Modulating immunogenicity of factor IX by fusion to an immunoglobulin Fc domain: a study using a hemophilia B mouse model.

Essentials Fc-fusion increases a therapeutic's half-life, but FcγR interactions may impact immunogenicity. Species-specific Fc-FcγR interactions allow for mechanistic in vivo studies using mouse models. Fc fusion modulates the immune response to factor IX in hemophilia B mice by eliciting Th1 bias. This model could inform future studies of IgE-associated anaphylaxis in hemophilia B patients. SUMMARY: Background Fc fusion is a platform technology used to increase the circulating half-life of protein and peptide therapeutics. However, there are potential immunological consequences with this approach, such as changes in the molecule's immunogenicity as well as possible interactions with a repertoire of Fc receptors (FcR) that can modulate immune responses. Objectives/Methods Using a mouse hemophilia B (HB) model, we compared the immune responses to infusions of recombinant human factor IX (hFIX) and hFIX fused to mouse IgG2a-Fc (hFIX-mFc). The mFc was employed to allow species-specific Fc-FcγR interactions. Results Although treatment with hFIX-mFc altered the early development of anti-FIX IgG, no significant differences in anti-FIX antibody titers were observed at the end of the treatment regimen (5 weeks) or upon anamnestic response (5 months). However, treatment with hFIX-mFc elicited higher FIX-neutralizing antibody levels and resulted in reduced IgE titers compared with the hFIX-treated group. Additionally, differences in plasma cytokine levels and in vitro CD4+ T-cell responses suggest that whereas hFIX treatment triggered a Th2-biased immune response, hFIX-mFc treatment induced Th1-biased CD4+ T cells. We also show that hFIX-mFc bound to soluble FcγRs and engaged with FcγRs on different cell types, which may impact antigen presentation. Conclusions These studies provide a model system to study how Fc-fusion proteins may affect immune mechanisms. We used this model to demonstrate a plausible mechanism by which Fc fusion may modulate the IgE response to hFIX. This model may be appropriate for investigating the rare but severe IgE-mediated anaphylaxis reaction to hFIX infusions in HB patients.

Outpatient laparoscopic cholecystectomy. Outcomes of 847 planned procedures.

BACKGROUND: Cholecystectomy is now being performed on an outpatient basis at many centers. The purpose of this study was to review the results of our large experience with this procedure. METHODS: Between 1990 and 1997, 2288 patients underwent laparoscopic cholecystectomy at our clinic. A total of 847 (37%) were scheduled as outpatients. The selection criteria for planned outpatient laparoscopic cholecystectomy called for nonfrail patients with an ASA < 4 who were living < 2 h from the hospital. All patients received detailed preoperative instruction about outpatient laparoscopic cholecystectomy. A questionnaire was sent to 309 patients to sample their opinions. RESULTS: Since 1993, we have increased the number of planned outpatient cholecystectomies performed at our clinic, but the percentage of cholecystectomies completed on an outpatient basis has remained approximately 60%. A total of 547 of 847 operations scheduled as outpatient procedures (74.5%) were completed as planned, and 204 patients (24%) were kept in the hospital overnight. Twenty-seven (3%) were converted to open procedures. Eighteen laparoscopic patients (2%) stayed > 1 day (range, 2-20). None of the patients died. Of the 142 patients (46%) who completed our opinion survey, 66% were happy with their experience, 32% would like to have stayed in the hospital, and 2% were undecided. CONCLUSION: Successful same-day surgery requires proper patient instruction, appropriate patient selection, and a low threshold to convert patients to inpatient status when the situation warrants. No major complications occurred as a result of same-day discharge, and two-thirds of the patients said that they preferred outpatient surgery.

Lessons learned from the initial 100 patient experience with sentinel lymph node mapping in the evaluation of breast cancer.

