Synovial chemokine expression and relationship with knee symptoms in patients with meniscal tears.

OBJECTIVE: In patients with knee OA, synovitis is associated with knee pain and symptoms. We previously identified synovial mRNA expression of a set of chemokines (CCL19, IL-8, CCL5, XCL-1, CCR7) associated with synovitis in patients with meniscal tears but without radiographic OA. CCL19 and CCR7 were also associated with knee symptoms. This study sought to validate expression of these chemokines and association with knee symptoms in more typical patients presenting for meniscal arthroscopy, many who have pre-existing OA. DESIGN: Synovial fluid (SF) and biopsies were collected from patients undergoing meniscal arthroscopy. Synovial mRNA expression was measured using quantitative RT-PCR. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was administered preoperatively. Regression analyses determined if associations between chemokine mRNA levels and KOOS scores were independent of other factors including radiographic OA. CCL19 in SF was measured by ELISA, and compared to patients with advanced knee OA and asymptomatic organ donors. RESULTS: 90% of patients had intra-operative evidence of early cartilage degeneration. CCL19, IL-8, CCL5, XCL1, CCR7 transcripts were detected in all patients. Synovial CCL19 mRNA levels independently correlated with KOOS Activities of Daily Living (ADL) scores (95% CI [-8.071, -0.331], P = 0.036), indicating higher expression was associated with more knee-related dysfunction. SF CCL19 was detected in 7 of 10 patients, compared to 4 of 10 asymptomatic donors. CONCLUSION: In typical patients presenting for meniscal arthroscopy, synovial CCL19 mRNA expression was associated with knee-related difficulty with ADL, independent of other factors including presence of radiographic knee OA.

Superficial zone chondrocytes in normal and osteoarthritic human articular cartilages synthesize novel truncated forms of inter-alpha-trypsin inhibitor heavy chains which are attached to a chondroitin sulfate proteoglycan other than bikunin.

OBJECTIVE: We have examined the occurrence of the inflammation-associated inter-alpha-trypsin inhibitor (IalphaI) components, bikunin, heavy chain (HC)1 and HC2 in normal cartilage and osteoarthritis (OA) cartilage and synovial fluids. DESIGN/METHODS: Cartilage extracts from normal donors and late-stage OA patients, and synovial fluids from OA patients were studied by Western blot with multiple antibodies to bikunin, HC1 and HC2. Cell and matrix localization was determined by immunohistochemistry and mRNA by RT-PCR. RESULTS: Bikunin.chondroitin sulfate (CS) and IalphaI were abundant in OA cartilages, but virtually undetectable in normal. In both OA and normal cartilages, HCs were largely present in a novel C-terminally truncated 50-kDa form, with most, if not all of these being attached to CS on a proteoglycan other than bikunin. Synovial fluids from OA patients contained bikunin.CS and full-length (approximately 90 kDa) HCs linked to hyaluronan (HA) as HC.HA (SHAP.HA). Immunohistochemistry showed intracellular and cell-associated staining for bikunin and HCs, consistent with their synthesis by superficial zone chondrocytes. PCR on multiple human normal and OA cartilage samples detected transcripts for HC1 and HC2 but not for bikunin. In OA cartilages, immunostaining was predominantly matrix-associated, being most intense in regions with a pannus-like fibrotic overgrowth. CONCLUSION: The truncated structure of HCs, their attachment to a proteoglycan other than bikunin, PCR data and intracellular staining are all consistent with synthesis of HC1 and HC2 by human articular chondrocytes. The presence of bikunin.CS and IalphaI in OA cartilage, but not in normal, appears to be due to diffusional uptake and retention through fibrillated (but not deeply fissured) cartilage surfaces.

[Clinical and genetic study in 22 patients with basal cell nevus syndrome]. / Etude clinique et recherche de mutations germinales du gène PTCH 1 dans le syndrome des hamartomes basocellulaires.

