Response to 35% CO2 in patients with chest pain and angiographically normal coronary arteries. Several interview studies have suggested that panic disorder (PD) exists in patients with angiographically normal coronary arteries (NCA). Interview studies require corroboration by other studies in order to validate them. The purpose of this study is to test whether response to the inhalation of 35% CO2 reliably discriminates between PD and non-panic disorder patients in this population. Three groups were studied: six with NCA and PD, five with NCA and no PD, and ten in the control group. All subjects breathed room air, then 35% CO2 in a single-blind fashion. Each completed the Acute Panic Inventory (API) before and during the procedure. The NCA-panic group scored significantly higher than the other two groups on the Acute Panic Inventory from baseline to post-inhalation. Despite several methodological limitations including a relatively small number people in each cells, 35% CO2 was shown to trigger more intense responses in panic patients, thus helping to validate the interview findings.


On the validity of an Augmented Structured Interview for measuring subcomponents of the Type A behavior pattern. This study was designed to provide validity data for the Augmented Structured Interview (ASI), which has been developed to measure subcomponents (as opposed to the global) Type A behavior pattern (TABP). Eighty subjects from a large private southwestern medical center were administered a self-report measure of the TABP (the Jenkins Activity Survey--JAS) and the ASI. Forty of the subjects were being treated for post-infarction coronary heart disease (CHD). The remaining forty subjects did not possess documented CHD. The obtained ratings for all the six ASI-measured Type A subcomponents were significantly higher for the CHD than for the non-CHD group. A discriminant functions analysis revealed that the ASI was superior to the JAS in correctly classifying CHD and non-CHD subjects. These outcomes are interpreted as providing initial support for the validity of the ASI.


Psychologic distress during the menopausal years in women attending a menopause clinic. This study measures psychologic distress in women attending a menopause clinic to determine if significant differences exist between peri-menopausal and menopausal women. Consecutive women attending a university hospital menopause clinic were administered the Brief Symptom Inventory (BSI) and a study questionnaire to determine menopausal symptoms, menstrual cycle status, and use of hormone replacement therapy (HRT). The BSI results were compared between menopausal and perimenopausal women, and to a normative sample of middle-aged women who were nonpatients. Two hundred and fifty-nine menopause clinic women completed the questionnaire: 113 perimenopausal and 146 menopausal women. There was significantly greater psychologic distress on the BSI among perimenopausal as compared to menopausal women on the global severity index, and each of the anxiety, hostility, somatization, depression, paranoid, and psychoticism subscales. Perimenopausal women met BSI caseness severity criteria significantly more often than did menopausal women on the global severity index, and on the subscales for depression, anxiety, and psychoticism. On the BSI, menopausal women showed results similar to those of a normative sample of nonpatient middle-aged women. Perimenopausal women attending menopause clinics have significantly higher levels of psychologic distress meeting case severity criteria on the BSI. Further research is warranted to define the subgroups of perimenopausal women who are at increased risk, in the hopes of developing effective interventions.


Underdiagnosis of depression in patients with coronary artery disease: the role of nonspecific symptoms. To determine whether the underdiagnosis of major depression (MD) in patients with coronary artery disease (CAD) may be explained by low specificity and mild severity of depressive symptoms in affected patients. The Beck Depression Inventory (BDI) was used to assess depression symptoms in thirty-one patients with both CAD and MD, and eighty-three patients with CAD but without MD. Only ten (48%) of the symptoms were significantly more common in the MD than in the non-MD group, and nine symptoms were present in at least 20 percent of both groups. Of these nine nonspecific symptoms, only one (insomnia) was more severe in the MD patients than in the non-MD group (p < .006). When all twenty-one symptoms were rank ordered by frequency, the most common symptoms in the MD group were also the most common in the non-MD group (r = .91, p < .001). The symptoms of major depression were found to be relatively mild and nonspecific in patients with CAD. This may help to explain why depression is underdiagnosed in cardiac patients.


Ictal and psychiatric aspects of suicide in epileptic patients. To evaluate the ictal and psychiatric aspects underlying the high risk of suicide among epileptic patients. We surveyed the records of 1611 epileptic patients seen in a neurology clinic during an eight-year period, found four who died by suicide, and characterized their ictal and psychiatric features. All four epileptic patients had partial complex seizures and temporal lobe foci. Two had an associated paranoid schizophrenia with suicidal ideation, and good or improving seizure control at the time of their deaths. Another patient killed himself during a brief psychotic episode associated with increasing epileptiform discharges. The fourth patient had ictal depression and committed suicide during a flurry of partial complex seizures. These findings suggest that the high suicide rate among epileptic patients has a greater association with psychotic behaviors and psychic auras than with major depression or the psychosocial burden of being epileptic. We further review other reported risk factors for suicide in epilepsy.


A retrospective study on the perceived need for and actual use of psychiatric consultations in older medical patients. The authors examined the (under) utilization of the psychiatric consultation service for patients aged sixty to seventy-five who were hospitalized for medical reasons, and explored whether one could retrospectively document and identify a greater need for psychological support than the one reflected in the number of actual consultations requested. Three questions were addressed: 1) the psychiatric consultation rate; 2) the frequency of unrecognized medical, psychiatric, and psychosocial complicating factors; and 3) whether the distribution of these factors differed by gender. Records of 203 consecutively-admitted elderly patients hospitalized on medical wards were reviewed by two experienced general hospital psychiatrists for any indication of medical, psychiatric, and psychosocial risk factors. The frequency of actual psychiatric consultations was also recorded. Three or more risk factors were noted in the records of 36 percent of all patients. Consultation was sought for only 3 percent. Gender differences in type and distribution of risk factors were identified. Indicators and profiles that define probable need for psychiatric consultation were identified and briefly discussed. More well-designed, prospective studies testing these indicators and profiles are needed.


Hypochondriacal concerns and attitudes toward illness in males and females. To review the published studies on the sex distribution of hypochondriasis, and to examine sex differences in hypochondriacal concerns and in attitudes toward illness. The Illness Attitude Scales, Factors 2 and 3 of the Whiteley Index and the Symptom Checklist-90 (SCL-90) were administered to fifty randomly-selected female family practice patients ages eighteen to sixty-five, and to male patients matched by age in decades. From a pool of 130 consecutive nonpsychotic psychiatric outpatients, fifty females and fifty males were matched with the family practice patients. Although females rated themselves as more depressed than males in both groups, there were no significant differences between the sexes in hypochondriacal fears and beliefs. Psychiatric male patients reported the most adverse effects of bodily symptoms on work and leisure. There were no other significant differences between the sexes in any of the other attitudes toward illness or symptoms. Hypochondriacal concerns were more common in the psychiatric patients than in the family practice patients of both sexes. The review of published studies on the sex distribution of hypochondriasis suggests that disease phobia is more common in females, except for the cardiophobic syndrome, which is more common in males. The other reported differences are inconsistent and appear to be caused by referral biases, varying diagnostic criteria, and cultural factors. In our study, we found no substantial differences between males and females in hypochondriacal concerns and attitudes toward illness.


Pheochromocytoma presenting as exacerbation of post traumatic stress disorder symptomology. The following case report and discussion is intended to increase awareness of the difficulties in diagnosing pheochromocytoma when a primary psychiatric diagnosis is first suspected. The case of a middle-aged combat veteran who was admitted with agitation and flashbacks is presented. Episodes of hypertension were initially believed to be related to agitation or alcohol withdrawal. When the hypertensive episodes persisted, further evaluation revealed a pheochromocytoma. In three years' follow-up since removal of the tumor, the patient has shown considerable improvement in the symptoms of Post Traumatic Stress Disorder (PTSD). Pheochromocytoma should be considered in patients with psychiatric disorders if a pattern of hypertensive episodes persists or worsens. The case highlights the importance of medical evaluation in patients presenting with psychiatric complaints.


Neurosarcoidosis presenting as schizophreniform disorder. A patient whose clinical presentation met criteria for schizophreniform disorder was ultimately found to have neurosarcoidosis, and the psychiatric symptoms responded to steroid treatment. The ongoing search for organic etiology was prompted by the presence of cognitive decline, perseveration and rare bizarre automatisms. This is virtually the first reported association between schizophreniform disorder and sarcoidosis. We reviewed the literature on neurologic involvement and psychiatric manifestations in sarcoidosis as well as the concurrence between organicity and schizophrenic psychosis. The importance of attending to all elements of the mental status examination in a patient with complex atypical findings is underscored.


Factitious apraxia.

Factitious apraxia. A case is described in which a patient had pseudoneurological symptoms that were present only upon direct observation or when the patient was in clinical test situations. The differential diagnosis of apraxia is discussed as well as clinical suggestions for evaluating patients with suspected factitious apraxia.


Resolution of depressive symptoms in medical inpatients after discharge. Most studies to date demonstrate a high prevalence of depressive symptoms and depressive disorders in general medical inpatients. In order to determine whether these symptoms represent a self limited epiphenomenon of medical illness or evidence of psychiatric comorbidity, assessment of the natural history of such symptoms in this population is necessary. In this study we focused on resolution versus persistence of depressive symptoms in hospitalized medical patients following medical, but not psychiatric, treatment. Every second admission to the acute care medical ward of a VA teaching hospital was assessed for inclusion in the study. Fifty-seven were screened, fifty participated initially, forty-two remained in the study for the one-week post-discharge follow-up, and thirty-three remained at the one-month follow-up. Depressive symptomatology was measured with the Beck Depression Inventory at each time point. Subjects whose scores at follow-ups were above threshold were considered to have persistent symptoms and those whose scores fell below threshold were considered to have resolved. No patients were treated with antidepressants prior to or during the study. With a conventionally accepted threshold score (14) on the BDI as representing clinically significant depression, roughly half of those patients identified as depressed at the time of admission were nondepressed at both follow-ups. The BDI predicted persistence of depression with a sensitivity of .64 and specificity of .74 at one week and .71 and .73 at one month. Raising the threshold score to 20 raised the sensitivity to 1.00 and the specificity to .95 at one week and 1.00 and .93 at one month. Depressive symptoms seen in acutely-ill medical patients can be expected to resolve without potentially-hazardous antidepressant treatment in a significant number of patients. Persistence of depressive symptoms may be better predicted by raising the threshold on commonly used self-report scales.


