Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

It has been established that both adult and larval zebrafish are capable of showing nociceptive responses to noxious stimuli; however, the use of larvae to test novel analgesics has not been fully explored. Zebrafish larvae represent a low-cost, high-throughput alternative to traditional mammalian models for the assessment of product efficacy during the initial stages of drug development. In the current study, a novel model of nociception using zebrafish larvae is described. During the recovery from an acute exposure to low levels of acetic acid, larvae display innate changes in behaviour that may be indicative of nociception. To assess the usefulness of this model for testing potential analgesics, three known synthetic pain medications were assessed (ibuprofen, acetaminophen and tramadol) along with three naturally occurring products (honokiol, tetrahydrocannabinol and cannabidiol). When the effect of each compound on both the acetic acid recovery and control activity was compared there appeared to be both similarities and differences between the compounds. One of the most interesting effects was found for cannabidiol which appeared to oppose the activity change during the recovery period of AA exposed larvae while having a nominal effect on control activity. This would appear to be in line with current research that has demonstrated the nociceptive properties of cannabidiol. Here we have provided a novel model that will complement existing zebrafish models and will expand on the potential use of zebrafish larvae for studying both nociception and new analgesics.

Gangrenous cellulitis associated with gram-negative bacilli in pancytopenic patients: dilemma with respect to effective therapy.

INTRODUCTION: Gangrenous (necrotizing) cellulitis is a progressive bacterial infection of skin and soft tissue; the infection can spread into subcutaneous tissue with involvement of superficial and deep fascia (necrotizing fasciitis). We describe two pancytopenic patients with polymicrobial gram-negative bacteremia and fulminating gangrenous cellulitis. CASE REPORTS: Pseudomonas aeruginosa was isolated from a localized hemorrhagic area of the face in one patient. The chronology of infection in these two patients is documented in a series of dramatic color photographs. Despite appropriate antibiotic therapy, the infections progressed relentlessly and both patients died. COMMENTS: We discuss the dilemma of establishing the correct diagnosis prior to the appearance of the characteristic cutaneous manifestations of hemorrhagic necrosis and gangrene. Once the diagnosis is established, surgical excision is universally recommended. Unfortunately, bleeding diatheses in pancytopenic patients with co-existing coagulation deficiencies pose logistic obstacles in urgent, real-life situations. The timing and conditions for surgery need to be elucidated in these patients. An approach to this infection is proposed. The utility of frozen-section biopsy of the involved tissue and computed tomographic scans of the involved area remains to be evaluated.

Cyclophosphamide in the treatment of orbital vasculitis.

When vasculitis, an angiocentric and angiodestructive process, occurs in the orbit, the clinical presentation and radiographic findings resemble those of idiopathic inflammatory pseudotumor. Three patients, two men and a woman, 28 to 72 years old, initially thought to have "pseudotumor" failed to response to corticosteroid therapy. Orbital biopsy specimens in all patients disclosed vasculitis. There was no evidence of systemic vasculitis. High-dose prednisone effectively eliminated pain and reduced inflammation but did not adequately control fibrosis formation leading to ultimate loss of function. Each patient eventually lost an eye to this process. Therapy with cyclophosphamide, a B-cell cytotoxic drug, produced a prompt response in terms of eliminating pain, inflammation, and formation of fibrous tissue. Cyclophosphamide therapy has been instrumental in preserving sight in each patient's remaining eye. In such cases we believe the benefits of cyclophosphamide therapy outweight the known risks.

Occurrence of three cases of carcinoma in individuals with Crohn's disease treated with metronidazole.

Controversy exists regarding the safety of metronidazole. Experimental studies have suggested both a carcinogenic and mutagenic effect in animals. In women treated with metronidazole for trichomoniasis which involves low dosages and short time periods, no carcinogenic effect was noted. Metronidazole is also used in the treatment of Crohn's disease which involves larger dosages over longer periods of time. The authors have recently encountered three individuals with Crohn's disease who were treated with large doses of metronidazole and who developed a malignancy [breast (two) and cholangiocarcinoma] at a rather young age (32, 31, and 27 years, respectively). Whereas this association based on three cases is not per se incriminatory or even suggestive, nevertheless, the cases are unusual and we urge prospective and long-term follow-up studies on individuals being treated with large doses of metronidazole over prolonged periods of time. Metronidazole (Flagyl) was introduced into The United States in the 1960's for the treatment of trichomoniasis (1). The conditions for which this drug is indicated and has been used have expanded to include such diverse entities as amebiasis (2), brain abscess (3), and Crohn's disease (4). A controversy exists regarding the safety of this drug (5, 6). Experimental studies have shown that metronidazole is both carcinogenic and mutagenic (7-9). However, a recent study (10) cited lack of evidence for a carcinogenic effect with the use of metronidazole in women treated for trichomoniasis. In the past 1 1/2 years we have encountered three unusual cases involving individuals who were treated with large doses of metronidazole for Crohn's disease and who developed a malignant neoplasm at a relatively young age. The features of these three cases are the subject of this report.

