Striking differences in transmission of corticospinal excitation to upper limb motoneurons in two primate species

There is considerable debate as to the relative importance, for cortical control of upper limb movements, of direct cortico-motoneuronal (CM) versus indirect, propriospinal transmission of corticospinal excitation to cervical motoneurons. In the cat, which has no CM connections, a significant proportion of corticospinal excitation reaches forelimb motoneurons via a system of C(3)-C(4) propriospinal neurons (PN). In contrast, in the macaque monkey most motoneurons receive direct CM connections, and, under the same experimental conditions as in the cat, there is little evidence for PN transmission. We have investigated corticospinal transmission in the New World squirrel monkey (Saimiri sciureus) because its CM projections are weaker than in the macaque. Intracellular recordings were made from motoneurons identified from the ulnar, median, and deep radial (DR) nerves in four adult squirrel monkeys under chloralose anesthesia and neuromuscular paralysis. Responses to stimulation of the contralateral medullary pyramid were recorded before and after a lesion to the dorsolateral funiculus (DLF) at C(5), designed to interrupt direct corticospinal inputs to the lower cervical segments and unmask PN-mediated effects. This lesion greatly reduced the proportion of motoneurons showing either CM EPSPs or disynaptic IPSPs, but the proportion showing late EPSPs with segmental latencies beyond the monosynaptic range, evoked by repetitive but not single PT stimuli, was unaffected: 23 of 29 motoneurons (79%) before and 32 of 37 (86%) after the lesion; 41% of these late EPSPs had strictly disynaptic latencies after the lesion, only 14% before. These results are in striking contrast to the macaque (late EPSPs in only 18% of motoneurons before a C(5) lesion, 19% after it). Transmission of the late EPSPs via C(3)-C(4) PNs in the squirrel monkey was indicated by their absence after an additional C(2) DLF lesion. Nearly all tested motoneurons also responded with short latency EPSPs to stimulation in the ipsilateral lateral reticular nucleus. By analogy with the cat, these EPSPs probably reflect antidromic activation of ascending collaterals of C(3)-C(4) PNs with monosynaptic connections to motoneurons; the EPSPs were significantly smaller than in the cat but larger than in the macaque. These results suggest that the positive correlation across species between more advanced hand function and the strength of the CM system is accompanied by a negative correlation between hand function and the strength of the PN system. We hypothesize that in primates with more advanced hand function, the CM system effectively replaces PN-mediated control. This would include a contribution to the control of reaching movements, which are said to be specifically under the control of the PN system in the cat, and we speculate that these differences may be related to the degree of dexterity exhibited by the different species. This interpretation of the results predicts that in man, where the CM system is highly developed, the PN system is unlikely to be responsible for significant transmission of cortical commands to upper limb motoneurons.     

Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer

Guanine ribonucleosides substituted at the 8 position of the guanine ring are a unique class of immunomodulators, the lead compound of which is 7-allyl-8-oxoguanosine (loxoribine). We conducted a double-blind randomized phase I study to evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine in patients with advanced cancer. Twenty-four patients were treated in three dose tiers of 8 patients each, utilizing a unique statistical design, so that within each group, patients were randomized in blocks of 4 to receive loxoribine initially and then placebo 4 weeks later--a sequence that was reversed in the remaining 4 patients. In 23 courses of loxoribine and 20 courses of placebo, toxicity was mild and infrequent at all dose tiers (1 mg/kg, 5 mg/kg and 10 mg/kg. Both antibody-dependent cellular cytotoxicity and lymphokine-activated killer cytotoxicity were transiently depressed following loxoribine administration at all doses. Loxoribine is safe at doses up to 10 mg/kg in patients with advanced cancer, and produces modest immunologic effects. Further testing, particularly in conjunction with other immunologic agents, is warranted.     