Chest pain in generalized anxiety disorder. The objectives of the current study were to evaluate the prevalence of chest pain and related medical utilization in patients with generalized anxiety disorder and to investigate the possible relationship between the occurrence of chest pain in these patients and the episodes of excessive worry which characterize this disorder. The presence of a history of chest pain in patients with generalized anxiety disorder was investigated in an outpatient psychiatric sample using a structured interview which also assessed related medical utilization and the relationship of chest pain to panic attacks and episodes of excessive worry. Of fifty sequentially evaluated patients meeting DSM-III R criteria for G.A.D., twenty-four (48%) reported a history of chest pain. Seven of these patients also had a history of panic attacks, however, four of the seven reported that their pain occurred independently of their panic attacks. Sixteen patients with G.A.D. reported that their chest pain episodes were associated with episodes of excess worry. Eleven had sought medical evaluation for their pain. Patients with chest pain and normal coronary arteries are frequently found to have panic disorder. The pattern of utilization of medical care was comparable in this sample of patients with G.A.D. and a group of patients with panic disorder recruited in a similar manner. These results suggest that in addition to panic disorder, G.A.D. may also be a common diagnosis in chest pain patients with no demonstrable coronary disease. Future studies of coronary artery disease negative patients with chest pain should include assessments for the presence of G.A.D. Our results also suggest that chest pain may be a common symptom in G.A.D. The possibility that chest pain should be included in the diagnostic criteria for this disorder should be the subject of further investigation.


Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. The Southwest Oncology Group, in cooperation with the National Cancer Institute and the other major cooperative oncology groups, has participated in the development of new toxicity criteria for reporting the results of cancer clinical trials. The new criteria (NCI Common Toxicity Criteria) respond to a recognized need to: (1) report toxicities consistently among cooperative groups, particularly for shared 'intergroup' clinical trials; (2) strive for comparability in toxicity reporting among clinical trials; and (3) recognize new toxicities accompanying new classes of anticancer treatment modalities. The Southwest Oncology Group has extended the toxicity criteria, incorporating additional new criteria for biological agents, radiation therapy, surgery, and hormonal agents. In addition, endpoint definitions and response criteria are discussed. These have been developed in response to previous uncertainties in clinical trials objectives, to limitations in the resolution of imaging methods, and to demands for greater rigor in response and endpoint definitions. Toxicity criteria, endpoint definitions, and response criteria are tabulated.


Comparative in vitro myelotoxicity of FCE 24517, a distamycin derivative, to human, canine and murine hematopoietic progenitor cells. FCE 24517, a derivative of distamycin A, exhibits an unusual antitumor profile in experimental models. As part of its preclinical development, we evaluated the in vitro myelotoxicity of FCE 24517 to human, canine and murine hematopoietic cells. Marrow cells were exposed to the agent (2.7 x 10(-5) - 2.7 nM) for 4 h and then assayed in capillary (human) or Petri dish (canine, murine) clonal cultures. FCE 24517 inhibited myeloid (CFU-gm), erythroid (BFU-e, CFU-e) and megakaryocytic (CFU-meg) colony formation in a concentration-dependent manner. The progenitor cells were generally similar in their response to FCE 24517 within a species. Comparing the different progenitor cell response to FCE 24517, canine CFU-gm and CFU-e were 26- to 221-fold more sensitive to this drug's toxic effects than their human and murine counterparts. This was demonstrated by extremely low IC70 values for the canine CFU-gm (0.001 nM) and CFU-e (0.007 nM). Murine progenitors displayed 1.3- to 10.9-times higher IC70 values than human CFU-gm, BFU-e and CFU-e following 4 hr exposure to FCE 24517. The data demonstrated that a mouse model may better predict human in vitro myelotoxicity to FCE 24517 than beagle dogs.


Binding of a new vinca alkaloid derivative, S12363, to human plasma proteins and platelets. Usefulness of an erythrocyte partitioning technique. The interactions of S12363 with human plasma proteins have been investigated in vitro by an erythrocyte partitioning technique that allows a quantitative estimation of the plasma and erythrocytes binding. S12363 was 85-95% plasma-bound and 97-98% blood-bound. The main binding protein in plasma was alpha-acid glycoprotein, with a binding constant of 0.6 x 10(6) M-1, accounting for 70% of total S12363 in plasma. Owing to extensive binding to platelets (40-50% of total blood amount), S12363 was mainly distributed in the non plasma blood compartment, with blood-to-plasma concentrations ratio of 1.2-1.4. These results indicate that, in vivo, the fraction of blood S12363 available for tissue diffusion, i.e., the free drug fraction in blood, should depend on both alpha 1-acid glycoprotein concentration in plasma and blood platelet count.


Lack of effects of recombinant human interleukin-4 on in vitro colony formation of freshly explanted human tumor cells. Interleukin-4 is a highly pleiotropic T-cell derived lymphokine that has been reported to stimulate a host cell-mediated antitumor response. Recombinant human interleukin-4 (rhuIL-4) is currently undergoing clinical phase I trials. We have studied the growth modulating effects of rhuIL-4 on a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 0.1 to 10 ng/ml were used in continuous incubation experiments. Of 147 specimens, 73 (50%) were evaluable for the determination of tumor growth modulating activity. The most common tumor types recruited included breast, non-small cell lung, ovarian cancer and melanoma. Stimulation of tumor colony forming units (colony formation > or = 1.5 x controls) was observed in 0/73 tumors. Similarly, only 1/73 (1.3%) specimens (a non-small cell lung cancer) had a significant decrease in tumor colony forming units (colony formation < or = 0.5 x controls) at 1 ng/ml. We conclude that rhuIL-4 is not a direct modulator of tumor colony formation in vitro. However, antitumor effects could perhaps be achieved in vivo via the immune-modulating effects of Interleukin-4.


Phase I evaluation of 773U82-HCl in a two-hour infusion repeated daily for three days. One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity in in vitro and in in vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study. Doses ranged from 50 to 1060 mg/m2/d x 3 days. Due to the possibility of local hemolysis with concentrations > 1.5 mg/ml, drug was administered in solutions containing < or = 1.5 mg/ml. Because large volumes were needed at the higher dose levels, the infusion duration was increased from 2 hours to 4 hours. Mild to moderate nausea, vomiting, fatigue, dizziness and headaches were observed. Myelosuppression was the dose limiting toxicity. The recommended phase II dose and schedule was determined to be 800 mg/m2/d x 3d every 3 weeks. 773U82-HCl plasma concentration-time data were analyzed using a two-compartment pharmacokinetic model. The t1/2 beta averaged 6 hours and the total body clearance was 75.9 L/hr/m2. The volume of distribution (Vdss) was large, averaging 470 L/m2.


Clinical pharmacology studies of oltipraz--a potential chemopreventive agent. Pharmacological studies on Oltipraz [4-methyl-5(pyrazinyl-2)-1-2-dithiole-3-thione)] were conducted with normal healthy subjects using various doses and schedules. Administration of single doses (1, 2 and 3 mg/kg) resulted in detectable drug levels in the serum (mean peak serum concentrations 16, 61 and 205 ng, respectively) and urine. The t1/2 was short (4.4, 4.1 and 5.3 hours respectively) and no steady state was achieved after multiple daily doses for 12 days. Introduction of a loading dose during the first day produced a steady state when 1.5 and 2.0 mg/kg/day were used. Daily administration of Oltipraz sustained the steady state with insignificant variations. Consumption of a high fat diet increased the serum and urine concentrations of Oltipraz (30-60%) compared to the low fat diet. Two subjects experienced flatulence during the administration of the drug. One subject developed numbness and pain in the thumbs with occurrence of small purplish-black spots resembling those observed in subacute endocarditis. These changes disappeared 10 days after discontinuation of the drug. No changes in peripheral blood counts, biochemical profile or thyroid function tests were observed after four weeks of Oltipraz. Further studies with a larger number of healthy subjects are needed for clarification of the safety and biological efficacy of small doses of Oltipraz during chronic administration.


Phase II trial of intravenous hexamethylmelamine in patients with advanced ovarian cancer. A Phase II trial of an intravenous preparation of Hexamethylmelamine was performed in ovarian cancer. Patients who had received prior Platinum based chemotherapy and had measurable disease were eligible. Among 15 evaluable patients, there were no objective responses. Two patients did show clinical and laboratory evidence of improvement. Toxicity was predominantly nausea and vomiting with minimal other toxicity. This intravenous form of Hexamethylmelamine has not shown meaningful activity in ovarian cancer patients who have failed prior platinum treatment.


Phase II study of a combination of elliptinium and vinblastine in metastatic breast cancer. Thirty nine patients with metastatic breast cancer, all previously treated with chemotherapy including anthracycline, were given Elliptinium acetate (80 mg/m2/day) and a continuous infusion of Vinblastine (2 mg/m2/day) for 3 consecutive days every 4 weeks. Twenty nine patients had measurable metastatic disease. Nine (31%) achieved a partial response. No complete response was observed. Median duration of response was 6 months. The response rate was dependent on the number of metastatic sites and independent of the number of previous chemotherapy regimes. Side effects were dry mouth (27 patients), vomiting (9), neutropenia (3 patients with grade IV, 2 with grade III), muscle cramps (5) and thrombosis (3). Xerostomia and vomiting contributed to weight loss and fatigue (8 patients). We conclude that Elliptinium-Vinblastine combination has moderate activity as second line treatment in metastatic breast cancer. This combination causes xerostomia and fatigue with moderate myelosuppression.


A phase II trial of CI-921 in advanced malignancies. CI-921, (9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino]- N,5-dimethyl-4-acridinecarboxamide 2-hydroxyethanesulfonate (1:1)), an anilinoacridine derivative with activity in experimental solid tumors was studied in a multicenter phase II trial in patients with solid tumors. Eligible tumor types included cancers of the breast, stomach, pancreas, nonsmall cell lung, small cell lung, colon, head and neck area, and melanoma. Prestudy requirements included an ECOG performance status of < or = 2, no CNS metastases, and measurable disease. CI-921 was administered intravenously over 1-2 hours on days 1, 8, and 15 of a 35-day course at an initial dose of 270 mg/M2, with modification in subsequent courses based upon tolerance. Principal toxicities included leukopenia, marked phlebitis, and mild nausea and vomiting. One hundred fifty patients were entered of whom 132 were evaluable for response. There was one complete and one partial response among 19 patients with breast cancer, and two partial responses, one each among 14 head and neck and 36 nonsmall cell lung cancer patients.