The initial reports of sentinel lymph node mapping for breast cancer currently appearing in the surgical literature are demonstrating the practicality and accuracy of the technique to evaluate patients for axillary nodal disease. We reviewed our initial 100 patient experience with sentinel node mapping to evaluate our ability to employ this technique in breast cancer patients. We combined a peritumoral injection of a radioactive substance and blue dye. Each sentinel node was evaluated with frozen section analysis, hematoxylin and eosin staining, and, if still negative, five re-cuts were taken from deeper levels of the node and evaluated for immunohistochemical evidence of cytokeratin staining. Sentinel node(s) were identified in all but two patients with 51% demonstrating metastasis. We have demonstrated the ability to accurately perform sentinel node mapping in the evaluation of our breast cancer patients. This exciting advance should become a standard part of breast cancer surgery.

Rates of sexually transmitted diseases among patients in a psychiatric emergency service.

OBJECTIVE: This study sought to estimate the prevalence of non-HIV sexually transmitted diseases among patients admitted to a psychiatric emergency service and to identify characteristics that might place members of this population at increased risk of acquiring these diseases. METHODS: Hospital medical records and records of public health departments' venereal disease control sections were retrospectively reviewed to determine if patients consecutively admitted to a psychiatric emergency service at a large urban public hospital had been tested for syphilis, gonorrhea, trichomonas, chlamydia, or herpes simplex in the 12 months before admission and whether the tests were positive. Data on patients' demographic and clinical characteristics were also collected. RESULTS: Of 426 consecutive patients studied, 214 (50.2 percent) were tested for one or more non-HIV sexually transmitted diseases. Forty of those patients (18.7 percent) had positive tests. The rates of syphilis and gonorrhea among the patients were significantly higher than those estimated for the city and state where the study was done and significantly higher than the national estimate. Patients whose tests were positive did not differ significantly from those with negative tests in presenting psychiatric symptoms or diagnosis. CONCLUSIONS: An alarmingly high rate of non-HIV sexually transmitted diseases was found among patients treated in a psychiatric emergency service. However, no particular clinical subpopulations at increased risk for acquisition of these diseases could be identified.

Suicide attempt histories in alcohol-dependent men: differences in psychological profiles.

Fifty-three alcohol-dependent men without additional Axis I disorders were divided into two groups based on past history of suicide attempts (SP = suicide positive, N = 15; SN = suicide negative, N = 38). Post-hoc analysis revealed that the two groups were matched for age, racial makeup, family history of suicide, and total number of years of drinking. A significantly higher percentage of SP group patients had personal and family histories of either illicit drug use, past psychiatric treatment, or both. Psychological profiles demonstrated exaggerated tendencies toward sociopathy, attitudinal deviance, heightened activity, anxiety, depression, hostility, and disordered thinking among the SP patients. These findings highlight the importance of designing individualized relapse prevention programs.

Mood congruent and incongruent psychotic depressions: are they the same?

DSM-III and DSM-III-R instruct the clinician, if possible, to classify major depression with psychotic features into either the mood congruent (MC) or mood incongruent (MI) subtype. Patients hospitalized on a psychiatric unit for major depression with psychotic features were classified as predominantly MC or MI. The MC and MI groups did not differ significantly on a number of demographic or symptom severity variables. Thirteen (50%) MI patients experienced at least one MC symptom and 10 (71%) MC patients experienced at least one MI symptom. Overall, 25 (58%) of these patients experienced both MC and MI symptoms. This study demonstrates that subtyping psychotic depression into MC and MI subtypes is seldom an 'either-or' decision. Indeed, these results combined with findings from previous research suggests that there is no compelling scientific evidence for subclassifying psychotic depression into subtypes.

Response of psychotic depression subtypes to pharmacotherapy.

Patients with psychotic depression respond well when treated with a combination of an antidepressant and antipsychotic medication. We previously reported that they will respond in a similar fashion when treated with amoxapine monotherapy. There are few prospective studies on the pharmacologic treatment response of psychotic depression subtypes. We treated 37 inpatients, 21 with mood congruent (MC) psychotic depression and 16 with mood incongruent (MI) psychotic depression, in a randomized double-blind fashion with either the combination of amitriptyline and perphenazine or with amoxapine for 4 weeks. Depression and psychosis ratings improved in a similar manner in both the MC or MI patients irrespective of medication treatment group. Global response rates were similar in the MI patients and MC patients. The data suggest that classifying psychotic depression into MC versus MI subtypes may have limited acute prognostic value in pharmacotherapy response rates.