BACKGROUND: Nevoid basal cell carcinoma syndrome is an autosomal dominant disorder characterized by developmental abnormalities and cancer predisposition. The PTCH 1 gene, the human homolog of the Drosophila segment polarity gene patched, has been shown to be involved in the development of nevoid basal cell carcinoma syndrome. PTCH 1 is mapped to chromosome 9q22.3. The aim of the present study was to report on clinical and genetic characteristics in patients followed for nevoid basal cell carcinoma syndrome and to compare them to the data in the literature. PATIENTS AND METHODS: Screening for PTCH 1 mutations was done in 22 patients followed between 1981 and 2003 for clinical suspicion of nevoid basal cell carcinoma syndrome. Clinical and radiological data were reviewed retrospectively from records. Genetic analysis was performed using blood samples after patient informed consent was obtained. When possible, DNA was also analyzed from the parents of patients in whom PTCH 1 mutations were found. RESULTS: All patients had developed basal cell carcinomas: 45% palmar and plantar pitting, 62% jaw cysts and 66% calcification of falx cerebri. Medulloblastomas and meningiomas were the most common associated tumors. PTCH 1 mutations were identified in 13 patients: 6 familial cases, 3 sporadic cases and for 4 patients, it was not possible to conclude. Nine different new germ-line mutations were identified. DISCUSSION: Genetic analysis allows molecular confirmation of diagnosis in about half of all patients. Early diagnosis is essential for detection of clinical and radiological manifestations in young patients and for provision of advice concerning protection of the skin from the sunlight.

[Hexylresorcinol induces chromosome aberrations in mouse peripheral blood cells].

Hexylresorcinol has been demonstrated to induce chromosome aberrations in eukaryotic cells at doses of 0.5, 0.05, and 0.005 mg/g body weight. The metabolic transformation of hexylresorcinol in mice decreases its genotoxic effect. The mutagenic effect is retained for three days only after the administration of the highest dose of hexylresorcinol (0.5 mg/g); during the first two days, lower doses are also genotoxic. Therefore, hexylresorcinol doses lower than 0.5 mg/g body weight are metabolized within two days to the extent precluding the expression of the cytotoxic effect. After a single administration to mice, exogenous hexylresorcinol is transformed at a rate of 0.0025-0.025 mg/day.

Tumor-infiltrating CD3- NK cells are more effective than CD3+ T cells in killing autologous melanoma cells.

We have studied the phenotype and functional activity of tumor-infiltrating lymphocytes (TIL) derived from eight human melanomas cultured for up to 60 d in the presence of recombinant IL-2. In the early period of the cultures, TIL were predominantly T cells of CD8+ phenotype and contained 10-30% of CD3- cells. Four of the five early TIL cultures tested in a cytotoxicity assay displayed a degree of MHC-unrestricted lysis on a series of autologous and allogenic melanoma cell lines as well as the K562 natural killer-sensitive target. With longer periods of time in culture, all TIL lines showed a decrease in lytic activity that was associated with the loss of CD3- cells. Thus, most of the killing of short-term TIL cultures appeared to be mediated by CD3- natural killer cells, whereas CD3+ T cells were found to be weak anti-tumor effectors. Even though the CD3+ T cells were not cytotoxic on K562 targets, their lytic activity (even weak) against melanoma cells appeared to be non-MHC restricted, and was blocked by anti-CD3 antibodies. In addition, cytotoxicity of the CD3+ TIL cultures was compared to that of a CD3-/NKH1+ cell line purified from peripheral blood. It was found that natural killer cells were much more potent than CD3+ TIL on the melanoma cell lines tested.

Emergent percutaneous cardiopulmonary bypass in patients having cardiovascular collapse in the cardiac catheterization laboratory.