Phase II trial of edatrexate in patients with advanced pancreatic adenocarcinoma. We conducted a phase II evaluation of edatrexate in 17 previously untreated patients with advanced adenocarcinoma of the pancreas; 14 patients had at least one month of therapy. The initial dose was 80 mg/m2iv. Treatment was administered weekly for 5 weeks, then every other week. Toxicity was generally mild. The median WBC nadir was 5.4 (range 0.6-7.4) x 10(3)/microliters, and the median platelet nadir was 164.0 (range 62.0-341.0) x 10(3)/microliters. One patient died with sepsis and gastrointestinal bleeding associated with pancytopenia. Five patients had a mild rash. Nausea occurred in 6 patients, including 3 who had vomiting. In addition, 11 patients complained of vague malaise which seemed to begin within 24-48 hours after administration of edatrexate, and lasted for 2 to 3 days, resolving within 6 days of drug administration. Median survival was 85 days. Although 5 patients had stable disease, including one with relief of pain, no major responses were seen, excluding, with 95% confidence, a response rate in excess of 20%.


Phase II trial of pirarubicin in the treatment of advanced bladder cancer. Doxorubicin is one of the standard drugs in the chemotherapy of advanced urothelial tumors. Pirarubicin, a new anthracycline, turned out to be equally active and less toxic than its parent compound in preclinical studies. Twenty one patients with either metastatic or inoperable locally advanced bladder carcinoma were treated with intravenous infusion of pirarubicin: 25 mg/m2/day for 3 days every 4 weeks in the first 15 patients and 20 mg/m2/day for 3 days every 3 weeks in the others. Fifteen patients were not pretreated and 6 received prior chemotherapy (5 patients with doxorubicin containing regimen). Twenty patients were evaluable for response; there were 2 partial response, 8 stable disease and 10 progressive disease. All pretreated patients progressed. Hematological toxicity was moderate, however there was one toxic death with grade 4 neutropenia which occurred in a heavily pretreated patient receiving a dose of 25 mg/m2/day for 3 days. There was no clinical cardiac toxicity. Single agent Pirarubicin displays an objective response rate of 10% (95% of CI 0 to 23%) which reaches 14% (95% CI 0 to 29%) when non pretreated patients are analyzed separately. This rate is in the range of doxorubicin activity.


Phase II study of gemcitabine in advanced colorectal adenocarcinoma. A phase II trial of gemcitabine (difluorodeoxycytidine) was conducted in 14 patients with advanced colorectal adenocarcinoma. Gemcitabine was administered intravenously over 30 minutes at weekly intervals for 3 consecutive weeks each month. The starting dose was 800 mg/m2, with dose escalation as tolerated. No complete or partial response were observed. Ten patients experienced progressive disease while on therapy. Toxic effects were primarily hematologic in nature. Grade 3 toxicities included leukopenia (one patient at 1000 mg/m2), granulocytopenia (two patients at 800 mg/m2), anemia (two patients at 800 mg/m2), and myalgia (one patient at 800 mg/m2). No grade 4 toxic effects or treatment-associated deaths were observed. Gemcitabine, at the doses and schedule used in this study, did not demonstrate activity against advanced colorectal adenocarcinoma.


An extended phase II trial of ifosfamide plus mesna in malignant mesothelioma. Forty three patients with histologically confirmed malignant mesothelioma were entered onto an Eastern Cooperative Oncology Group phase II study of ifosfamide given with mesna. Eligibility criteria included adequate performance status, hemogram and renal functions. Ifosfamide was given at 1.5 g/m2 in 200 ml of normal saline over 30 minutes by intravenous infusion on days 1 to 5 of each 21 day cycle. Mesna was given at 300 mg/m2 on each day of ifosfamide at 0, 4 and 8 hours. Two patients were cancelled and one patient was ineligible. The most common toxicity was haematologic. More than 50% of the patients had at least one episode of severe or life threatening toxicity and 2 patients had lethal toxicity (1 renal and 1 pulmonary oedema attributed to treatment), and an additional 4 patients died while on study (2 of cardiac and 2 of cerebral vascular disease not considered directly related to treatment). Of the 40 eligible patients one was unevaluable for response, and one patient had a partial response lasting 6.3 months. Twenty four patients had a no change status with a median duration of 5 months. The median time to treatment failure for all eligible patients was 2.5 months. The median overall survival time (from registration) for all eligible patients was 6.9 months. In multi variable models, factors that predicted for a statistically significant poorer survival were age > or = 62, stage > or = 3, performance status poorer than 0 to 1 and prior surgery (i.e.: more than biopsy).(ABSTRACT TRUNCATED AT 250 WORDS)


Phase II trial of merbarone in soft tissue sarcoma. A Southwest Oncology Group study. Thirty-seven patients with advanced soft tissue sarcoma were treated with merbarone utilizing a daily intravenous schedule for five days. Only one partial response was observed in the thirty-three evaluable patients. The major toxicities were renal, with elevation of creatinine and/or proteinuria, and gastrointestinal, with mild to moderate nausea and vomiting. Merbarone in this dose and schedule has minimal activity in soft tissue sarcoma.


Maintenance therapy with interferon alfa 2b in patients with diffuse large cell lymphoma. Forty-eight consecutive patients with diffuse large cell lymphoma (DLCL) in complete remission (CR) after conventional chemotherapy were enrolled in a prospective clinical trial. The maintenance therapy was a random either nothing or interferon alfa 2b (IFN) 5.0 MU three times a week for one year. The median duration of CR in the patients treated with IFN has not been reached. After five years 60% of patients remain in CR compared to the control group who had a median CR of 40 months (p < 0.001). Actuarial five-years survival in the IFN treated patients was 88% compared to 42% in the control group (p < 0.001). Maintenance therapy with IFN has been beneficial in patients with DLCL with improvement of duration of CR and survival without the excessive toxicity of most common third generation regimen chemotherapy. We felt that IFN could be explored in most controlled clinical trials in patients with DLCL in CR after conventional chemotherapy.


Coronary atherectomy: report of the first experience in Hawaii. Since Andreas Gruentzig first introduced percutaneous transluminal coronary angioplasty (PTCA) in 1977, the ability to revascularize occluded coronary vessels with a catheter has enjoyed an explosive and unimaginable growth. As the equipment and operator experience improved, the possibilities appeared boundless. However, balloon angioplasty is hampered by a significant restenosis rate in the dilated vessel (approximately 30%), which is higher in selected locations (up to 60% in the proximal left anterior descending artery), even in the best of hands. This fundamental limitation may in part be due to the actual nature of the technique itself--stretching the vessel and fissuring the plaque causing remodeling without removal. The uneven, exposed vessel surface post-plaque rupture may contribute to activation of the hemostatic system, with acute thrombosis and release of various platelet and endothelial-derived growth factors, leading to long-term tissue proliferation and restenosis. Atherectomy, the mechanical removal of plaque from the vessel wall, appears to be an answer. This process actually debulks the culprit tissue and leaves behind a smoother, presumably less thrombogenic surface. We wish to report our first experience with a specific form of this technique in 4 consecutive patients, with a brief discussion of its promises and limitations.


Neonatal survival during a 2,500-mile flight. Neonatal respiratory failure, no matter what the cause, may not always respond to standard mechanical ventilation techniques. Extracorporeal membrane oxygenation has emerged over the last 15 years as an adjunct to the treatment of these babies with a greater than 80% survival nationwide. Limited resources and personnel costs can be prohibitive, forcing regionalization of extracorporeal membrane oxygenation (ECMO) centers. Geographic distance from a center should not limit its potential application, however. Familiarity with the technique, early application of the modality and the availability of medical air transport, allows for referral and transfer of neonates over great distances with excellent results and outcomes. We present a case of respiratory failure in a neonate transported 2,500 miles for ECMO therapy with an excellent outcome and a rapid return home.


Sickle and thalassemic erythroid progenitor cells are different from normal. Blood erythroid progenitors (BFU-E) from patients with sickle and thalassemic syndromes were compared with those from normal individuals. The day of maximal colony formation in methyl cellulose was slightly later in the cultures from the patients with hemoglobinopathies than in the normal cultures. The number of colonies/100,000 mononuclear cells was similar in all cultures on day 13, but was higher in the hemoglobinopathy cultures on the day of maximal growth. The number of BFU-E/mL of blood was significantly higher than normal at all times in both sickle cell anemia and thalassemia. The proportional synthesis of gamma globin was twice normal in all sickle cultures, and 4 times normal in those from beta+-thalassemia. Hemin and interleukin-3 increased the numbers of erythroid colonies in all cultures, but did not consistently alter the globin synthesis patterns. Each progenitor population has a unique pattern in terms of time course, number of BFU-E, and level of gamma globin synthesis. These features indicate distinct types of BFU-E, or differences in accessory cells, or both, which distinguish blood-borne erythropoiesis in normals and those with hemoglobinopathies.


Clinical, hematological, and molecular features in Sicilians with sickle cell disease. We report the clinical, hematological, and molecular findings observed in 32 Sicilian patients with sickle cell disease. None of our patients received regular blood transfusions and careful infectious disease prophylaxis was carried out for all. Haplotyping of beta S chromosomes was performed in all patients; all were homozygous for haplotype #19 (Benin). Gene mapping excluded the presence of an alpha-thalassemia in 13 of our patients; none of the relatives showed any evidence of the presence of alpha-thalassemia. Hb F levels were 11.8 +/- 5.9% with G gamma representing 39.6 +/- 3.6% of total gamma chain. Hb F levels were higher in females than in males (12.5 +/- 5.9% versus 9.7 +/- 6.5%) but the difference was not statistically significant. All patients, regardless of age and sex, were anemic with normal mean corpuscular hemoglobin concentration, high mean corpuscular volume and mean corpuscular hemoglobin, and mild reticulocytosis. Analysis of clinical manifestations suggests that our patients have a disease of moderate severity.