Methylphenidate hydrochloride as an antidepressant: controversy, case studies, and review.

The use of psychostimulants as antidepressants remains controversial in the field of psychiatry. While methylphenidate hydrochloride (MPH) and dextroamphetamine (DA) are often considered to be equivalent drugs, differences in their neurobiologic mechanism of action may account for different clinical response patterns. Hence, clinical trials and literature reviews that examine the antidepressant efficacy of psychostimulants without distinguishing between MPH and DA may reach inaccurate conclusions. This paper is a critical review of controlled and uncontrolled studies examining the use of MPH as an antidepressant. We discuss the methodologic limitations of existing placebo-controlled trials that have reached mixed conclusions about the efficacy of MPH as an antidepressant. These studies are offset by uncontrolled open trials and clinical case reports that endorse the drug's effectiveness in alleviating depressive symptoms. The series of patients we treated with MPH demonstrates the safety and efficacy of this drug in alleviating depressive symptoms in the medically ill elderly with a variety of mood disorders. Reviewing these six cases and balancing the positive and negative reports in the literature, we provide practical guidelines for identifying patients who are potential candidates for treatment with MPH.

Regulation of fungal proteolysis on cyclic AMP-dependent protein kinase, cyclic AMP phosphodiesterase, glycogen synthase and histones.

Limited proteolysis of catalytic and regulatory subunits of cyclic AMP-dependent protein kinase (A-pk), cyclic AMP phosphodiesterase, glycogen synthase, and histones by fungal protease (type XIX) was analyzed by the digested peptide bands in SDS polyacrylamide gel electrophoresis. The modulatory effects on proteolysis by nucleotides, polypeptides, and phospholipids may greatly depend on the intrinsic nature of substrates. The proteolysis of the regulatory subunit of A-pk and glycogen synthase was not regulated by nucleotides and nucleic acids. In comparison, phosphatidyl serine, cardiolipin, and pepstatin A stimulated the proteolysis of the catalytic subunit of A-pk. Whereas, lambda DNA (Hind III digest), t-RNA, GTP-, phosphatidyl serine, sphingosine inhibited the proteolysis of cyclic AMP phosphodiesterase. Moreover, MS2 RNA, lambda DNA, t-RNA, dGTP, Phosphatidyl serine, phosphatidyl inositol, antipain, and chymostatin exerted inhibitory proteolytic effect on histone VIII-S. Some of these agents also had similar inhibitory effect on other types of histones (types III-S and VII-S). The inhibitory effect of phosphatidyl serine on proteolysis of histone may be due to their interaction which was monitored by the drastic increase of uv absorbance.

The effects of alcoholism and smoking on platelet eicosanoid production in vitro.

Ethanol induces changes in eicosanoid synthesis in blood platelets and brain tissue. Cigarette smoking also causes alterations in eicosanoid formation. This preliminary report examined in vitro platelet sonicate eicosanoid production using 14C-arachidonic acid (14C-AA) and in separate experiments, 14C-PGH2, as substrates. Radiometric thin layer chromatography (TLC) was used to identify the products formed. Eicosanoid product formation in platelet sonicates collected from 28 abstinent male alcoholics were compared to those from 11 male control subjects. All but one of the alcoholics were chronic smokers and all control subjects were non-smokers. All smokers abstained from smoking for 12 h prior to the blood collection to control for any acute effects of cigarette smoke on eicosanoid production. Significant reductions in platelet sonicate production of PGD2 and PGE2 in vitro were observed in alcoholic smokers when 14C-PGH2, but not 14C-AA, was the substrate. These reductions were predicted equally well by two variables, smoking and alcoholism, using several statistical models. This is the first investigation that controlled for the acute effects of smoking and accounted for the potential effects of cigarette smoking on platelet eicosanoid production in alcoholics. Because cigarette smoking is prevalent among alcoholics, future studies on the role of eicosanoids in alcoholism should control for smoking.

Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression.