Percutaneous cardiopulmonary bypass (PCB) was instituted in 30 initially stable patients who developed either cardiac arrest refractory to resuscitation (n = 7) or cardiogenic shock (mean arterial blood pressure < 50 mm Hg unresponsive to fluid resuscitation or vasopressors) (n = 23) after a catheterization laboratory complication. Events leading to collapse included abrupt closure during percutaneous transluminal coronary angioplasty (PTCA) (n = 22), complications from diagnostic cardiac catheterization (n = 6), left ventricular perforation during mitral valvuloplasty (n = 1), and right ventricular perforation during pericardiocentesis (n = 1). PCB was initiated within 20 minutes of cardiovascular collapse in 83% of patients (arrest: 21 +/- 13 minutes [range 10 to 50]; and shock: 17 +/- 6 minutes [range 10 to 30]). Mean arterial blood pressure increased on PCB from 0 to 56 mm Hg in patients with cardiac arrest and from 37 to 63 mm Hg in those with cardiogenic shock at mean PCB flow rates of 2.5 to 5.0 liters/min. Subsequent therapy on PCB included emergent cardiac surgery (n = 14), PTCA (n = 13) and medical therapy (n = 3). Six patients (20%) survived to hospital discharge (3 with cardiac surgery, 2 with PTCA, and 1 with medical therapy). All 7 patients with refractory cardiac arrest died despite further interventions on PCB, whereas 6 of 23 (26%) with cardiogenic shock survived to hospital discharge. Thus, in response to cardiovascular collapse in the catheterization laboratory, PCB does not salvage patients who do not regain a stable cardiac rhythm. PCB can stabilize patients who develop cardiogenic shock for further interventions which are lifesaving in only a minority of patients.

A new clinical classification for hospital prognosis of unstable angina pectoris.

Unstable angina represents a heterogeneous spectrum of clinical entities between chronic stable angina and acute myocardial infarction. To facilitate prognostication of in-hospital outcome, we prospectively tested on a priori unstable angina classification scheme based on information available at the time of acute presentation. Prospective database enrollment at the time of emergency room presentation was performed and patients were classified into 1 of the following categories: class IA, acceleration of previous exertional angina without electrocardiographic (ECG) changes; class IB, acceleration of previous exertional angina with ECG changes; class II, new-onset exertional angina; class III, new-onset rest angina; class IV, protracted rest angina with ECG changes. The study consisted of 1,387 consecutive patients with unstable angina. Baseline demographics and aggregate in-hospital major cardiac event rates were recorded (myocardial infarction, refractory angina, and death). There was a significant increasing trend in cardiac events from class I to IV (p < 0.0001). Class IA patients had the lowest aggregate event rate at 2.7% (p = 0.0005). Paired chi-square tests of adjacent categories showed no differences in event rates for class IB and II (p = 0.3). A significantly higher rate of adverse events was seen for class III patients (20.1%, p < 0.0001). Class IV patients demonstrated the highest rate of in-hospital adverse events (42.8%, p < 0.0001). We conclude that this easily deduced, universally applicable categorization of unstable angina is highly prognostic of in-hospital adverse cardiac events and hence could have potential use for triage decisions regarding hospital admission and intensity of therapy.

Clinical nuclear magnetic resonance imaging of the body.

NMR promises great advances in diagnosis and has delivered so much already that it is expected that in the future it will replace many applications of the currently used imaging modalities. Although x-ray computed tomography is continuing to advance in speed of scanning and resolving power, NMR will most likely soon eliminate its use in many studies of the central nervous system and also in many other areas of the body. The promise of combining topical spectroscopy with imaging is also exciting and should provide further information about metabolic processes of various organs. Progress in NMR is so rapid and the future is so bright that one of the great problems will be to develop a new breed of radiologists who are versatile in biochemistry, mathematics, and computers, as well as competent in morphologic anatomy and pathologic physiology. As time goes on, advances in NMR will be achieved only by teams of clinical and basic scientists encompassing multiple disciplines.

The bovine rod outer segment guanylate cyclase, ROS-GC, is present in both outer segment and synaptic layers of the retina.