Hb Q-Thailand [alpha 74(EF3)Asp-->His]: gene organization, molecular structure, and DNA diagnosis. Hb Q-Thailand [alpha 74(EF3)Asp-->His] is often found in Thailand, China, and other Southeast Asian countries. The alpha-Q-Thailand gene is strongly linked to an alpha gene deletion and has important implications in the identification and diagnosis of hemoglobinopathies and thalassemias. The alpha-Q-Thailand mutation was previously mapped to the alpha 1 gene in a study of Chinese patients. In this paper, a Thai patient with Hb Q-Thailand/Hb H disease and his mother were studied at the DNA level, and the gene organization of Hb Q-Thailand in the Thai patient was found to be the same as that of Chinese patients (i.e. the Hb Q-Thailand gene is located on the alpha 1 gene of chromosome #16, while the -4.2 kb or leftward deletion involves the alpha 2 gene). Also, the GAC-->CAC mutation proposed at codon 74, has been confirmed by DNA sequencing and a simple and accurate method for diagnosis of the Hb Q-Thailand variant has been developed based on restriction enzyme analysis. Since the GAC-->CAC mutation generates new cutting sites for both restriction enzymes Apa LI and Hgi AI, polymerase chain reaction amplification of a specific region around codon 74, followed by digestion with these enzymes and agarose gel electrophoresis of the digested products, permits rapid and accurate identification of Hb Q-Thailand.


Hb Graz or alpha 2 beta 2(2)(NA2)His-->Leu; a new beta chain variant observed in four families from southern Austria. Two abnormal hemoglobins were accidentally detected by cation exchange high performance liquid chromatography with the Diamat system of Bio-Rad Laboratories; the variants eluted together with the fast-moving Hb A1c. Structural analysis of isolated beta chains and sequence analysis of amplified DNA identified a new variant, i.e. Hb Graz that has a His-->Leu replacement at position 2 of the beta chain, in four healthy, apparently unrelated, adults. The second variant was identical to Hb Sherwood Forest or alpha 2 beta 2(104)(G6)Arg-->Thr; it is believed that this may be the second observation of this abnormal hemoglobin.


Normal delta-globin gene sequences in Sardinian nondeletional delta beta-thalassemia. In order to clarify the reasons for the reduced Hb A2 levels in Sardinian delta beta-thalassemia, we characterized, both by cloning and sequence analysis and by direct sequencing of amplified DNA, the delta-globin gene from an individual of Sardinian descent who is a compound heterozygote for the beta zero-thalassemia codon 39 (C-->T) nonsense mutation and the Sardinian delta beta-thalassemia [codon 39(C-->T)/-196(C-->T)A gamma]. The analysis of the delta-globin gene from the delta beta-thalassemia chromosome revealed an entirely normal sequence. The defective function of the delta-globin gene in this determinant is thus likely related to a suppressive effect of the in cis nondeletional high persistence of fetal hemoglobin mutation of the A gamma gene, probably resulting from an increased capability of the relative promoter to interact with the locus control region.


Hemoglobinopathies in Yugoslavia: an update. This paper summarizes information on the epidemiology and molecular basis of hemoglobinopathies in Yugoslavia. Over the past 25 years, population surveys of more than 28,000 school children from all over the country, except Slovenia, have shown that the average incidence of beta-thalassemia (beta-thal) trait is 1.2%, ranging from 2.9% in the south (Macedonia) to 0.8% in the northwest (Croatia). The frequency of delta beta-thal is 0.2%, while the frequency of the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) is 0.4%. Screening of 6,400 newborns has shown that the frequency of alpha-thal trait is 1.6%. The molecular basis of the different forms of beta-thal among Yugoslavians has been almost completely defined. Over 250 beta-thal chromosomes have been studied, and in over 90% the molecular defect was determined. Eighteen different beta-thal mutations have been detected, three of which (IVS-I-110, G-->A; IVS-I-6, T-->C; IVS-I-1, G-->A) account for more than 70% of all beta-thal chromosomes. Four new mutations [-87 (C-->A); IVS-II-850 (G-->C); initiation codon mutation T-->C; poly A (AATAAA-->AATGAA)] and one new deletion (1605 bp) have been characterized. Molecular analyses of DNA from over 30 unrelated cases with delta beta-thal have shown that this condition is mainly caused by a 13 kb deletion (Sicilian type); in one family a deletion of > 18 to 23 kb (Macedonian type), and in another family a deletion of 148 kb (Yugoslavian type of epsilon gamma delta beta-thal) of the globin gene complex was discovered. Limited studies of alpha-thal in Yugoslavia have shown the following types of molecular defects: approximately 20.5 kb deletion, approximately 17.5 kb deletion, -3.7 kb deletion, 5 nucleotide (nt) deletion, and Hb Icaria. The incidence of abnormal hemoglobins (Hbs) in Yugoslavia is 0.3%. Five different alpha chain variants among 21 families, 15 different beta chain variants among 53 families, one delta chain variant in one family, one variant with a deleted residue in one family, and two types of Hb Lepore among 122 families, have been observed.


Mitotic and salivary gland chromosome analyses in the Musca domestica L. (house fly) (Diptera: Muscidae). The mitotic chromosomes in Musca domestica consist of five pairs of autosomes and an X, Y sex chromosome pair. They respond to C-banding with procentric bands on all autosomes and deep staining over most of the X and Y chromosomes. Polytene chromosomes were previously found in several larval and pupal tissue of Musca domestica. Polytene chromosome reference maps of the two sexual and the five autosomal chromosomes of Musca domestica from salivary gland cells are shown. Characteristic features of each chromosome are described identifying areas that are difficult to analyse.


Natural selection on body size in Tribolium: possible genetic constraints on adaptive evolution. To determine whether genetic constraints on adaptive evolution were operating in a laboratory population of a flour beetle, Tribolium castaneum, we first estimated the direct selection acting on each of several body size traits. Strong selection in males for an increase in pupal weight and a decrease in the ratio of adult to pupal weight occurred. In addition, a non-significant trend for a decrease in adult width was found. No significant selection on females was detected, although there were trends toward an increase in pupal weight and a decrease in adult width. These estimates were then combined with estimates of the genetic variances and covariances of the traits to predict the multivariate response to selection, that is, the evolutionary change in the traits across one generation. These projections showed only a small predicted change in male pupal weight in spite of the strong selection on pupal weight, and a relatively large predicted increase in width in spite of the possible negative direct selection on this trait. Both of these results were due in part to the positive genetic covariance between pupal weight and width, and they therefore suggest the possibility of genetic constraints on adaptive evolution of these traits.


Localization of collagen X in human fetal and juvenile articular cartilage and bone. The tissue localization was analysed of collagen X during human fetal and juvenile articular cartilage-bone metamorphosis. This unique collagen type was found in the hypertrophic cartilage zone peri- and extracellularly and in cartilage residues within bone trabeculae. In addition, occasionally a slight intracellular staining reaction was found in prehypertrophic proliferating chondrocytes and in chondrocytes surrounding vascular channels. A slight staining was also seen in the zone of periosteal ossification and occasionally at the transition zone of the perichondrium to resting cartilage. Our data provide evidence that the appearance of collagen X is mainly associated with cartilage hypertrophy, analogous to the reported tissue distribution of this collagen type in animals. In addition, we observed an increased and often "spotty" distribution of collagen X with increasing cartilage "degeneration" associated with the closure of the growth plate. In basal hypertrophic cartilage areas, a co-distribution of collagens II and X was found with very little and "spotty" collagen III. In juvenile cartilage areas around single hypertrophic chondrocytes, co-localization of collagens X and I was also detected.


Phenotypic changes in germ cells during gonadal development of the common carp (Cyprinus carpio). An immunohistochemical study with anti-carp spermatogonia monoclonal antibodies. A procedure is described in which large early spermatogonia were isolated from carp testes and purified from an initial 4-5% recovery up to 60-70% using equilibrium density centrifugation on a continuous Percoll gradient. Mice were immunized with the spermatogonia via the intrasplenic route. Six hybridoma cultures, producing monoclonal antibodies (MAbs) reacting selectively with germ cells, were selected and further analysed. Reactivity with five of these MAbs was observed on primordial germ cells (PGCs) in the developing indifferent gonads at the onset of proliferation, i.e. the age of 7 weeks. One MAb, encoded WCG6, appeared to define a new surface marker on PGCs being gradually expressed on the surface membrane between the age of 2 and 4 weeks, concomitantly with an increase in size of these mitotically silent cells. The reactivity of germ cells with five of the MAbs disappeared completely (WCG 7, 12, 15, 21) or nearly completely (WCG 6) during spermatogenesis, providing a striking difference from patterns obtained with MAbs raised previously against carp spermatozoa. Differences between male and female germ cells were not observed with the WCG-MAbs during gonad development, indicating that a common set of surface antigens is shared between germ cells of both sexes up to and including spermatogonia and oogonia.


Immunoelectron microscopic study of proteoglycans in rat epiphyseal growth plate cartilage after fixation with ruthenium hexamine trichloride (RHT). The localization of proteoglycans in rat epiphyseal growth plate cartilage was investigated immunoelectron microscopically by the post-embedding method, using mouse monoclonal antibody (2-B-6) which specifically recognizes 4-sulphated chondroitin or dermatan sulphate after digestion of proteoglycans with chondroitinase ABC. Fixation with ruthenium hexamine trichloride (RHT) and embedding in LR White served to preserve chondrocytes in the expanded state and matrix proteoglycans were observed as a reticular network of filaments. Immunoelectron microscopy revealed gold labelling of the secondary antibodies for the demonstration of proteoglycans on these filamentous structures and in elements of the Golgi apparatus. Filaments associated with matrix vesicles were also labelled. After fixation in the presence of RHT, it was clearly demonstrated that cartilage matrix proteoglycans are retained approximately in their original spatial distribution and their antigenicity is well preserved.


A comparison of tooth structure in Neanderthals and early Homo sapiens sapiens: a radiographic study. Tooth components of 1st and 2nd erupted permanent molars were measured from standardised radiographs of Homo sapiens sapiens and Homo sapiens neanderthalensis. Enamel height was greater in Homo sapiens sapiens but pulp height and width and the height of the enamel to floor of the pulp chamber were greater in Homo sapiens neanderthalensis. Dentine height, crown width and enamel width showed similar results in the two groups. Unerupted first molars were measured to analyse the influence of function on tooth components and the results obtained were always within the range measured for the erupted teeth. Discriminant analysis between groups, using tooth components, showed accuracy of 93% for identification of Homo sapiens sapiens and 94% for identification of Homo sapiens neanderthalensis. The results support the hypothesis of a distinct evolutionary line for the Neanderthals.


