Antidepressant therapy in the physically ill: a therapeutic opportunity for the selective 5-HT re-uptake inhibitors?

Depression is common in physically ill populations, although it is frequently unrecognized and untreated. Diagnosis and antidepressant treatment are discussed. The side-effect profiles of the selective 5-HT re-uptake inhibitors suggest they may offer new therapeutic opportunities in physically ill patients. Sertraline may be of particular benefit in some patients due to its distinct pharmacological profile and the potential for fewer drug interactions. Further evaluation is necessary to determine the risk-benefit ratio for drugs of this class.     

Predicting recurrence in axillary-node negative breast cancer patients

Summary This study attempted to identify the risk groups in axillary node negative breast cancer patients using validated first-generation prognostic clinical and pathologic factors. An updated 10-year follow-up in 407 such patients treated by surgery alone at Roswell Park between 1976–1987 showed a 10-year recurrence rate (RR) of 19% (95% confidence interval ±5%). Predictors of outcome were, in order of strength: (1) Tumor size (p= 0.0006); RR at 10 years was 2% ± 4 for tumors 0.5cm, 6% ± 7 for tumors 0.6-1.0cm, 16% ± 9 for 1.1–2cm, 29% ± 12 for 2.1–5cm, and 40% ± 31 over 5cm; (2) Histologic differentiation (p = 0.017); poorly differentiated/anaplastic (P/A) tumors had a greater RR (24% ± 8) than well or moderately differentiated (W/M) tumors (13% ± 8); (3) Age (p = 0.046); patients < 35 showed a RR of 28% ± 20, pts 35–50, 22% ± 10, and pts > 50, 17% ± 7 (p = 0.046). Cox Model analysis showed tumor size (4 groups) significant at < 0.0001, histologic differentiation (2 groups) significant at < 0.0005 after allowing for size, and age (±50) significant at <0.05 after allowing for size and differentiation.Combining these variables into subgroups enables selecting groups at various risks of recurrence. Groups with low risk are: (1) patients with tumor1cm, W/M (0% RR), (2) patients with ductal carcinomain situ with microinvasion (0% RR), and (3) patients with tumors 1cm, P/A (8% RR). In a suggestive finding in this last group, those over age 50 achieved a RR of 3% ± 6, while those age 50 or less had RR 14% ± 15. With the exception of this last group, all should be considered highly curable using loco-regional therapy alone, and might be spared the risks and costs of routine systemic adjuvant therapy. Groups with high risk are: (1) patients with tumors > 2cm (RR 32% ± 12), and (2) patients with tumors 1.1–2cm, P/A (RR 21% ± 14). These should receive adjuvant therapy. Groups with intermediate risk are patients with tumor 1.1-2cm, W/M (RR 12% ± 12). In a suggestive finding, those in this group over age 50 had a RR of 11% ± 12, while those up to 50 had a RR of 17% ± 30. These patients should be considered to be prime candidates for clinical trials.Adding second generation factors such as DNA ploidy or S-phase fraction to first generation factors should provide additional information on which to base therapy decisions, particularly in the gray area of intermediate risk. Our study indicates that node-negative breast cancer patients represent a heterogeneous population in terms of risk and prognosis, and that an individualized approach to adjuvant therapy should be taken.Presented in part at the 14th annual San Antonio Breast Cancer Symposium, December 6-7, 1991, and the American Association for Cancer Research, San Diego, CA, May 20-23, 1992     

The Pulmonary Absorption of Aerosolized and Intratracheally Instilled rhG-CSF and monoPEGylated rhG-CSF

