiva. There was no correlation between different histopathological subgroups, success of therapy and prognosis of the disease. There is little hope in using new systemic immunosuppression such as cyclosporine A and mycophenolate mofetil.

Endovascular treatment of experimental aneurysms by use of biologically modified embolic devices: coil-mediated intraaneurysmal delivery of fibroblast tissue allografts.

BACKGROUND AND PURPOSE: Our long-term goal is to improve intraaneurysmal fibrosis after aneurysm embolization, by implanting exogenous fibroblasts, using platinum coils. For the current project, we tested two hypotheses: 1) that exogenous, fluorescence-labeled rabbit fibroblast allografts remained viable and proliferated within rabbit carotid arteries, and 2) that these fibroblast allografts could be reliably implanted into experimental aneurysms by use of platinum coils. METHODS: Part 1. New Zealand White rabbit synovial fibroblasts obtained from a commercial vender were labeled with a fluorescent membrane marker. The common carotid arteries of New Zealand White rabbits were surgically exposed, ligated proximally and distally, and entered with 22-g angiocatheters. Through the angiocatheter we injected either phosphate-buffered saline-containing fluorescence-labeled fibroblasts (treatment vessels) or saline only (control vessels). The wounds were closed, and the subjects were kept alive for various time points up to 2 weeks. After sacrifice, the carotid artery segments were resected, processed for frozen-section histologic examination, and evaluated using epifluorescent microscopy and hematoxylin and eosin staining. Cell viability and proliferation were determined by comparing the treatment versus control vessels. Part 2. A) Fluorescence-labeled cells were grown in culture on platinum coils, which were then exposed to systemic arterial flow in the rabbit thoracic aorta for various lengths of time up to 40 minutes. The coil segments were then examined using fluorescent microscopy and the presence and relative amount of cells remaining on the coil were documented. B) Experimental aneurysms in rabbits were embolized with control platinum coils (n = 9) and platinum coils bearing rabbit synovial fibroblasts that were grown onto the coils in culture prior to implantation (n = 9). Subjects were sacrificed 3, 7, and 14 days after coil implantation. Histologic samples were studied to assess the presence or absence of nucleated cells within and around coil winds in order to determine whether fibroblasts had been successfully implanted into aneurysms. Data were evaluated using the chi-square test for statistical significance. RESULTS: Part 1. Fluorescence-labeled cells were examined in the treatment carotid artery segments and results were recorded at all time intervals. The treatment vessel segments showed evidence of progressive cellular proliferation, leading to complete vessel fibrosis at 2 weeks. Conversely, control vessel segments were filled predominately with unorganized thrombus at each time interval. Part 2. A) Numerous labeled fibroblasts remained adherent to the coil despite prolonged exposure to systemic arterial flow. B) Fibroblasts were seen adjacent to or within the central lumen of coils in eight (88%) of nine aneurysms treated with cell-bearing coils. Nucleated cells were not present in any of the nine control coil subjects. This represented a statistically significant difference (P < .001). CONCLUSION: Fibroblast allografts remain viable and proliferate in the vascular space in rabbits. Furthermore, these same fibroblasts, after seeding onto platinum coils in culture, remain protected within the lumen of the coils and are retained within the coil lumen even after prolonged exposure to arterial blood flow. Coils can be used to deliver viable fibroblasts directly into experimental aneurysms successfully. These findings indicate that coil-mediated cell implantation is feasible and may be a potential method of increasing the biological activity of embolic coils.

Value of bone scan imaging in predicting pain relief from percutaneous vertebroplasty in osteoporotic vertebral fractures.

BACKGROUND AND PURPOSE: Patient selection for percutaneous vertebroplasty is often complicated by the presence of multiple fractures or non-localizing pain. Our purpose was to determine whether increased activity revealed by bone scan imaging is predictive of a positive clinical response to percutaneous vertebroplasty. METHODS: A retrospective chart review conducted at our institution yielded 28 vertebroplasty treatment sessions that had been performed after obtaining bone scan imaging for painful, osteoporotic compression fractures in 27 patients. Thirty-five compression fractures were treated during these 28 treatment sessions. In all cases, increased activity was revealed by bone scan imaging before treatment with vertebroplasty. Positive outcome was defined as subjective decrease in pain severity and/or increased level of patient mobility. RESULTS: Subjective pain relief was noted in 26 (93%) of 28 treatment sessions. In 14 (100%) of 14 cases with quantifiable pain levels, pain improved at least 3 points on a 10-point scale (range of improvement, 3-10 points; mean improvement, 7.4 points). Among the remaining 14 treatment sessions in which patients were unable or unwilling to quantify pain severity, the pain relief was described as complete or excellent pain relief in 11 (78%) of 14 cases. In 14 (100%) of 14 cases for which semiquantitative assessment of mobility was available, mobility improved at least one level (5-point graded scale; range of improvement, 1-4 points; mean improvement, 1.7 points). CONCLUSIONS: Increased activity revealed by bone scan imaging is highly predictive of positive clinical response to percutaneous vertebroplasty.