Neurotropic influence of the distal stump of transected peripheral nerve on axonal regeneration: absence of topographic specificity in adult nerve. Observations have been made on the growth of regenerating axons from transected rat sciatic nerve through Y-shaped silicone tubes. When the distal stump of the nerve was sutured into 1 distal limb of the tube and a fat pad into the other, a clear preference for the axons to regenerate towards the distal stump was found. In other experiments regenerating axons from the peroneal or tibial divisions of the sciatic nerve were given the choice of growing towards either the peroneal or tibial nerves, each being inserted into 1 of the 2 distal limbs of the Y-tube. No significant preference of the proximal stump to regenerate towards its appropriate distal stump was detected. A neurotropic influence of the distal stump on the nerve has therefore been confirmed, but topographic specificity of regeneration at the level of the nerve trunk has not been established.


The morphology and innervation of facial vibrissae in the tammar wallaby, Macropus eugenii. The morphology of the vibrissal follicles on the mystacial pad of the tammar wallaby is similar to that seen in other species except that the follicles lack a ringwulst or ring sinus. Instead, the mesenchymal sheath is thickened around the central region of the hair shaft. The follicle is innervated by both deep and superficial vibrissal nerves. The deep nerve enters as 4-11 fascicles which can be in close proximity or widely distributed around the hair. C1 follicles received more myelinated nerve fibres (252 +/- 31) than the smaller C4 follicles (174 +/- 43). The deep vibrissal nerve supplies the thickened mesenchymal sheath, the narrow 'waist' region above and the majority of endings in the inner conical body (ICB), while the superficial nerves provide a sparse innervation to the ICB and rete ridge. Receptors present in the follicle were of 4 types: (1) Merkel cells, especially numerous in the outer root sheath of the 'waist' region and occasionally in the ICB and rete ridge; (2) and (3) lanceolate and lamellated endings parallel to the hair shaft in both the mesenchymal thickening and the 'waist' region where they were particularly dense; (4) free nerve endings in the mesenchymal thickening, 'waist' region and ICB. No corpuscular, bulbous or Ruffini endings were seen. The innervation of the intervibrissal fur was similar to that described in other species.


Comparative morphology of the mandibulodental complex in wild and domestic canids. The relationships between mandibular and dental measurements were investigated in a sample of 60 adult domestic dogs, 17 black-backed jackals Canis mesomelas, 18 side-striped jackals C. adustus and 16 Cape foxes Vulpes chama. Standard mesiodistal and buccolingual tooth measurements, together with 8 mandibular measurements (intercondylar distance, intercarnassial breadth, mandibular length, arch length, condylar height, canine-condylar length, mandibular width, mandibular height) were scaled allometrically to total skull length. Despite wide differences in diet and sexual dimorphism between the 3 wild canid species, larger canids were found to be scaled up versions of smaller canids. While males showed a highly concordant patterning when compared with domestic dogs of equivalent size, females showed a remarkably mosaic pattern. Relative to skull size, the only teeth that appear to be larger than those of equivalently sized domestic dogs were the second molars. It is suggested that those theories of sexual dimorphism and functional integration which apply to skeletodental dimensions in primates may not be applicable to canids.


Distribution of subchondral bone density and cartilage thickness in the human patella. Subchondral bone density (by means of CT osteoabsorptiometry), and cartilage thickness (directly measured on photocopies of frozen sections), were examined in 30 human patellae, with an age range from 47 to 90 y. A surface demonstration of the distribution was prepared, and representative pictures produced by summation with a computer. Subchondral bone-density maxima were found in the proximal part of the lateral facet, and the density pattern interpreted as the expression of the long-term distribution of stress in the joint. It is reasonable to assume that cartilage thickness, of which two-thirds of the maximum values occupy a lateral position, is also dependent on the local stress. The 2 distributions show correlation coefficients > 0.5 in approximately a third of the cases we examined. Displacement of the higher values of cartilage thickness relative to the subchondral density maxima is attributed to incongruence in the medial part of the joint.


Distribution of enkephalin-like immunoreactivity in the central nervous system of the rainbow trout: an immunocytochemical study. The distribution of enkephalin-like immunoreactive (ELI) cell bodies and fibres in the brain of the teleost Salmo gairdneri L. was demonstrated with the indirect peroxidase-antiperoxidase immunocytochemical technique using a highly specific antiserum. In the telencephalon, ELI cell bodies were located in the area ventralis. In the diencephalon, they were found in the nucleus ventromedialis of the thalamus, nucleus lateralis tuberis, nucleus recessus lateralis, and nucleus recessus posterioris. In the mesencephalic tegmentum, ELI cell bodies were found in the nucleus of the rostral mesencephalic tegmentum, and in a group of neurons which was located dorsal to the nucleus of the rostral mesencephalic tegmentum. In the medial torus semicircularis, small numbers of immunoreactive cell bodies were found. In the cerebellum, numerous cell bodies were observed in the granule cell layer and at the border between the granular and molecular layer. ELI cell bodies were also seen in the nucleus tegmenti dorsalis lateralis and nucleus fasciculi solitarii. ELI fibres were widely distributed in the rainbow trout brain. The highest density of immunoreactive fibres was found in the area ventralis telencephali, the mesencephalic tegmentum, the stratum opticum of the optic tectum, the central gray of the brainstem, the caudal part of the fasciculi solitarii and the dorsal horn of the spinal cord. In the stratum fibrosum et griseum superficiale, stratum griseum centrale and stratum album centrale of the optic tectum, a moderate number of immunoreactive fibres was observed. In the olfactory bulb only a few immunoreactive fibres were present. No effect in the labelling was found after colchicine injections. These results provide the first complete mapping of the ELI in a fish brain. It is clear that enkephalins show a similar distribution pattern in Salmo gairdneri to that in other vertebrates; however, the number of ELI cell bodies in the fish brain is smaller than in land vertebrates. The distribution of enkephalins in specific hypothalamic nuclei, visual areas, and in the brainstem of the rainbow trout brain, suggests that these peptides are involved in the modulation of neuroendocrine and as well in visual and somatosensory functions.


The relationship between capillarisation and fibre types during compensatory hypertrophy of the plantaris muscle in the rat. Compensatory hypertrophy of the plantaris muscle was obtained by denervation of its synergists. This hypertrophy is characterised by a 32% increase in muscle mass. The muscle consists of type I and IIa (oxidative), and IIb (glycolytic) fibres. Fibres of all types were enlarged in hypertrophied muscles and the proportion of type I fibres was increased. We investigated the capillarisation after hypertrophy as related to fibre type. In order to obtain this information a new technique was used, capable of estimating not only the traditional overall capillary density (CD) but also an index of heterogeneity in capillary spacing (LogSD), the 'local capillary to fibre ratio' (LCFR), obtained separately for each muscle fibre type, and finally a capillary density for each respective fibre type, the 'capillary fibre density' (CFD). It was found in both control and hypertrophied muscles that CD was higher in the deep (few IIb fibres) than in the superficial part of the muscle (considerable number of IIb fibres). The LogSD was lower, indicating less heterogeneity, in the deep than in the superficial part of the muscle. The LCFR and CFD of each fibre type was greater in the deep than in the superficial region of both control and hypertrophied muscles. Furthermore the CFD and LCFR were larger in type I and IIa fibres than in IIb fibres in each region of control and hypertrophied muscles. In hypertrophied muscles the CD was not significantly different from that of control muscles. However, LCFR of all fibre types was increased significantly in hypertrophied muscles as compared with controls, demonstrating capillary proliferation. The decreased CFD of type I and IIa fibres in the deep region of hypertrophied muscles as compared with controls suggests that here the capillary proliferation lags behind the increase in muscle mass. Endurance training had no significant effects for any region in any of the indices that were used.


The harderian gland of desert rodents: a histological and ultrastructural study. This study describes the structure of the harderian gland in desert rodents: 3 Gerbillidae species (Gerbillus gerbillus, Meriones crassus, Psammomys obesus) and 1 Ctenodactylidae species (Ctenodactylus vali). In all these species the gland consists of tubules lined by a single layer of epithelial cells and possesses myoepithelial cells within their basal laminae. The gland contains porphyrin which is stored as solid intraluminal deposits. The glandular epithelium presents a single cell type (type I) in Psammomys obesus, 2 cell types (I and II) in Ctenodactylus vali and 3 (I, II and III) in Gerbillus gerbillus and Meriones crassus. The type I and II cells are columnar. They are characterised by many lipid vacuoles and a well developed vesicle-like structure of smooth endoplasmic reticulum. In Gerbillus gerbillus and Meriones crassus the type I cells can be distinguished from type II cells by cytoplasmic clefts approximately 1 micron in length. In Ctenodactylus vali type I cells are characterised by cytoplasmic rod-shaped crystalloid structures approximately 0.5 microns in length which are frequently observed in the mitochondrial matrix. These structures are also present in the sole cell type of Psammomys obesus. Most of the secretory lipid vacuoles of the type I cell contain an electron-dense material, possibly porphyrin, which presents different appearances according to species: it is lamellar in Gerbillus gerbillus, trilamellar in Meriones crassus, and amorphous in Psammomys obesus and Ctenodactylus vali. Secretory lipid vacuoles are released primarily by exocytosis, but holocrine and apocrine secretion is also observed. The type III cells are pyramidal. This cell type is characterised by the presence of an extraordinarily well developed granular endoplasmic reticulum, organised in concentric lamellae in Gerbillus gerbillus, and very numerous mitochondria. Epithelial cells are frequently binucleate. The single excretory duct contains both mucous and serous cells. Mast cells, plasma cells, macrophages, fenestrated capillaries and unmyelinated nerve endings with clear or dense-cored vesicles are present in the connective tissue. Melanocytes are very numerous in the interstices of the Gerbillidae harderian gland. The gland is surrounded by a collagenous capsule and an outer layer of endothelial cells derived from the orbital venous sinus.