Purpose. The objective of this study was to highlight differences in the pulmonary absorption of a monoPEGylated rhG-CSF and rhG-CSF after intratracheal instillation and aerosol delivery. Methods. Male Sprague Dawley rats (250 g) were anesthetized and intratracheally instilled (IT) with protein solution or were endotracheally intubated and administered aerosol for 20 min via a Harvard small animal ventilator. A DeVilbiss Aerosonic nebulizer containing 5 ml of protein solution at 3 mg/ml was used to generate aerosol. The volume of protein solution deposited in the lung lobes was estimated to be 13 µl after delivery of Tc-99m HSA solutions. The PEGylated proteins consisted of a 6 kDa (P6) or 12 kDa PEG (PI2) linked to the N-terminus of rhG-CSF. rhG-CSF also was administered IT in buffers at pH 4 and pH 7 and in dosing volumes ranging from 100 to 400 µl. Blood samples were removed at intervals after dosing and the total white blood cell counts (WBC) were determined. Plasma was assayed for proteins by an enzyme immuno assay. Results. The plasma protein concentration v. time profiles were strikingly different for aerosol v. IT delivery. The C _max values for rhG-CSF and P12 after aerosol delivery were greater than found after IT (Aerosol: 598 ± 135 (ng/ml) rhG-CSF; 182 ± 14 P12 v. IT: 105 ± 12 rhG-CSF; 65.9 ± 5 P12). Similarly, T_max was reached much earlier after aerosol administration (Aerosol: 21.7 ± 4.8 (min) rhG-CSF; 168 ± 31 P12 v. IT: 100 ± 17 rhG-CSF; 310 ± 121 P12). Estimated bioavailabilities (F_lung %) were significantly greater via aerosol delivery than those obtained after IT (Aerosol: 66 ± 14 rhG-CSF; 12.3 ± 1.9 P12 v. IT: 11.9 ± 1.5 rhG-CSF; 1.6 ± 0.1 P12). An increase in circulating WBC counts was induced by all proteins delivered to the lungs. The rate and extent of absorption of rhG-CSF was not influenced by the pH employed nor the instilled volume. Conclusions. Estimates of bioavailability are dependent upon the technique employed to administer drug to the lungs. Aerosol administration provides a better estimate of the systemic absorption of macromolecules.     

Alternatives to Autogenous Bone Graft: Efficacy and Indications

Bone grafting is frequently used to augment bone healing with the numerous approaches to reconstructing or replacing skeletal defects. Autologous cancellous bone graft remains the most effective grafting material because it provides the three elements required for bone regeneration: osteoconduction, osteoinduction, and osteogenic cells. Autologous cortical bone graft provides these three components to a limited extent as well and also provides the structural integrity important in reconstruction of larger defects. However, because autogenous grafting is associated with several shortcomings and complications, including limited quantities of bone for harvest and donor-site morbidity, alternatives have been used in a wide range of orthopaedic pathologic conditions. Grafting substitutes currently available include cancellous and cortical allograft bone, ceramics, demineralized bone matrix, bone marrow, and composite grafts. No single alternative graft material provides all three components for bone regeneration. The clinical applications for each type of material are dictated by its particular structural and biochemical properties. Composite grafts consisting of several materials are often used to maximize bone healing, especially where the grafting site is compromised.     

Early postpartum discharges. Impact on distress and outpatient problems.

OBJECTIVE: To determine the impact of shortened postpartum hospital stays on common clinical phenomena in a sociodemographically diverse, unselected group of general maternity patients. DESIGN: Observational cohort study in which the preapproved hospital stay duration of either 1 or 2 nights was set by third-party payers before each mother's admission. SETTING: Yale-New Haven Hospital, New Haven, Conn, from June 19 through August 10, 1995. PATIENTS: Two hundred forty-four volunteers from among 400 eligible deliveries. MAIN OUTCOME MEASURES: Readmission within 1 month of hospital discharge, report of outpatient morbidity and use of outpatient health services within 1 week of discharge, status of breast-feeding during the first post-discharge week, and patient satisfaction. RESULTS: At discharge from the hospital, the hospital stay was regarded as "too short" by 80 (47%) of 171 mothers and 19 (26%) of 73 mothers in the 1- and 2-night groups, respectively (P = .002). Although readmission rates were similar (5% vs 3%, P = .48), the 1-night group reported significantly more morbidity in the newborns (31% vs 16%, P = .03) and averaged more pediatric visits (96 vs 54 per 100 newborns, P = .002). Mothers in the 1-night group also reported more fatigue (49% vs 29%, P = .001) and more worries about their newborns' health (24% vs 11%, P = .02). They were less likely to start breast-feeding (64% vs 77%, P = .06), and, if they started, were somewhat more likely to stop prematurely (14% vs 8%, P = .43). A series of disturbing events was reported only in the 1-night group. CONCLUSIONS: In a relatively unselected group, mothers who stayed 1 night after routine vaginal delivery reported more distress and more pediatric problems and had greater use of outpatient health services than mothers who stayed 2 nights.     