Cyclic-GMP, which plays a pivotal role in visual transduction in the vertebrate retina, is synthesized by guanylate cyclase. The purpose of this study was to localize a rod outer segment-derived particulate guanylate cyclase (ROS-GC) to the retina of several species that have different populations of rods and cones. A rabbit antibody was raised against a synthetic peptide, corresponding to the sequence A107-L125 of bovine ROS-GC. Western blot analysis showed a single immunoreactive band at about 115 kDa with bovine rod outer segments but not with human rod outer segments. Light microscopic immunocytochemistry of tissue sections revealed immunoreactivity in the outer segment layer and in the outer and inner plexiform layers. The rod-rich rat retina showed uniform immunolabeling of outer segments; the cone-containing cat retina showed heavily labeled cone outer segments and lighter labeling of rod outer segments; the cone-rich chicken retina showed a uniformly and intensely labeled outer segment layer. Preincubation of the primary antibody with the peptide completely blocked antibody binding. Electron microscopic immunocytochemistry of the cat retina confirmed the presence of guanylate cyclase in photoreceptor outer segments and demonstrated its association with disk and plasma membranes. These data support a concept in which guanylate cyclase is much more concentrated in the outer segments of cones than rods. The immunolabeling of the plexiform layers suggests that the particulate guanylate cyclase is not unique to the photoreceptor outer segments, and may also play a role in transduction processes of retinal synapses.

Intracolonic pressures during barium-enema studies using the single- and double- contrast techniques.

Six dogs were examined by means of single- and double-contrast barium enemas, and colonic pressures and diameters were recorded at five intervals while the volume of the contrast medium was increased. Examinations were performed with and without administration of glucagon. Changes in colonic pressure and diameter were similar for the two techniques in 77% of the studies with and in 65% of the studies without administration of glucagon. Neither technique produced significantly different pressure or diameter changes with glucagon as compared to without it. Limitations in the experimental technique must be considered before extending results to human subjects.

Vascular alterations in canine histiocytic ulcerative colitis.

The large intestines of eight boxer dogs with canine histiocytic ulcerative colitis (CHUC) and 10 normal dogs were studied by in vivo angiography and postmortem microangiography. The vascular abnormalities were correlated with the gross and histologic pathology found at necropsy. The angiographic abnormalities were variable, non-specific and were gross indicators of disease. Intestinal segments with mild, focal inflammatory lesions appeared normal, while diseased segments with more extensive inflammatory change exhibited variable vascular dilatation and hypervascularity. Microangiograms of bowel specimens with an early mucosal lesion were normal. With increased disease severity, there was microvascular dilatation with attenuation of mucosal arterioles. Areas with focal or confluent ulcerations demonstrated complete disruption of the mucosal microvascular bed and replacement with the chaotic tangle of ectatic vessels, characteristic of granulation tissue. Anatomic arteriovenous shunts were not observed.

Radical resection of radiation-induced sarcoma of the chest wall: report of 15 cases.

BACKGROUND: Surgical management of radiation-induced sarcoma of the chest wall remains difficult because of its impressive local aggressiveness. METHODS: Between 1987 and 1995, 15 patients (median age, 58 years) underwent radical resection of radiation-induced sarcoma of the chest wall. This type of tumor was defined as a metachronous, histologically different neoplasm in the irradiated field of the original tumor. Ten patients had a history of primary breast cancer and 5 patients, Hodgkin's disease. The median delivered radiation dose to the primary tumor area was 45 Gy, and the median interval between radiotherapy and diagnosis of sarcoma was 14 years. Seven tumors were located on the sternum, three on the lateral chest wall, and five in the thoracic outlet. Four total and three partial sternectomies, three lateral chest wall resections and five resections of tumors in the thoracic outlet (three first-rib resections) were performed. Seven patients required stabilization of the chest wall with prosthetic material. Soft tissue reconstruction was carried out with either muscle flaps and skin advancement in 9, musculocutaneous flaps in 4, or skin flaps alone in 2 patients. RESULTS: One patient died 3 months after total sternectomy of respiratory failure. Two patients (13.3%) had a local complication: sepsis after sternectomy in 1 and cutaneous necrosis in 1. Local recurrence occurred in 7 patients after a median interval of 10 months. Two of them died, and 4 underwent a repeat resection, 3 of whom are still alive. Four patients died of systemic recurrence. With a median follow-up of 30 months, overall 5-year survival and 5-year disease-free survival rates were 48% and 27%, respectively. CONCLUSION: Despite poor long-term disease-free survival, radical resection of radiation-induced sarcoma of the chest wall is justified on the basis of low postoperative morbidity and the lack of other available therapies.