Distribution of 125iodine-labelled mouse immunoglobulin G injected intravenously in pregnant mice. Mouse immunoglobulin G (IgG) was iodinated with 125iodine (I) and injected intravenously into pregnant mice in order to examine whether mouse granulated metrial gland (GMG) cells are able to take up IgG in vivo. The mice were injected intravenously on days 8, 12 or 16 of pregnancy and killed either 5 min, 2 h or 24 h after injection. Implantation sites and spleen, thymus, liver and para-aortic lymph nodes were fixed and autoradiographs of sectioned (1 micron) material prepared to examine the distribution of labelled IgG. In general, at all stages of pregnancy and time intervals examined after injection of the 125I IgG, radioactivity was detected at higher levels in blood vessels than in tissue spaces of the same regions. No evidence for the uptake of radioactive IgG by normal GMG cells in the decidua basalis, metrial gland or in the maternal blood spaces of the labyrinthine placenta was found. The only GMG cells which had accumulations of silver grains showed signs of pyknosis. The uptake of IgG by stromal cells in close proximity to GMG cells and the distribution of radioactivity in the extravascular tissues showed that the intravenously injected 125I IgG was available to the GMG cells. Accumulations of silver grains were a prominent feature of the regions immediately adjacent to most GMG cells in the placental labyrinth and some were clearly associated with degenerate layer 1 trophoblast cells. The radioactivity detected in degenerate GMG cells and degenerate layer 1 trophoblast cells may be the result of nonspecific uptake as a consequence of the cells' death.


Fibre size and type adaptations to spinal isolation and cyclical passive stretch in cat hindlimb. Impulse activity is known to have a strong influence in determining the characteristics that distinguish skeletal muscle fibres into types. The control of muscle proteins by the neural systems that innervate the muscles, however, is not complete (Edgerton et al. 1985, 1990). The purpose of the present study, therefore, was to determine the effects of inactivity for 6 months on the size and fibre type composition of selected cat hindlimb muscles. Inactivity was produced by isolating the lumbar region of the spinal cord, i.e. transecting the cord at T12-T13 and again at L7-.S1 and then performing a bilateral dorsal rhizotomy between the transection sites (SI). In each SI cat, one hindlimb was passively manipulated for 30 min per day through a range of motion at the ankle mimicking a step cycle. SI resulted in an atrophic response in most muscles, with predominantly slow extensors showing the largest effect. In general, the predominant fibre type, which also had the largest mean size, in each muscle atrophied the most. The mean fibre size of all fibre types were similar after SI, suggesting that there may be a minimal size for inactive intact fibres. In comparison with control animals, all muscles in the SI cats had a higher proportion of fast fibres. Further, the relative contribution of the slow fibres to the total cross-sectional area of the muscle was decreased following SI. Some slow fibres in each muscle, however, were resistant to change. These data demonstrate the extent to which size and myosin type of mammalian muscle fibres are independent of activation characteristics.


The inheritance of vertebral shape in the mouse. I. A study using Fourier analysis to examine patterns of inheritance in the morphology of cervical and upper thoracic vertebrae. The shapes of cervical and upper thoracic vertebrae from large samples of 2 inbred strains of mice and their F1 offspring were examined using Fourier analysis to investigate in detail the distributions and magnitudes of differences in vertebral shape between different strains of mice, the relationships between parents and offspring and any differences in the inheritance of vertebral shape between successive vertebral levels. Consistent with the findings of an earlier study there was evidence for considerable differences between vertebral levels in the degree to which offspring resemble one or other parent. The results demonstrate that the inheritance of vertebral morphology conforms to a model in which F1s between inbred strains form a triangular relationship with their parents. Furthermore, this relationship varies between vertebral levels. The significance of these findings is considered in relation to the understanding of the mechanisms of character inheritance and evolution and some new directions for research into vertebral column morphogenesis are proposed.


The human anterior cruciate ligament: histological and ultrastructural observations. In transverse and longitudinal paraffin-embedded sections, the human anterior cruciate ligament (ACL) is made up of wavy bundles of collagen fibres arrayed in various directions, the majority around the axis of the ligament with a few running parallel to it. The fascicles making up the larger bundles are also characterised by this undulating appearance. In thin sections 2 types of collagen fibrils are observed: small (with a single diameter peak at 45 nm) and large (3 peaks at 35, 50 and 75 nm respectively), organised into distinct areas made up of either large or small bundles of fibrils. The numerous fibroblasts that are present appear elongated in the direction of the bundles with branches and short cytoplasmic processes. The elastic system is made up of both elastic and oxytalan fibres. The varied orientation of the bundles in the ACL, the complex ultrastructural organisation and the abundant elastic system make it very different from other ligaments and tendons, providing a structure able to withstand the multiaxial stresses and varying tensile strains imposed upon it.


Postcranial morphological features of homozygous tetraploid mouse embryos. The postcranial morphological features of 22 homozygous tetraploid mouse embryos were studied. The latter were produced by electrofusion of blastomeres at the 2-cell stage in vitro, and were transferred to appropriate recipients that were autopsied on d 12-16 of gestation. Seven embryos were isolated on d 15 or d 16 of gestation and were developmentally equivalent to control diploid embryos of 13-14.5 d p.c. In each of these embryos, their sex could be determined from the histological analysis of their gonads. A further 15 embryos were isolated on d 12-14 of gestation and most were developmentally equivalent to controls of between 11-11.5 and 12-12.5 d p.c. The sex of these embryos could not be determined from the analysis of their gonads, as these were all at the 'indifferent' stage. Twelve of the 22 embryos had a normal postcranial axial morphology, while 10 had an abnormal postcranial axial morphology associated with an enormous omphalocele which contained most of the abdominal viscera and often, particularly in the more advanced specimens, the heart as well. In each of the 7 developmentally most advanced embryos studied, a major congenital abnormality involving at least one organ system was present, but none of these was believed to be life-threatening. The most interesting finding was that 3 of these embryos had abnormalities of the aortic arch arterial system; in 2 embryos the arch of the aorta was retro-oesophageal and retrotracheal, while a 3rd embryo had transposition of the great vessels associated with a right-sided descending aorta. In a 4th embryo, an aneurysmal dilatation of the posterior cardinal vein was present, and this was associated with the anomalous persistence of the left subcardinal/supracardinal venous system. These abnormalities represent a degree of mirror imaging of the normal vascular arrangement. Analysis of the gonads revealed that all of the embryos with vascular abnormalities in this group were male (XXYY), and no vascular abnormalities were present in the females (XXXX). The histological features of the viscera were normal. In 5 of the 15 developmentally less advanced embryos, the distal part of the bulbus cordis region of the heart was displaced medially, and consequently the outflow tract was located on the left part of the pericardial cavity rather than on the right where it is normally found. This may represent an early stage in the differentiation of the aortic arch arterial vascular anomalies indicated above. In 2 additional embryos, abnormally located (i.e. retro-oesophageal) innominate vessels were present.(ABSTRACT TRUNCATED AT 400 WORDS)


Enhanced horseradish peroxidase uptake in the electrically stimulated cochlea of the guinea pig. Stimulation with alternating current at the round window causes an accelerated uptake of extracellular HRP by endocytotic vesicles in inner hair cells at the base of the stimulated cochlea, near the site of the electrode, but does not noticeably affect uptake into outer hair cells. After unilateral electrical stimulation, efferent endings on outer hair cells at the cochlear base show increased vesicular and endosomal labelling in both the ipsilateral and contralateral ears. It is concluded that round-window electrical stimulation increases afferent synaptic activity in inner hair cells near the electrode site, and also increases synaptic activity in OHC efferent endings, not only of the ipsilateral cochlea but also of the corresponding region of the contralateral cochlea. Rapid diffuse cytoplasmic labelling of inner and outer hair cells also occurs sporadically in both stimulated and unstimulated cochleae. However, in efferent terminals, diffuse labelling is restricted to stimulated animals, and occurs bilaterally, in corresponding basal regions of the cochlea.


Tissue reactions induced by hydrocolloid wound dressings. Porcine full-thickness excisional wounds were treated with 4 different hydrocolloid (HCD) dressings--DuoDERM (ConvaTec/E. R. Squibb), Intrasite HCD (Smith and Nephew Medical), Tegasorb (3M) and Replicare (Smith and Nephew Medical). Animals were killed at 4, 10, 21 and 90 d post-wound, excision sites were fixed in formalin and processed for histological analysis. Granulomatous lesions were observed following treatment with each of the 4 HCD dressings. Such lesions developed between 4 and 10 d post-wound, exhibiting little evidence of resolution at 90 d post-wound. Of the 4 dressings examined, DuoDERM and Intrasite HCD precipitated the most severe reaction, each treatment resulting in granulomata with a distinct and different morphology. Treatment with DuoDERM resulted in granulomata characterised by a random distribution of dendritic cells, epithelioid cells, multinucleated giant cells, lymphocytes and plasma cells. In contrast, treatment with Intrasite HCD resulted in highly organised granulomata, consisting of a central focus of epithelioid cells surrounded by a peripheral cuff of macrophages, lymphocytes and plasma cells. This experimental study highlights chronic inflammatory lesions that may, if reflected in the clinical environment, question the efficacy and indication of HCD dressings in the treatment of wounds having a number of different aetiologies.


[The progress of National Leprosarium].

[The progress of National Leprosarium]. Leprosy Prevention Law was proclaimed in 1907 in Japan. According to the regulation, Leprosy Control Policy has got under way by the Government. In 1909, five leprosaria were established in the leprosy endemic areas by local government to admit vagrant leprosy patients who were estimated as one thousand and two hundred. The vagabonds had many troubles, especially, they often escaped from leprosaria. Dr. Kensuke Mitsuda who was one of the directors of leprosaria suggested the Government to establish the National Leprosarium in small island to admit them. In 1930, the Government had Ten-year Program to eradicate leprosy and decided to set up ten thousand beds in existing leprosaria and newly-established National Leprosarium. The plan has been almost completed by the construction of five National Leprosaria by 1940. The number of in-patients was 9,125, including 4,389 in five national institutions. In 1941, five local leprosaria were transferred their superintendence to the Central Government, after then, in 1943 and 1944, two National Leprosaria were established. The total number of National Leprosarium in Japan came to thirteen in 1945.