In a double-blind study lasting for 4 weeks, the authors compared the effectiveness of amoxapine, an antidepressant with potential antipsychotic properties, with a combination of amitriptyline plus perphenazine in the treatment of 38 patients who had the diagnosis of major depression with psychotic features (psychotic or delusional depression). Patients in each group showed similar improvement in depression and psychosis. There was a tendency for the patients treated with amitriptyline plus perphenazine to have higher global response rates. However, the patients given amoxapine had significantly fewer extrapyramidal side effects.

Variables contributing to distress in male cardiac patients.

Fifty-five male subjects attending a cardiology clinic were examined using a structured interview keyed to a 12-item Hamilton Anxiety Scale (HAS). Sixty-five percent scored in the range of moderate to severe distress with highest mean scores on the following subscales: anxious mood, tension, insomnia, muscular complaints, and global behavioral distress. Two-way analysis of variance revealed the following factors to be significantly associated with higher total HAS scores: greater number of medical diagnoses (P = .007), taking more medications (P = .001), history of psychiatric treatment (P = .007), being declared disabled (P = .002), and living with others (P = .025). Each of these variables might contribute to greater psychological or physical discomfort, increased medical utilization, and difficulty with cardiac rehabilitation. The complexity of psychosocial factors in determining distress is addressed, since subjects living with others scored higher than those who were socially isolated (HAS mean score = 17.9 +/- 8 vs 10.7 +/- 5.5, respectively, P = .025).

Interaction between cortisol and microbial proteases.

Binding (or interaction) of cortisol with microbial molecule(s) was observed by employing Bio-Gel HTP affinity chromatography and subsequently by fluorescence spectrophotometry. Molecule(s) in the crude extract of baker's yeast and in other microbial proteases exhibited varied degrees of cortisol-binding. Bacterial protease (type IX) had highest, while the type XXVI enzyme had the lowest, binding capacity. In addition, these two proteases exhibited a distinct difference in the alterations of ultraviolet spectra due to interaction with cortisol. Using casein as a substrate, cortisol, CTP, trypsin inhibitor or leupeptin appreciably inhibited type IX protease at low concentrations of Ca2+. However, thyroxine had no effect on this protease.

Secondary mania from cerebral embolization with nonfocal neurologic findings.

We have reported a unique example of an organic affective syndrome in a patient who had focal brain lesions, but whose initial neurologic examination was nonfocal. In retrospect, the only clue to an organic disorder was hyperreflexia in this patient with a history of alcohol abuse and clinical signs of a distal sensory neuropathy. This case emphasizes the importance of pursuing a neurologic work-up (including CT scan) in older patients with sudden mood changes, even in the absence of focal neurologic findings.

Cognitive dysfunction in psychiatric consultation subgroups: use of two screening tests.

Elderly patients are highly vulnerable to illness-related and drug-induced cognitive changes, especially during the acute phase of a medical or surgical illness. Using a structured cognitive screening examination enhances the accurate identification of patients with cognitive impairment. We compared the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-COG) to the Mini-Mental State Examination (MMSE) in screening for the presence of organic brain dysfunction. Using cutoff scores, the two tests were in agreement in 94.4% of 36 cases, with total scores on the two tests correlated at r = -.90 (P less than .01). Of these 36 patients for whom psychiatric consultations were requested, 14 (38.8%) were found to be cognitively impaired. We discuss the relationship of test scores to the stated reason for the consultation, as well as variables influencing test results. Finally, we demonstrate the usefulness of cognitive testing in patients who refuse treatment.

Comparison of two cognitive rating scales in medically ill patients.

Patients with acute, complex behavioral syndromes combined with impaired comprehension and communication are difficult diagnostic challenges. Using a structured mental status interview can significantly reduce the chance of overlooking the presence of cognitive dysfunction. The authors tested the applicability of the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-COG) as a screening instrument on a psychiatric consultation service. The ADAS-COG compared favorably with the Mini-Mental State Exam (MMSE), but appeared to be less influenced by educational level. The advantages and disadvantages of using each of these tests on a psychiatric consultation service are discussed.