A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

Stereotyped neuropil branching of an identified stomatogastric motor neuron

Anatomical studies of the crab stomatogastric ganglion (STG) have suggested only minimal organization within the neuropil of this structure. Here, we present evidence that, for at least one intrinsic neuron type, the ventricular dilator (VD) neuron, a highly organized and stereotyped branching structure exists within the stomatogastric neuropil. Specifically, we show the morphology of the VD neuron consists of a single primary neurite that projects from the soma into the neuropil and bifurcates into a pair of subprimary neurites, which in turn exit the neuropilar region, one entering the left and the other the right medial ventricular nerve. Nearly all secondary neurite branching of the VD neuron is from the subprimary neurites. There are approximately 22 secondary branches/neuron (range 14-28), with no significant difference between the number of secondary branches off the right vs. the left subprimary neurite, although the ratio of secondary branches between subprimaries varies (range 0.4-1.6). The fine neurites that branch from the secondary processes segregate hemispherically within the neuropil, based on the subprimary neurite of origin. Within this hemispherical organization, another level of fine neurite segregation is present, namely, the fine neurites derived from each secondary branch are restricted to discrete regions of the hemisphere with only minimal overlap with those derived from other secondary branches. Monte Carlo simulations show that this segregation differs significantly from a random distribution. The organization of branching seen in the VD neuron may play a critical role in the electrotonic and local computational organization of this neuron and sets the stage for physiological experimentation addressing these issues.     

A novel ultrasound method for evaluation of collateral development in limb ischemia

Although clinical studies are underway to evaluate the effectiveness of angiogenesis, there are no validated, non-invasive methods to assess peripheral collateral development. This study was performed to validate a novel ultrasound-based method of assessing collateral formation in a pig model of hindlimb ischemia. Ultrasonography of predefined ultrasound planes was performed on 12 pigs immediately after ligation of the right common femoral artery, and 7, 14, 28 and 42 days thereafter. A custom software program was used to evaluate both color Doppler (CD) and power Doppler (PD) images to generate flow indices. Collateral development was observed with ultrasound as early as 7 days post-arteriectomy and increased dramatically by 28 days. Areas of persistent ischemia resulting from inadequate collateral formation were easily quantified in all images. Collaterals detected on ultrasound were confirmed by angiography and histology, and tissue perfusion by a fluorescent microsphere method. As demonstrated with color and power Doppler measurements, collateral formation is initiated early after ischemic injury in this large juvenile animal model of angiogenesis. This non-invasive method is useful to quantify blood flow, visualize angiogenesis and determine areas of persistent lower limb ischemia, and may have an important role in evaluating new approaches to modulate angiogenesis.     

A community based study of failure to thrive in Israel

OBJECTIVE: To examine the characteristics of infants suffering from failure to thrive in a community based cohort in Israel and to ascertain the effect of failure to thrive on their cognitive development. METHODS: By review of records maintained at maternal and child health clinics in Jerusalem and the two of Beit Shemesh, epidemiological data were obtained at age 15 months on a cohort of all babies born in 1991. For each case of failure to thrive, a matched control was selected from the same maternal and child health clinic. At age 20 months, cognitive development was measured, and at 25 months a home visit was carried out to assess maternal psychiatric status by questionnaire, and the HOME assessment was performed to assess the home environment. RESULTS: 3.9% of infants were found to have fallen below the third centile in weight for at least three months during the first year of life. Infants with failure to thrive did not differ from the general population in terms of obstetric or neonatal complications, birth order, or parents' ethnic origin, age, or years of education. The infants with failure to thrive did have lower birthweights and marginally smaller head circumferences at birth. Developmental assessment at 20 months of age showed a DQ of 99.7 v 107.2 in the matched controls, with 11.5% having a DQ below 80, as opposed to only 4.6% of the controls. No differences were found in maternal psychiatric problems as measured by a self report questionnaire. There were, however, significant differences in subscales of the HOME scale. CONCLUSIONS: (1) Infants who suffered from failure to thrive had some physiological predispositions that put them at risk; (2) failure to thrive may be an early marker of families providing suboptimal developmental stimulation.     

State-funded comprehensive primary medical care service programs for medically underserved populations: 1995 vs 2000

OBJECTIVES: We analyzed responses to the 2000 Comprehensive Primary Medical Care programs for Medically Underserved Populations Survey and compared them with the 1995 survey results to identify trends. METHODS: Surveys were mailed to all primary care program offices. State primary care program associations reviewed primary care program offices' responses and completed surveys for offices that did not respond. RESULTS: We identified 30 qualified primary care programs in 24 states that had an overall funding level of $215 million. Most states allowed funds to be spent on expanding service areas, buying equipment, and hiring and training staff. CONCLUSIONS: Although state funding has increased overall, many states do not have comprehensive primary care programs, and an increasing number of states are experiencing budget deficits that may lead to reductions in existing programs.