[Biwasaki Leprosarium--a century of dedication]. Biwasaki Leprosarium, or Biwasaki Tairo Hospital, was established by Father Jean Marie Corre, a French Priest, in 1898. He was born in Brittany France, 1850. After being ordained to the priesthood, he came to Nagasaki, Kyushu, in 1876. He was just twenty six years old. He was greatly moved at the sight of the Hansenites and other sick people around the Honmyoji Temple in Kumamoto, Kyushu, which is one of the well-known temples in Japan. They were making a bare living by the charitable contributions of the pilgrims who visited the Temple, in those days. Fr. Corre moved from Nagasaki to Kumamoto. First, he built a church in Tetori, Kumamoto, and rented a house near the Honmyoji and began to look after the needs of the Hansenites. In 1896, he bought a large lot at Biwasaki in the Shimasaki area, Kumamoto, where is not far from Honmyoji. He remodeled some houses into the so-called sanatorium and started to accommodate those suffering from Hansen's disease. At the outset, he had the cooperation of nuns and church workers to look after the patients' needs. Furthermore, Fr. Corre appealed to Rome for the help and/or support in 1898 in order to expand this kind of project, and five nuns were dispatched in the following year from the Franciscan Missionaries of Mary in Rome. And since then the sisters have devoted themselves assiduously and faithfully to help the Hansenites as far as possible and they are still doing this. However, in 1963, a fire broke out from one of toilets and made a clear sweep of the whole building.(ABSTRACT TRUNCATED AT 250 WORDS)


[Bacteriology of Mycobacterium leprae: from the gene technological viewpoint]. Recent studies on molecular biology of the mycobacterial gene, especially, of the M. leprae gene were reviewed. The properties of 65KDa, alpha-antigen, 36KDa and other proteins were focused.


[Monokine production by mouse peritoneal macrophages after phagocytosis of mycobacteria]. It is well known that monokines, IL-1 (Interleukin-1) and TNF (Tumor Necrosis Factor), are produced by macrophages after stimulated with various agents. These cytokines are involved in various aspects of the inflammatory process and immunological response in addition to their original activities to proliferate T lymphocytes and causing tumor necrosis, respectively. Recently, there have been reported that IL-1 and TNF also play an important role in mycobacterial infections such as granuloma formation. In the present study, IL-1 and TNF productions were observed by mouse peritoneal exudate and resident macrophages after incubation with heat-killed M. lepraemurium and M. avium in vitro. The production was enhanced by phagocytosis of these mycobacteria in a dose dependent manner, and the time course of the production was maximum within 24 hr after phagocytosis of these mycobacteria. It was also shown of morphological changes and enhanced glucose consumption in media by these macrophages. Above results suggest that phagocytosis of mycobacteria by macrophages leads to monokine production, which would not only causes well known immunological reactions but also makes characteristic phenomena to be observed in mycobacterial infections.


[Patients with calcinosis cutis in National Leprosarium Matsuoka Hoyo-En]. As of the year 1991 there were 358 leprosy patients in National Leprosarium Matsuoka Hoyo-En, including 223 patients (62.3%) who had received the injections of chaulmoogra oil before. Calcinosis cutis caused probably from the injections was noted on 73 patients (32.7%): 67 lepromatous and 6 tuberculosis cases. It has never been reported before that the T type patient suffering from calcinosis cutis was observed in the cases of the chaulmoogra oil injection in Japan. The detectable positions of calcinosis cutis were mostly at the injected sites, that is, outside the right brachium followed by bilateral-branchia and crura. In the group of patients with calcinosis cutis, the anti-PGL antibody was negative for the most part. Urinalyses, peripheral blood figure analyses, histopathological tissue examinations of calcium deposition, X-ray diffraction patterns, differential thermal and gravitational analyses, and chemical analyses were performed on all patients with this disease. Further, as the result of this study six patients with calcinosis cutis caused by sulpyrine was also found. The major component of the deposit by the drug was calcium phosphate. These calcinosis cutis were considered to be of trophopathic calcinosis based on the disorder of subcutaneous tissue due to the injections of respective drugs: chaulmoogra oil and sulpyrine.


Effects of propafenone on function and metabolism in the ischemic working rat heart. We examined the effects of propafenone, a new anti-dysrhythmic agent, on myocardial function and metabolism in ischemic working rat heart preparations. In the treated hearts, propafenone, 0.3 micrograms/ml and 3 micrograms/ml, were added to Krebs-Henseleit bicarbonate buffer perfusate throughout the experiments. Whole heart ischemia was induced through a one-way aortic valve for 15 min followed by 'reperfusion for 30 min. After induction of ischemia, the cardiac output, peak aortic systolic pressure, left ventricular dP/dtmax, and myocardial ATP concentration were greater in the treated hearts than in the untreated ones. All hearts in the untreated group developed ventricular fibrillation (Vf) at the beginning of the reperfusion period. On the other hand, no treated hearts had Vf at any time during the experiment. However, propafenone, 3 micrograms/ml, evoked a negative inotropic effect before and after ischemia. These results indicate that propafenone may contribute to early recovery from ischemia in myocardial function and metabolism, although it has a negative inotropic action.


Mechanical and energetic changes in short-term volume and pressure overload of rabbit heart. The mechanical and energetic consequences of a short-term volume overload (STVOL) hypertrophy and short-term pressure overload (STPOL) hypertrophy have been investigated in rabbits and compared with short-term sham-operated controls (STSOC). Hypertrophy was induced either by creating an aortocaval shunt (volume overload) or by banding the pulmonary artery (pressure overload). Suitable papillary muscles were excised from the hearts 8-10 days after the surgical procedure. At 27 degrees C and a stimulus frequency of 1.0 Hz, peak stress development of the STVOL preparations was significantly reduced from the control group, whereas no significant difference in peak stress development was evident between the STPOL and STSOC groups. Surprisingly, the STPOL preparations displayed pulsus alternans after only 8-10 days of inducing the overload. At steady-state conditions, the isometric 10%-90% rise times, the 90%-10% relaxation times, and the 1/2-widths were not significantly different between the treated and control groups. In isotonically contracting muscles working against a range of afterloads, the enthalpy (energy) and work output of the STVOL and STPOL preparations were depressed compared to the STSOC preparations; the differences were statistically significant for the STVOL group. Due to the parallel change in work and enthalpy, the mechanical efficiency was unaltered. A force-length-area (FLA) analysis, analogue of the pressure-volume-area (PVA) analysis, was applied to the isotonic data of this study. The isotonic enthalpy at the various load levels was plotted against the measured FLA and the data were fitted by linear regression. It was evident that the FLA correlated closely with the energy used. The STVOL and STPOL mean total energy:FLA regression lines lay parallel to but were below the STSOC line, signifying a drop in the activation heat, although this reduction did not achieve statistical significance. It is concluded that significant mechanical and energetic changes are evident after a short-term volume overload although earlier work has shown that these differences are absent at the later, compensated stage of hypertrophy. Changes associated with the pressure overload model suggest a disturbance in calcium regulation: this effect is also seen in long-term pressure overload.


Investigation of the dependence of human middle cerebral artery contractile activity on the presence of an atherosclerotic patch. In some cases, human middle cerebral artery segments reacted to vasoconstrictor stimuli, including noradrenaline, KCL, prostaglandin F2 alpha, and activated platelets and neutrophils, by showing abnormally long-term contraction. All the segments were atherosclerotic, the atherosclerotic patch constricting the lumen to 30%-50%. Vasodilator concentrations that remove the ordinary contraction of vessels, only slightly limited the abnormal spastic reaction. A positive interaction between nifedipine and prostacyclin was revealed, and their combined use had a more marked anti-spasmatic effect than when these agents were used separately.


A case of pediatric cardiomyopathy with severely restrictive physiology. A rare case of a 6-year-old male with idiopathic familial cardiomyopathy manifesting severely restrictive physiology is reported. The patient showed congestive heart failure with dilatation of both atria with a normal ventricular cavity. A square-root configuration was revealed in the ventricular pressure tracings. His elder brother had died of hypertrophic cardiomyopathy at the age of 3 years. Endomyocardial biopsy disclosed marked disorganization of muscle bundles with hypertrophy of the myocytes and interstitial fibrosis. The patient died suddenly during hospitalization. Autopsy revealed diffuse hypertrophy of both the ventricular walls and the ventricular septum with extensive myocardial disorganization and interstitial fibrosis. These advanced myopathic changes in the myocardium may have been related to the restrictive physiology in this case.


Extensive arterial calcification of unknown etiology in a 29-year-old male. A 29-year-old male with generalized arterial calcification is presented. The roentgenogram showed extensive calcification bilaterally in the facial, brachial, renal, external iliac, femoral, and popliteal arteries. There was also calcification around the joints of the fingers, toes, elbows, and shoulders. The uniformity of arterial calcification in the radiograph differentiated this lesion from Mönckeberg's arteriosclerosis. The serum concentration levels of calcium, phosphorus, alkaline phosphatase, and calcium regulatory hormones were normal. The patient did not have diabetes mellitus, renal disease, or connective tissue disease, thus the etiology of the calcification was not identified. However, a bone scintigram showed that the uptake of 99 mTc-methylene diphosphate was significantly increased in the calcified arteries. Therefore, increased metabolic activity was associated with the derangement leading to arterial calcification.


[Imaging of aortic dissection: a retrospective study of 27 patients]. Aortic dissection can be a life threatening condition which requires an early diagnosis. As initial signs and symptoms may be nonspecific and confusing, reliable imaging techniques are requested for immediate and accurate diagnosis. This retrospective study of 27 patients with proven aortic dissection assesses the relative value of angiography, CT, and MR imaging. Contribution of these imaging modalities is discussed and illustrated. Aortic dissection was correctly identified by angiography and CT respectively in 100% and 83% of the cases. MRI was diagnostic in all six examined cases. Both angiography and CT proved to be reliable imaging modalities; in addition, they can be easily performed in the critically ill patient. We consider MRI useful in the evaluation of suspected dissection in stable patients and follow-up of medical or surgical therapy.


[Follow- up of a pleural malignant mesothelioma]. A case of malignant pleural mesothelioma is presented. The initial pleural abnormalities were radiologically rather non-specific and were wrongly interpreted anatomo-pathologically as pleural metastases. Chemotherapy however resulted in an exceptional survival of more than 10 years. CT scan showed the extensive pleural damage. The histologic, symptomatologic and radiologic features of this rare tumor are discussed.


Congenital arterial anomaly in the middle ear presenting as a glomus tumor. A case of congenital agenesis of the cervical internal carotid artery with rerouting via the inferior tympanic artery and the embryonic hyoid artery to the horizontal internal carotid artery is presented. At otoscopy the anomaly simulated a glomus tumor. CT scan, by demonstration of the absence of the vertical portion of the carotid canal, the enlargement of the inferior tympanic canaliculus, and the soft tissue mass within the middle ear in continuity with the horizontal internal carotid artery, diagnosed the anomaly very accurately.