Secondary non-hematopoietic cancers arising following treatment of hematopoietic disorders.

Aggressive treatment of neoplastic disease has resulted in improved survival and, in some cases, cure of the primary malignancy. One of the most serious complications of such anticancer treatment has been the occurrence of an acute leukemia (primarily non-lymphocytic) several years after the successful treatment of the original neoplasm. Within the last 12 years, the authors have encountered 26 individuals who developed a second non-hematopoietic malignancy (excluding skin cancers) following primary aggressive treatment of a hematopoietic malignancy. All individuals had been treated with chemotherapy (24 of 26 with alkylating agents). The secondary tumors included lung (7), colon (6), gastric (4), bladder (3), esophageal (3), rectal (2) and pancreatic (1) tumors. The average time to development of the second malignancy in this series was 55.1 months, and the survival period following the diagnosis of the second malignancy averaged 7.3 months. It may be that aggressive anticancer treatment may be responsible for the emergence of a host of second non-hematopoietic carcinomas in addition to the now well established association with induced acute non-lymphocytic leukemias.

Malignant myositis ossificans: occult gastric carcinoma presenting as an acute rheumatic disorder.

A patient developed ossifying skeletal muscle metastases from a primary gastric mucin-producing adenocarcinoma. The unusual nature of skeletal muscle metastases and the inflammatory-like syndrome associated with heterotopic ossification is reviewed. It is suggested that this case of 'neoplasm-induced post-traumatic myositis ossificans' may be caused by the interaction of local haemorrhage and thrombosis, mucin-producing tumour implants, and the presence of large quantities of gamma-carboxyglutamic acid, an amino acid associated with the calcification of bone matrix formation.

Bone-forming gastric metastases in muscle-computed tomographic demonstration.

Bone-forming metastases to soft tissues and muscle are a rare entity. An unusual case of heterotopic ossification occurring within metastases to muscle arising from a primary gastric adenocarcinoma is reported. No bone was found in the primary gastric malignancy. There is one prior report of ossification in muscle occurring in metastases from gastric malignancy, but no previous computed tomographic demonstration of this. The mechanism of osseous metaplasia is discussed, but its precise morphogenesis remains obscure.

Adenocarcinoma of the Fallopian tube. An ultrastructural study.

A case of fallopian tube adenocarcinoma was studied by light and transmission electron microscopy. The neoplastic cells contained abundant mitochondria, moderate to large amounts of rough endoplasmic reticulum (RER) arranged in parallel arrays and often containing amorphous material, annulate lamellae, possible secretory vesicles, and glycogen. The presence of stacked RER and annulate lamellae together is unusual in papillary serous cystadenocarcinoma of the ovary, and has not been described in Fallopian tube adenocarcinoma. Golgi complexes were are. Small acini with projecting microvilli as well as junctional complexes were present, but cilia were not found. The electron microscopic findings suggest secretory activity, and are remarkably similar to those found in papillary serous cystadenocarcinomas of the ovary. The findings also support the hypothesis that ovarian serous tumors and adenocarcinomas of the Fallopian tube are derived from coelomic epithelium.

Induced acute non-lymphocytic leukemia following long-term chemotherapy: a study of 20 cases.

Twenty individuals developed acute non-lymphocytic leukemia (ANLL) following long-term chemotherapy for other disorders. The primary disorders included non-Hodgkin's lymphoma (five), Hodgkin's disease (five), carcinoma (four), multiple myeloma (three), chronic leukemia (two), and rheumatoid arthritis. Leukemia developed from 11-132 months (mean approximately 60 months) following institution of chemotherapy and all cases have occurred since 1974. Pre-leukemic cytopenias were present in 15 individuals. Fifteen of the 20 patients had chromosome analyses and 14 were abnormal. The leukemia was invariably refractory to chemotherapy with a median survival of only two months. Of the patients autopsied, only one individual had any evidence of the primary malignancy. This study illustrates the need for surveillance for secondary ANLL following long-term chemotherapy with/without radiotherapy. Duration of optimal chemotherapy for the primary disease must be determined by control trials and weighed against the risk of developing a secondary leukemia.

Treatment of amyloidosis associated factor X deficiency.

This is the tenth patient in thirteen years to be reported with the findings of an isolated factor X deficiency associated with primary amyloidosis. A favorable response to factor IX concentrate was manifested by temporary clinical and laboratory correction of her diathesis. This mode of treatment, therefore, provides an approach to therapy for bleeding complications in this group of patients who have previously failed to response to fresh frozen plasma.

Human leukemic cells: in vitro growth of colonies containing the Philadelphia (Ph) chromosome.

Human leukemic cells with a marker (Philadelphia; Ph(1)) chromosome gave rise to granulocytic and mononuclear cell colonies when grown in vitro. All metaphases from a single colony were either Ph(1) positive or Ph(1) negative. No colonies contained a mixed cell population. This suggests that leukemic and normal cells exist simultaneously and that in vitro colonies are clonal in origin.