Synthetic complementary peptides inhibit a neutrophil chemoattractant found in the alkali-injured cornea

PURPOSE: We have previously presented evidence that the neutrophil chemoattractant, N-acetyl-proline-glycine-proline (N-acetyl-PGP), triggers the initial polymorphonuclear leukocyte (PMN) invasion into the alkali-injured eye. In this study, sense-antisense methodology was used to develop novel complementary peptides to be potential inhibitors of N-acetyl-PGP. METHODS: The polarization assay was used to measure the potential chemotactic response of PMNs to synthetic N-acetyl-PGP, the ultrafiltered tripeptide chemoattractants obtained from alkali-degraded rabbit corneas, or leukotriene B4 (LTB4). Inhibition was expressed as the peptide concentration producing 50% inhibition (ID50) of polarization. Five complementary peptides were tested as potential inhibitors of N-acetyl-PGP: arginine-threonine-arginine (RTR), RTR-glycine-glycine (RTRGG), RTR dimer, RTR tetramer, and alanine-serine-alanine (ASA) tetramer. In addition, the RTR tetramer and both monomeric peptides (RTR and RTRGG) were separately tested for inhibition of the ultrafiltered tripeptide chemoattractants or LTB4. RESULTS: The complementary RTR tetrameric peptide was a powerful antagonist of N-acetyl-PGP-induced PMN polarization (ID50 of 200 nM). The RTR dimer was much less potent (ID50 of 105 microM). Both monomeric peptides, RTR and RTRGG, were only antagonistic at millimolar concentrations. The ASA tetramer showed no capacity to inhibit N-acetyl-PGP. The RTR tetramer also inhibited PMN activation by the ultrafiltered tripeptide chemoattractants (ID50 of 30 microM) but had no effect on LTB4. CONCLUSIONS: A complementary peptide (RTR) was designed which is an effective inhibitor of the neutrophil chemoattractant, N-acetyl-PGP. The potency of the RTR complementary peptide is dramatically enhanced by tetramerization. Inhibition of N-acetyl-PGP by complementary peptides offers great promise for control of the inflammatory response in the alkali-injured eye.     

What predicts incident use of cannabis and progression to abuse and dependence? A 4-year prospective examination of risk factors in a community sample of adolescents and young adults

OBJECTIVES: To determine risk factors of incident onset of use, abuse and dependence of cannabis in a community sample of adolescents and young adults. METHODS: Risk factors were examined in a prospective longitudinal design across 4 years in a representative sample (N = 2,446) aged 14-24 at the outset of the study (EDSP). Patterns of DSM-IV defined cannabis use, abuse and dependence were assessed with the Composite International Diagnostic Interview (M-CIDI). Potential risk factors were assessed at baseline. Incident cannabis use, abuse and dependence at second follow-up (on average 42 months after baseline) were the main outcome measures in this study. Associations were analyzed with logistic and negative binomial regressions. RESULTS: Using 11 of a total of 56 variables examined, the predictive value of the final multiple logistic regression for incident cannabis use was moderately good (area under the ROC curve = 0.78). Cannabis use frequency was predicted in the final model by 18 variables, cannabis abuse by two variables in the younger subsample and nine factors in the older group, and dependence by eight variables (dependence: ROC curve area = 0.97). Incident cannabis use was predicted mainly by availability of drugs, peers' drug use, a more 'positive' attitude towards future drug use, and regular previous use of licit drugs, while cannabis dependence was predicted primarily by parental death before age 15, deprived socio-economic status, and baseline use of other illicit drugs. CONCLUSION: Different factors predict the onset or severity of cannabis use and the progression to abuse and dependence. In addition to well-documented risk factors such as peer group pressure, drug availability, and low self-esteem, findings suggest that family history (e.g. parental mental disorders, early parental death), and prior experiences with legal drugs play a significant role in the initiation of cannabis consumption and the transition to cannabis use disorders in adolescents and young adults. Findings suggest that early intervention and prevention might be improved by better targeted treatment.     

Panniculectomy--an option for people who are morbidly obese

Obesity is becoming a major health issue across the nation. Surgical procedures to alleviate problems of severely limited ambulation, development of open wounds, and overeating may be an option for people who are morbidly obese. A gastric bypass procedure and panniculectomy are among the surgical options available. In this article, the preoperative, intraoperative, and postoperative care of a patient undergoing a panniculectomy are presented. A safe, complication-free procedure can be performed with preplanning; a precise, detailed team effort; and an informed, motivated patient. AORN J 77 (April 2003) 782-794     