Intraarticular osteoid osteoma of the elbow. The case of a man who developed osteoid osteoma of the elbow is presented. Intraarticular osteoid osteoma of the elbow is a rare lesion presenting both diagnostic and therapeutic problems. The radiologic features of intraarticular osteoid osteoma include osteosclerosis (usually a dominant feature at initial imaging and typically enveloping the nidus), joint effusion and periosteal reaction that can involve the bone in which the osteoid osteoma arises and the adjacent bones. Awareness of these features facilitates correct diagnosis, thereby enabling timely and appropriate treatment.


[Superselective cerebral embolization of an arteriovenous malformation in the temporal lobe following partial neurosurgical resection]. We report a case of cerebral embolization of an arteriovenous malformation in the temporal lobe after partial neurosurgical resection. The lesion consisted of two compartments of which only the lateral part with combined large hematoma was resected. The medial compartment was treated by superselective embolization using a microcatheter and polyvinyl alcohol particles. Because of his psychiatric condition, general anaesthesia was used in this young male.


Obstruction of unusual origin in a small preterm baby-girl. Intussusception is a rare cause of obstruction in the neonate. The authors report the case of a preterm babygirl operated at D8 for total rupture of the distal ileum proximal to intussusception. They suggest that the great prematurity might be responsible for this lesion similar to small bowel atresia secondary to antenatal intussusception.


Pulmonary lymphangiomyomatosis.

Pulmonary lymphangiomyomatosis. We report a case of pulmonary lymphangiomyomatosis in a young female. CT--and especially high resolution CT--is more specific and sensitive than chest radiography in showing the lung abnormalities. Pathognomonic CT findings are the presence of thin walled cystic air spaces spread throughout the lung parenchyma without nodules and without regional predominance and mostly surrounded by normal parenchyma. The superposition of the multiple thin walls of the cysts is responsible for the reticular interstitial pattern observed at chest radiography.


Pictorial essay: right aortic arch.

Pictorial essay: right aortic arch. Right aortic arch is a rare congenital anomaly. It can be either an isolated finding or it can be part of a double aortic arch. This article discusses the radiographic appearance of this congenital anomaly on conventional chest X-ray, angiography, CT, and MRI.


CT imaging of soft tissue pathology of the ankle. A pictorial essay. Despite the increasing importance of MR imaging, CT investigation remains a very useful and frequently applied method in the study of ankle pathology. In a short pictorial essay, the contribution of this technique to the diagnosis of soft tissue pathology of the ankle is discussed and illustrated.


Paroxetine versus placebo: a double-blind comparison in depressed patients. Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI). The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed outpatients. A double-blind, parallel-group study was undertaken in four stand-alone centers. Patients aged 18-65 years, meeting DSM-III criteria for major depression, and having a Hamilton Rating Scale for Depression (HAM-D) score > or = 18 on the first 17 items of the HAM-D-21 were randomized to paroxetine or placebo for 6 weeks of treatment. Efficacy outcome variables included the HAM-D, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impressions Scale (CGI), and the Covi Anxiety Scale. Tolerability was assessed by asking a non-leading question. Routine laboratory safety and vital sign data from all four centers were pooled. The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed. Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables. Significant differences (p < or = .05) were found between paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4. Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor. Similar results were obtained when an adequate treatment group (therapy for > or = 28 days) was considered. A full clinical response (CGI-severity of illness score 1 or 2) was seen in over 40% of subjects. Adverse events were more common for paroxetine compared with placebo (p < or = .01). Somnolence was twice more common than nervousness. Dropout due to adverse events was similar between therapies. Paroxetine had no clinically significant effect on laboratory safety data or vital signs. Paroxetine was an effective, well tolerated, and safe antidepressant. Side effects were typical of the SSRI class of drugs. Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects.


Emergence of obsessive compulsive symptoms during treatment with clozapine. Clozapine differs from other currently available antipsychotics in its prominent serotonin blockade. We explore the relationship between clozapine and obsessive compulsive symptoms, which have been linked to deficient serotonin. We reviewed our experience in treating 49 chronic schizophrenic patients with clozapine. Five patients were identified who experienced either de novo obsessive compulsive symptoms or exacerbation of preexistent symptoms. Clinical details are provided for each case. Clozapine may produce or unmask obsessive compulsive symptoms. This may reflect a variation on the normal course of clinical improvement, or may more specifically result from clozapine's atypical pattern of CNS receptor antagonism. Further attention to this issue is warranted.


Bupropion in the treatment of bipolar disorders: the same old story? The treatment of bipolar disorders with mood stabilizing agents is complicated by breakthrough episodes of depression. Currently there are no consistently safe and effective medications for these episodes. The authors address the use of bupropion for this purpose. Bupropion was added to the treatment regimens of 3 male and 8 female patients who had bipolar disorders as diagnosed by DSM-III-R criteria and were depressed and nonresponsive to current treatment. Ten of the 11 had previously cycled into manic episodes when treated with either a tricyclic antidepressant, fluoxetine, or phenelzine. Seven of the 11 patients had moderate-to-marked improvement after 6 weeks of treatment. A moderate-to-marked improvement continued in 4 of the 11 patients after a mean of 12 months of treatment (range, 0-20 months), justifying the continuation of bupropion. Baseline Global Assessment of Functioning scores, history of previous response to other antidepressants, treatment refractoriness, comorbid diagnoses, bipolar subtype, family history, cycle length, and demographics did not discriminate between bupropion responders and nonresponders. However, 6 of the 11 patients experienced manic or hypomanic episodes that necessitated discontinuation of bupropion. Five of the 6 patients who had manic episodes had been stabilized on lithium and carbamazepine or valproate prior to the addition of bupropion. These findings, based on consecutive cases, suggest that bupropion may pose the same risks as other antidepressants in precipitating manic episodes in depressed bipolar patients. The authors conclude that caution should be exercised when using bupropion in the treatment of bipolar disorders.


Efficacy and side effects of methylphenidate for poststroke depression. Depression after stroke impedes the rehabilitation process and causes additional suffering to patient and family. Few studies have systematically examined pharmacologic treatments of poststroke depression. In the present paper, the use of the stimulant methylphenidate is studied in a depressed, elderly stroke population. Ten subjects (mean age = 73.2 years) meeting DSM-III-R criteria for major depression were followed-up during a 3-week efficacy and side effect trial involving methylphenidate. Subjects were selected from rehabilitation patients referred for psychiatric consultation. A total of 80% (8 of 10) of the subjects showed either a full or partial response as measured by Hamilton Rating Scale for Depression scores. The incidence of problematic side effects was low, and no subjects had to be discontinued from the study. Results of this methylphenidate trial for poststroke depression in elderly patients suggest that it is a safe and effective treatment for poststroke depression. Future studies are called for in which methylphenidate is compared with placebo controls and antidepressant medication.


Trends in the pharmacologic treatment of insomnia. Data from the National Disease and Therapeutic Index for the time period 1987-1991 (IMS, America) were examined for recent trends in the pharmacologic treatment of insomnia. All medications given with the desired action of promoting sleep or sedation at night were categorized as benzodiazepine hypnotics, benzodiazepine nonhypnotics, antidepressants, or other. From 1987 to 1991, the following trends were found: (1) overall pharmacologic treatment for insomnia decreased by approximately 10%, (2) use of benzodiazepine hypnotics fell about 30% during this time period, (3) use of antidepressants for insomnia increased by 100%, and (4) the noted changes were somewhat stronger for institutionalized patients than for ambulatory patients. These changes in the pharmacologic treatment of insomnia may be related to widespread media attention and are not supported by scientific data.


New epidemiologic findings about insomnia and its treatment. This paper examines several clinical concerns about the shorter half-life benzodiazepine hypnotics from an epidemiologic perspective. It draws on data from (1) 1979 and 1990 comprehensive probability-based U.S. national household surveys of the medical use of psychotherapeutic medications; (2) a 1990 four-city community-based volunteer call-in survey of the beneficial and adverse effects of hypnotics; and (3) an analogous random-digit dialing telephone survey in the general population. The issues addressed are abuse liability, rebound, depersonalization/derealization, paranoid feelings, accidents/injuries, and the unexamined consequences of the target illness in assessments of benefit-risk. In populations representative of everyday outpatient practice, we found that (1) the abuse liability of benzodiazepine hypnotics with shorter and longer elimination half-lives was generally low and comparable; (2) prevalence rates for rebound were low and not differential for flurazepam, temazepam, triazolam, and OTC sleeping pills; (3) reports of a single or an occasional experience involving depersonalization/derealization or paranoid feelings were fairly frequent in normals, in insomnia patients prior to treatment, and in persons with untreated insomnia; (4) treatment-emergent rates of occurrence for these same symptoms were low and not drug-specific; (5) past-year prevalence rates for serious accidents/injuries were much higher for chronic untreated insomnia than for normal controls and most groups treated with psychotherapeutic medications. A high proportion of past-year users of hypnotics were satisfied with their medication and would take it again.


Clinical distinctions between long-acting and short-acting benzodiazepines. After their clinical introduction in the 1960s, the benzodiazepines rapidly became the most widely prescribed sedative/hypnotics because of their many advantages over barbiturates and other older agents. Along with this popularity came controversy, which has continued to this day. The most recent form this has taken has been the concern that the short-acting benzodiazepines may have a predisposition to induce certain forms of clinical complications. The author reviews the historical framework in which this controversy arose. In the late 1970s and early 1980s, it became increasingly clear that long-acting agents were associated with daytime sedation as well as cognitive and psychomotor impairment, particularly in the elderly. The short-acting benzodiazepines, which greatly reduced the frequency of these types of effects, rapidly became the most widely prescribed agents. A growing body of data indicates that the short-acting hypnotics are less likely to be associated with falls and hip fractures in the elderly and also have less respiratory depressant qualities, compared with the older long-acting agents. The short-acting compounds may also be more efficacious in inducing sleep during the first night of administration. In contrast, the long-acting agents may be more desirable in those cases in which daytime sedation is desired and may be associated with a delayed and milder withdrawal sleep disturbance. With the short-acting agents, however, sleep disturbance upon drug cessation is dose dependent and may be greatly reduced by tapering the dose.