Comparison between familial and nonfamilial melanoma in France.

BACKGROUND AND DESIGN: Five percent to 10% of cutaneous malignant melanomas (CMMs) occur in a familial setting. Clinical, epidemiologic, and genetic studies of familial CMM in different regions of the world have led to various results. To assess the characteristics of familial CMM in France, the clinical, histologic, and epidemiologic characteristics of 295 patients with CMM were recorded, and a comprehensive familial investigation was performed for each case. Patients with a family history of CMM were compared with nonfamilial cases. RESULTS: Cutaneous malignant melanoma occurred as a familial cancer in 22 (8%) of 295 patients. Among the multiple variables studied, those significantly associated with the familial occurrence of CMM were red hair, inability to tan, and presence of clinically atypical moles. When these variables were considered together in a multivariate analysis, only the association with red hair (P = .001) and atypical moles (P < .05) remained significant. In addition, the patients with familial melanoma exhibited the following tendencies: a younger age at diagnosis, a higher number of moles, and the development of multiple primary melanomas, but these results did not reach statistical significance. Factors relating to UV light exposure, histologic features of CMM, course of the disease, and occurrence of nonmelanoma cancers showed a similar distribution between familial and nonfamilial cases. CONCLUSION: A familial investigation should be performed for each patient with CMM in France, particularly when he or she exhibits phenotypic risk factors for CMM such as red hair and atypical moles.

Effect of lithium on rod photoreceptor rhodopsin-coupled G-protein (transducin).

1. Lithium was known to inhibit both adrenergic and cholinergic agonist-induced activation of G-proteins in cerebral cortex. 2. Doly et al (1989) observed that lithium reduced the b-wave of the electroretinogram and suggested that the effect was due to inhibition of G-protein in photoreceptor cells. 3. This study was undertaken to test this hypothesis directly on photoreceptor cell membranes. Rod disk membranes containing the visual transduction machinery were isolated in the dark and the effect of lithium was tested on (a) activation by bright light of G-protein-mediated cyclic GMP hydrolysis, (b) light sensitivity of the activation, (c) the lifetime of the light-activated receptor, and (d) light activation of GTP-gamma-S binding to the membranes. 4. None of these processes were affected by lithium. It is therefore concluded that the effects of lithium on the b-wave of the electroretinogram should be due to influences on G-proteins in other parts of the retina.

Radiologic diagnosis of disordered esophageal motility: a unified physiologic approach.

Fluoroscopy and cineradiography of the esophagus with swallowed contrast media are indispensable in the study of normal and abnormal contractions of the esophagus, and when performed by experienced radiologists they are believed to be superior and easier on patients than motility studies with pressure recordings.

Intratumoral oxygen tension in metastatic melanoma.

Tumour hypoxia can lead to a decrease in the biological effectiveness of radiation and alkylating agents. Few data are available on oxygen tension (PO2) in melanoma. In 20 patients with past history of melanoma, PO2 was evaluated in normal tissues and suspected metastatic lesions (nodes and skin metastases). Oxygen tension was measured using a needle probe technique (KIMOC-6650 histograph, Eppendorf, Germany), the day before the surgical removal of the suspected metastatic lesion. Histological confirmation of the malignant origin of the removed lesion was obtained in 18 cases. In two cases invasion by the known melanoma was not seen histologically. The median PO2 for normal tissues was 40.5 mmHg. For tumours, the median PO2 was 11.6 mmHg, and it was 17.1 mmHg in nodes and 6.7 mmHg in skin metastases. Very low values (< 2 mmHg) accounted for 20% of the recorded values in nodes and 15% in skin metastases. When analysed according to the node size (< or > or = 3 cm in diameter), the median PO2 was 10.4 mmHg in large nodes (six patients) and 53.3 mmHg in small nodes (six patients). For the two non-tumoral lesions, the median PO2 values were 20.9 and 25.1 mmHg, with no values below 10 mmHg. Thus a decrease in PO2 values, probably corresponding to tumour hypoxia, was found in most of the metastatic tumours when compared with normal tissues. The prognostic value of these PO2 measurements in melanoma remains to be demonstrated in the tumour response to radiotherapy or alkylating agents. However, tumour hypoxia can already be investigated as a target for new treatment modalities in metastatic melanoma.

