Haloperidol: effect of long-term treatment on rat striatal dopamine synthesis and turnover.

The short- and long-term effects of neuroleptic drugs differ both clinically and biochemically. Short-term treatment with such a drug causes a kinetic activation of striatal tyrosine hydroxylase. Long-term treatment causes a prompt activation of the enzyme which is followed by a delayed, compensatory deactivation below control levels. Tolerance also develops to the stimulating effect of haloperidol on striatal dopamine turnover.

Schizophrenia: dopamine beta-hydroxylase activity and treatment response.

Cerebrospinal fluid levels of dopamine beta-hydroxylase, found to be relatively constant over time in individual patients, were significantly lower in schizophrenic patients who became nonpsychotic during neuroleptic treatment than in those who remained psychotic. Dopamine beta-hydroxylase activity may delineate a subgroup of patients who have a dopamine-sensitive brain disorder.

Dopamine beta-hydroxylase in CSF. Relationship to personality measures.

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 32 subjects. Those individuals with a low level of DBH in the CSF had significantly elevated profiles on the Minnesota Multiphasic Personality Inventory, suggesting a relationship between the central noradrenergic system and some aspects of personality in man.

CSF dopamine beta-hydroxylase in schizophrenia.

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 30 schizophrenic patients and 27 normal controls. The CSF DBH activity in the patients was not significantly different from that in controls. Levels of CSF DBH activity in individual patients were highly constant over time and were not influenced by clinical state or neuroleptic treatment. Low levels of DBH in CSF did significantly relate to good social and sexual functioning, good prognosis, less symptoms between hospitalizations, and excellent clinical response to neuroleptic treatment. We speculate from these data that low brain DBH activity may produce a type of vulnerability to psychotic decompensation and thereby influence the clinical course, although it does not cause schizophrenia, in general. Low CSF DBH activity may delineate a "reactive" subgroup from the heterogenous population of patients with diagnoses of schizophrenia.

Dopamine-beta-hydroxylase in the cerebrospinal fluid: relationship to disulfiram-induced psychosis.

Cerebrospinal fluid (CSF) dopamine-beta-hydroxylase (DBH) activity in 32 male alcoholics was measured using a modification of the radioenzymatic method of Molinoff et al. In most, the CSF was obtained before treatment with disulfiram, while in others it was obtained while they were on the drug (250 or 500 mg). As expected, treatment with this reversible DBH inhibitor had no effect on the activity of the enzyme measured in our in vitro assay. However, low pretreatment DBH activity was found to correlate with adverse reactions to disulfiram. Mean DBH activity of four individuals who went on to become psychotic on disulfiram was 0.13 +/- 0.02 nmole/ml per hr (mean +/- SEM). An additional four individuals who developed dysphoric but nonpsychotic reactions had a mean DBH of 0.23 +/- 0.03. Both these values were significantly lower than the mean DBH activity of the remaining 24 individuals treated with disulfiram who had no adverse side effects, 0.53 +/- 0.06 p less than 0.02 and p less than 0.05, respectively, 2-tailed t-test.

Dopamine-beta-hydroxylase in the cerebrospinal fluid of psychiatric patients.

The activity of dopamine-beta-hydroxylase (DBH) in cerebrospinal fluid (CSF) from 59 psychiatric patients has been analyzed by a highly sensitive radio-enzymatic assay. There was no sex difference in DBH, but there was a significant positive correlation with age. Probenecid administration had no effect on CSF DBH. DBH in CSF correlated positively (r = 0.60) with the plasma enzyme. Among patients hospitalized for major depressive disorder, unipolar or bipolar, schizo-affective disorder, schizophrenia, alcoholism, or personality disorders there were no significant between-group differences. Among the patients with bipolar affective disorder, DBH activity from manic patients was significantly lower than that from depressed or euthymic patients. The results are discussed with reference to the theory that the amount of DBH in CSF may serve as an indicator of central noradrenergic activity.

Infections due to Lancefield group F and related Streptococci (S. milleri, S. anginosus).