Autonomic dysfunction and hemodynamics in vitamin B12 deficiency

Orthostatic hypotension in patients with cobalamin (Cbl) deficiency has been reported previously in isolated cases but we are not aware of detailed systematic studies of hemodynamic and autonomic nervous system function in patients with cobalamin deficiency. We investigated hemodynamic and autonomic responses to 60 degrees passive head up tilt (HUT) in 21 patients with vitamin B12 deficiency, 21 healthy age-matched control subjects and 9 age-matched patients with diabetes mellitus (DM) and established diabetic neuropathy. To systematically assess hemodynamic and autonomic nervous system function, we performed measurements of heart rate, beat-to-beat systolic and diastolic blood pressure, stroke index, cardiac index, total peripheral resistance index, total power, low (LF) and high (HF) frequency oscillatory component of heart rate variability, LF/HF ratio and spontaneous baroreflex sensitivity. As compared to controls, we found a significant fall of systolic blood pressure during 60 consecutive beats directly after head up tilt; furthermore, a significantly blunted fall of stroke index, cardiac index and a lack of increase of total peripheral resistance index for the duration of tilt in patients with diabetes mellitus and in patients with vitamin B12 deficiency. As compared to controls, we observed an altered response of spectral indices of sympathetic activation and vagal withdrawal and an impaired modulation of baroreflex sensitivity during head up tilt suggestive of a complex modification in the neural control activities in patients with cobalamin deficiency, which was comparable to that observed in patients with diabetes mellitus and established autonomic neuropathy. The results suggest that vitamin B12 deficiency causes autonomic dysfunction with similar hemodynamic consequences and patterns of autonomic failure as seen in diabetic autonomic neuropathy. Defective sympathetic activation may be the cause for orthostatic hypotension, which is occasionally seen in patients with vitamin B12 deficiency. It is concluded that patients with orthostatic hypotension should be screened for cobalamin deficiency.     

Role of Caspase-1 in experimental pneumococcal meningitis: Evidence from pharmacologic Caspase inhibition and Caspase-1-deficient mice

Caspase 1 plays a pivotal role in generating mature cytokine interleukin-1beta. Interleukin-1beta is implicated as a mediator of pneumococcal meningitis, both in experimental models and in humans. We demonstrated here that (1) Caspase 1 mRNA and protein expression is upregulated in the brain during experimental pneumococcal meningitis, and (2) Caspase 1 levels are elevated in the cerebrospinal fluid of patients with acute bacterial meningitis. The upregulation/activation of Caspase 1 was associated with increased levels of interleukin-1beta. Depletion of the Caspase 1 gene and pharmacologic blockade of Caspase 1 significantly attenuated the meningitis-induced increase in interleukin-1beta. This was paralleled by a significantly diminished inflammatory host response to pneumococci. The antiinflammatory effect of Caspase 1 depletion or blockade was associated with a marked reduction of meningitis-induced intracranial complications, thus leading to an improved clinical status. In humans, cerebrospinal fluid Caspase 1 levels correlated with the clinical outcome. Thus, pharmacologic inhibition may provide an efficient adjuvant therapeutic strategy in this disease.     

Improved outcomes in patients with osteogenic sarcoma of the head and neck

BACKGROUND: The current study reviews the authors' recent institutional experience in the treatment of osteosarcoma of the head and neck (OSHN). METHODS: The clinical records of 44 patients who were treated between 1981 and 1998 for OSHN were reviewed retrospectively. Archived histologic material was reviewed and data were analyzed to identify factors predictive of disease control and survival. Outcomes were compared with a previously reported historic cohort treated at the study institution. RESULTS: Patients ranged in age from 6 to 64 years (median, 31 years). The mandible was the primary site in 18 patients (41%), the maxilla in 20 patients (45%), and the skull in 6 patients (14%). Surgery was employed in all 44 patients, neoadjuvant chemotherapy was administered in 30 patients (68%), and postoperative radiation therapy was given to 7 patients (16%). The surgical excision margins were positive in 13 patients (30%). High-grade lesions were reported in 50% patients and low-grade lesions were noted in 18% of patients (grade was not assessable in 32%). Histologic response was "unfavorable" in 22 of 30 patients (73%) who were treated with neoadjuvant chemotherapy. The 3-year overall, disease-specific, and recurrence-free survival rates were approximately 81%, 81%, and 73%, respectively (median follow-up of 41 months). Positive surgical margins were found to be the only significant predictor of worse disease-specific survival. Compared with the historical cohort, the current experience demonstrated an obvious improvement in the 5-year local control (35% vs. 78%), distant metastases (37% vs. 13%), and overall survival (23% vs. 70%). CONCLUSIONS: Negative surgical margins were found to be the only significant predictor of overall and disease-specific survival. The results of the current study represent a considerable improvement over the authors' previously published experience and compare favorably with the results reported in the literature.     

Localized invasive intracranial aspergillosis with multiple cranial nerve failure -- case report and review of the literature

Contrary to the more frequent hematogenously spread cerebral aspergillosis, localized invasive intracranial aspergillosis is a fungal infection that can also occur in patients who are not severely immunosuppressed. This illness can be effectively treated in some of these patients by early and rigorous therapy. Localized invasion of the fungus, generally from one of the nasal sinuses, causes intracranial growth mainly along the base of the skull and larger vessels,where fibrous, granulomatous tissue develops. This generally leads to damage of the cranial nerves (primarily I-VI) as well as localized pain syndromes. We report on the clinical course documented by MRI of a patient with localized invasive intracranial aspergillosis who had multiple failure of cranial nerves following surgery for an aspergilloma of the maxillary sinus. Clinical course, imaging findings, and treatment of the illness are discussed with a review of the relevant literature.