Isolated congenital tuberculosis otitis in a preterm infant

We report an unusual case of localized congenital tuberculosis otitis in a preterm infant. Unlike disseminated congenital cases, the manifestations of localized otitis are associated with a triad of signs: (i) regional lymphadenopathy in the absence of typical systemic features of tuberculosis; (ii) delayed onset of presentation; and (iii) refractory otitis unresponsive to conventional antimicrobial agents. The need for greater diligence in looking for neonatal tuberculosis is emphasized, especially in an ethnic or socioeconomic environment where the disease is prevalent. Congenital tuberculosis, otitis, preterm
PC Ng, Department of Paediatrics, Level 6, Clinical Sciences Building, Prince of Wales Hospital, Shatin, NT, Hong Kong     

Regional isolated perfusion of high risk melanoma of the extremities with imidazole carboxamide

Twenty-four patients have been treated by regional isolated perfusion with decarbazine for melanoma of an extremity, with a follow-up period of seven to 72 months. None of these patients had any signs or symptoms of toxicity from the drug. The serum glutamic-oxalacetic transaminase level was elevated by the first postoperative day and returned to normal within the next six days. Fourteen of these 24 patients are free of disease for a follow-up period of 23 to 70 months. Three of the seven patients treated for local or intransit metastases are free of disease for five, 60 and 61 months; a fourth patient had subcutaneous metastases of the trunk develop while remaining disease-free in the perfused extremity for 72 months, and a fifth patient perfused for numerous intransit metastases of a leg had resolution of many of the nodules and remains without new lesions for nine months. Decarbazine is recommended as a safe and valuable drug for the perfusion of extremities with melanoma.     

The Institute for Ageing and Health,University of Newcastle,UK

The Institute For Ageing And Health (IAH) is the largest cross-disciplinary research grouping within Newcastle University's Faculty of Medicine, which recently obtained the highest 5 or 5* ratings in all fields evaluated in the UK Research Assessment Exercise 2001. The IAH was set up in 1994 to bring together clinical, basic and social scientists in partnership with colleagues in the National Health Service. It builds upon a long tradition of outstanding clinical research on age-related disorders, particularly in the field of dementia where the pioneering studies of Tomlinson and Roth in the 1960s first showed Alzheimer's disease to be the commonest cause of cognitive decline in later life. The clinical research of the IAH now extends to both neurodegenerative and vascular dementia in a joint Medical Research Council-University Development for Clinical Brain Ageing, and to studies in many other areas including depression in later life, falls and neurovascular instability, stroke and ischaemic brain disease, and health services research on the medical and social care of older people. These diverse areas of clinical investigation are now complemented by strong research on the basic biology of ageing within the new Department of Gerontology with its programmes on the genetics of ageing and longevity; molecular mechanisms of cellular ageing, including oxidative stress, DNA damage and genomic instability, telomere reduction and regulation, mitochondrial DNA mutations, and accumulation of aberrant proteins; and theoretical models of the ageing process. An ambitious strategy for future research on ageing and age-related disorders is based on the synergy between these complementary approaches.     

Recombinant human neutral endopeptidase ameliorates pancreatic elastase-induced lung injury

BACKGROUND: Genetic deletion of neutral endopeptidase (NEP), a cell-surface metalloprotease that degrades proinflammatory peptides, exacerbates lung injury induced by pancreatic elastase in a model of pancreatitis-associated lung injury. We tested 3 hypotheses: (1) genetic deletion of NEP prolongs lung recovery after elastase injections; (2) elastase-mediated lung injury is associated with down-regulation of NEP; and (3) pretreatment of NEP (-/-) and (+/+) animals with recombinant human NEP (rhNEP) reduces pulmonary damage in this model. METHODS: NEP (+/+) or (-/-) mice were injected with pancreatic elastase (0.085 U/g/dose intraperitoneally) or saline carrier at t = 0 hours and t = 1 hour. Some mice were pretreated with rhNEP (3 mg/kg intraperitoneally). Serum elastase, lung histologic score, myeloperoxidase, and NEP activities were measured at 4, 8, or 12 hours. RESULTS: NEP (-/-) mice had worse pulmonary inflammation at 4 and 8 hours versus (+/+) mice. Lung NEP activity was similar in elastase-treated and control (+/+) animals. Pretreatment with rhNEP reduced myeloperoxidase and improved histology at 4 hours in NEP (-/-) and (+/+) mice. CONCLUSIONS: Pancreatic elastase induces lung injury that is worse and prolonged in NEP (-/-) mice. Pretreatment with rhNEP ameliorates this injury. Thus, upregulation of NEP is a potential therapeutic approach for pancreatitis-associated lung injury.     

Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690

BACKGROUND: The clinical antitumor activity of recombinant interferon alpha2b (IFNalpha2b) has been well documented in patients with advanced and high-risk melanoma; however, its mechanism of action remains conjectural. Trial E2690 evaluated the immunomodulatory effects of IFNalpha2b in vivo during treatment at high doses (the HDI arm; n = 51 patients) and at low doses (the LDI arm; n = 54 patients) in relation to standard observation (OBS; n = 43 patients). METHODS: This study evaluated peripheral blood lymphocytes (PBLs) for phenotypic markers and cytotoxic functions at 1 month, 3 months, and 12 months in the HDI arm, the LDI arm, and the OBS arm and examined correlations between changes observed in PBLs or in tumors with regard to treatment dosage and disease outcome. Tumor biopsy samples were studied for response to IFNalpha2b at a range of concentrations in vitro. RESULTS: Baseline blood phenotypic and functional assays did not predict disease outcome; however, modulation of these immunologic assays by IFNalpha2b treatment was observed and was associated with IFNalpha2b dosage. Tumor cell class II major histocompatibility antigen expression (human leukocyte/lymphocyte antigen DR) and adhesion molecule expression (ICAM-1) were modulated by exposure to IFNalpha2b in a dose dependent manner. Blood natural killer (NK) cell function, T-cell function, and subset distribution were modulated early by patients in the HDI arm and later by patients in the LDI arm. None of the variables tested in these studies predicted recurrence free survival. The numbers of patients studied were smaller than may be needed to detect potentially clinically significant changes. CONCLUSIONS: These data demonstrate changes in immunologic parameters associated with IFNalpha2b treatment and dosage that may account for some of the differences in the clinical efficacy of this modality. The current results also suggest the need for further study of newer molecular intermediates of IFNalpha2b and T-cell response to specific antigens of melanoma.     

Decreased tumor blood flow as measured by positron emission tomography in cancer patients treated with interleukin-1 and carboplatin on a phase I trial

BACKGROUND: Positron emission tomography (PET) scanning can be used to measure blood flow. When interleukin-1alpha (IL-1) is given in a murine model, it induces acute hemorrhagic necrosis, tumor vascular injury and decreased tumor blood flow, and when given prior to carboplatin, there is enhanced antitumor activity compared to either agent alone. METHODS: In a phase I trial of IL-1 and carboplatin, eligible patients with metastatic disease to the lung had PET scanning performed with (15)O water to assess tumor blood flow before and after IL-1 administration. Doses of IL-1 were 0.03, 0.06, 0.10, 0.15, 0.20 and 0.30 micro g/kg given i.v. over 2 h. At 4 h after IL-1 initiation, carboplatin was administered as a 30-min i.v. infusion at a dose of 400 mg/m(2). Treatment was repeated every 28 days. Other measured parameters included granulocyte kinetics, integrin expression on circulating WBC, and carboplatin pharmacokinetics. Of 16 patients, 11 (8 evaluable) underwent PET scanning before and at 2, 4 and 24 h after IL-1 initiation. RESULTS: Mean measured pretreatment tumor blood flow was 1.82 ml/min per g. At 2, 4 and 24 h it was 1.35, 1.67 and 1.62 ml/min per g respectively. Tumor blood flow was significantly decreased ( P<0.008) at 2 h after IL-1 initiation. In four patients, liver blood flow was measured at the same time-points as tumor blood flow. Liver blood flow was discordant with the tumor blood flow measures, showing no statistically significant change. IL-1 also caused a decreased WBC at 2 h after initiation ( n=14, P=0.025). In addition, polymorphonuclear leukocyte (PMN) and monocyte surface expression of CD11b at 2 h was increased when measured by mean fluorescence intensity flow cytometry (PMN P=0.0269, monocytes P=0.0420). No consistent effect of IL-1 on either carboplatin AUC or platelet nadir was demonstrated. CONCLUSIONS: We conclude that IL-1 has measurable effects on tumor blood flow and causes a significant decrease in blood flow as measured by PET scanning with (15)O water at 2 h after initiation. This decrease is temporally associated with a significant leukopenia and an increased expression of the adhesion integrin CD11b on the circulating cell surface (PMN and monocytes). These results suggest that IL-1 causes decreased tumor blood flow in vivo in human cancer patients, an effect that was temporally related to cytokine-induced peripheral blood cellular changes. Furthermore, our findings suggest that PET scanning may be useful to assess the effect of a systemic antineoplastic agent on tumor blood flow in cancer patients.