Melanoma arising de novo in childhood: experience of the Gustave-Roussy Institute.

Between January 1956 and December 1990, 17 patients younger than 17 years with available pathological screens of de novo cutaneous melanoma, and with no other risk factors (xeroderma pigmentosum, giant congenital naevi, congenital melanoma or a proven family history of dysplastic naevus syndrome) were seen at the Gustave-Roussy Institute. The median age was 9 years and 9 months (range 2 years and 3 months-16 years and 9 months). The primary disease was located in the lower extremities in 10 cases, the trunk in five cases, and the upper extremities or head and neck in one case. The disease was localized for 10 patients at presentation (stage I), six had proven nodal metastasis (stage II) and one patient had nodal and breast metastases. The median thickness of the primary lesion was 2.89 mm (range 0.64-10). Five tumours were at level III on Clark's index, eight at level IV and four at level V. Six cases were classified as superficial spreading, two as unclassified radial growth, three nodular, three with Spitzoid cells, and three were unclassified. Two patients presented local recurrence with an initial unclassified melanoma, with a thickness greater than 2.5 mm. At a median follow-up time of 7 years, two patients had died from recurrent disease, and one patient had died from a second malignancy.

Chest wall reconstruction following resection of large primary malignant tumors.

Reconstructive procedures following radical resection of large primary malignant chest wall tumors (PMCWT) continue to evolve. Between 1982 and 1993, 32 consecutive patients (18 males/14 females) with a median age of 47 years (range, 12-77) underwent radical resection for large (median 10 +/- 5.4 cm) PMCWTs arising either from the bone (n = 15) or soft tissues (n = 17) of the chest wall. Nine (28%) had previous surgical resection before referral. Sixteen (50%) required extensive skin excision. Twelve sternectomies (5 total and 7 partial) and 20 lateral chest wall resections were performed. In this latter group, 16 patients (80%) had at least three ribs resected. Resection extended to the lung (10 wedge resections, 2 lobectomies and 1 pneumonectomy) in 13 patients, diaphragm in 3, abdominal wall in 2, brachiocephalic and subclavian vessels in 5, superior vena cava in 1 and upper limb in 1. Stability of the chest wall was obtained with prosthetic material in 27 patients, including Marlex (n = 21), polytetrafluoroethylene (PTFE) (n = 4) and polyglactin (n = 2) meshes. After sternectomy, six patients had a methyl methacrylate mesh reinforcement while soft tissue reconstruction was carried out using the pectoralis major muscle (PM), either alone with skin advancement (n = 8) or as a myocutaneous flap in three males (unilateral n = 2, bilateral n = 1) and by a latissimus dorsi (LD) myocutaneous flap in one female. Muscle transposition was used to reconstruct defects of the lateral chest wall and included 10 LD, 6 PM and 2 serratus anterior (SA) muscles, with associated advancement of the diaphragm in two cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Nuclear magnetic resonance imaging clinical experience in San Francisco.

NMR is a new extremely promising imaging modality that combines the advantages of X-ray computed tomography by giving high resolution tomograms, of ultrasound by allowing imaging in any desired plane without the dangers from ionizing radiation and nuclear medicine by offering information about physiology and metabolic processes. These advantages are not combined with any of the drawbacks of the other modalities, and are due to the ability of NMR to provide information from four imaging parameters: 1) H density; 2) T1--the spin lattice relaxation parameters; 3) T2--the spin-spin relaxation parameter; and 4) information about proton motion. NMR is already a useful clinical tool in the study of brain, cord, mediastinum, pelvis, and is promising in the study of heart, kidneys, adrenals, liver, pancreas, and spleen.