Hyaluronic acid: a specific prognostic indicator of hepatic damage in biliary atresia

BACKGROUND/PURPOSE: Hepatic fibrosis can progress in biliary atresia (BA) and is associated with capillarization of hepatic sinusoids. The significance of serum hyaluronic acid (HA) as a noninvasive indicator of histological sinusoidal endothelial cell (SEC) damage and hepatic fibrosis in BA, is investigated. METHODS: A total of 28 postoperative BA patients (mean age, 11.0+/-3.7 years) and 20 normal controls (mean age, 10.5+/-2.8 years) were studied. BA patients were divided into group I, good liver function (n = 8); group II, moderate liver dysfunction (n = 10); and group III, severe liver dysfunction (n = 10). Serum HA was determined using a one-step sandwich enzyme immunoassay, and liver histological damage was confirmed immunohistochemically using an antibody against factor VIII-related antigen (FVIIIRAg), which is specific for detecting damaged SEC. RESULTS: Serum HA was significantly higher (P < .0001) in group III (84.6+/-36.5 ng/mL) than in group I (15.9+/-6.9 ng/mL) or group 11 (28.7+/-10.7 ng/mL). Although immunoreactive products of FVIIIRAg were abundant in group III, they were not detected in SEC from group II. CONCLUSION: Serum HA may be of value for monitoring postoperative BA patients as a noninvasive indicator of SEC damage and progressive hepatic fibrosis.     

Serum IFN-inducible protein-10: a new clinical prognostic predictor of hepatocyte death in biliary atresia

PURPOSE: The aim of this study was to determine whether chemokines such as serum IP-10 levels in patients with biliary atresia (BA) correlate with liver function and histology and assess its value as a medium to long-term prediction of prognosis in postoperative BA patients. METHODS: Thirty postoperative BA patients (mean age, 10.8+/-3.5 years) and eight normal controls (mean age, 10.3+/-3.3 years) were studied. The BA patients were divided into three groups according to liver function. Group I (n = 8) was jaundice free, had normal liver function and no evidence of severe cholangitis or portal hypertension. Group II (n = 12) had moderate liver dysfunction. Group III (n = 10), had severe liver dysfunction. Hepatic histology was assessed using conventional needle biopsy. Serum IP-10 levels were determined using a specific enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum levels of IP-10 in group III (458.0+/-240.0 pg/mL) were significantly higher than those in group II (233.6+/-126.9 pg/mL; P < .0001). Levels in group II were also significantly higher than those in group I (144.8+/-23.4 pg/mL; P < .05), but there was no significant difference between group I and controls (107.9+/-34.0 pg/mL). Liver biopsy findings showed a progression of fibrosis and mononuclear cell infiltration from group I to group III. There was intimal hyperplasia and swelling of endothelial cells of branches of the hepatic artery in the portal area in group III. CONCLUSION: Because IP-10 levels correlate closely with histological findings in postoperative BA patients, it would appear to play a specific role in hepatocyte death and hepatic artery changes, thus providing important information about progressive fibrosis in BA patients that facilitates treatment decision making and prediction of prognosis.     

Ondansetron is more effective than metoclopramide for the treatment of opioid-induced emesis in post-surgical adult patients. Ondansetron OIE Post-Surgical Study Group

Nausea and vomiting are common side effects of opioids administered for pain control. This double-blind, randomized, parallel-group study evaluated the anti-emetic efficacy and tolerability of single intravenous (i.v.) doses of ondansetron 8 mg, ondansetron 16 mg and metoclopramide 10 mg in the treatment of opioid-induced emesis. Adult patients undergoing low emetogenic surgical procedures, using a standardized anaesthesia regimen were assessed for 24 h following administration of study anti-emetic to treat established post-surgical opioid-induced emesis. A total of 4511 patients were enrolled of whom 1366 experienced opioid-induced emesis and received randomized study medication. Ondansetron 8 mg and 16 mg were significantly better than metoclopramide 10 mg (P < 0.05) for both complete control of emesis, complete control of nausea and other efficacy measures. There were no significant differences between the two ondansetron groups. All three treatments were well tolerated. In conclusion, this large, multicentre study demonstrates that ondansetron is more effective than metoclopramide in the treatment of opioid-induced emesis following administration of post-surgical opioids to control pain.