We can no longer accept classification of streptococci solely on the basis of hemolytic reactions or Lancefield agglutinations. While the "viridans" streptococci cannot be serologically differentiated, physiological separation of the species offers a satisfactory method of classifying human isolates. We review the microbiology of Lancefield group F and related streptococci (S. milleri, S. anginosus), emphasizing microbial ecology and current taxonomic considerations. A series of 28 patients infected with these organisms is presented. There was a striking male predominance in the series (6:1) as well as an obvious association with underlying diseases and/or antecedent trauma. The most remarkable feature of these pathogens is their predilection for abscess formation, confirming their overdue recognition as the most common "viridans" streptococcus recovered from abscesses within internal organs. We observed purulent disease of the nervous and skeletal systems, oral cavity, lung and pleural space, abdomen and subcutaneous tissues. Microbial synergy (i.e. polymicrobic infection) was not a requisite for abscess formation. Four of the five deaths in this series occurred in patients 60 years of age of older. Some degree of variability in antimicrobial susceptibility was noted, so speciation alone may not always provide sufficient information on which to base a therapeutic decision.

Infections due to Lancefield group G streptococci.

The group G streptococcus has surfaced in the past 10 to 15 years as an important opportunistic and nosocomial pathogen. Although more precise organism recognition accounts for a portion of these cases, there can be little doubt that the group G streptococcus has become a more prevalent pathogen. Commercial kits, utilizing staphylococcal coagglutination or latex agglutination, are now available, affording all clinical laboratories the opportunity to identify this organism easily. Published reviews encompassing the experiences of a single institution or even several institutions affiliated with a single medical center, particularly as they were influenced by referral patterns, did not reflect the broad scope of infections that we discovered by extending our survey into the community, beyond the medical center complex and its immediate affiliated hospitals. Although malignancy is the single most obvious background factor, alcoholism and diabetes are also important host determinants of infection. Skin and soft-tissue infections (and surface sources of infection) are equally important among patients with or without the element of malignancy. Polymicrobial infection, including polymicrobial bacteremia, is an important feature, with S. aureus infections accounting for most of these cases, relating to the skin and soft tissue sources of infections so commonly seen. We saw a panorama of problems including endocarditis, septic arthritis, pleuropulmonary infections, bone and joint infections, puerperal sepsis and neonatal infection, peritonitis and ophthalmitis; we also saw a significant number of patients with bacteremia and no apparent primary source of infection. Response to antibiotic therapy was dictated by the nature of the underlying diseases, and individuals without a background of malignant disease did well, particularly those with skin and soft-tissue infections. While the literature suggests that patients with endocarditis and septic arthritis due to this organism respond poorly to antibiotic therapy, implying that such failures relate to in vitro antibiotic phenomena, we preferred to examine the problem from the viewpoint of the host(s) involved. Subacute endocarditis and acute endocarditis due to the group G streptococcus may be clinically separable, and thus require separate therapeutic approaches. In patients with septic arthritis, prosthetic devices, prior joint disease and immunosuppressive diseases and therapy often adversely influence the response to antibiotic therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Infective endocarditis caused by slow-growing, fastidious, Gram-negative bacteria.

In a review of endocarditis caused by fastidious, slow-growing gram-negative rods, similarities in the spectrum of disease overshadow differences among cases grouped by specific organisms. Cardiobacterium hominis, Actinobacillus actinomycetemcomitans and Haemophilus species usually seed previously damaged cardiac valves presumably during bacteremia from an upper respiratory site. The clinical presentation resembles that of Streptococcus viridans endocarditis and is usually subacute or chronic. Despite bacteriologic cure, severe CHF and/or systemic embolization frequently develops during or following the course of antibiotics, resulting in significant morbidity and a high mortality rate. This report of nine cases diagnosed at five hospitals in a 7-year period suggests that endocarditis due to these organisms is more common than previously appreciated and frequently goes unrecognized. This is probably due to a lack of attention to the requirements for culture of this group of bacteria with propensity for granular growth in broth. We have proposed specific cultural techniques appropriate to the search for these organisms in patients with apparent culture-negative endocarditis.

Infections due to Lancefield group C streptococci.

Our experience with group C streptococcal infection over the past 15 years demonstrates an important and emerging role for this hemolytic organism as an opportunistic and nosocomial pathogen. Significant risk factors in this predominantly male population included chronic cardiopulmonary disease, diabetes, malignancy, and alcoholism. Bacteremia occurred in 74% of cases seen in our series. Nosocomial acquisition of infection was observed in 26%, and infection was frequently polymicrobial in nature with gram-negative enteric bacilli isolated most commonly along with group C streptococci. We observed a broad spectrum of infections including puerperal sepsis, pleuropulmonary infections, skin and soft-tissue infection, central nervous system infection, endocarditis, urinary tract infection, and pharyngeal infections. Several cases of bacteremia of unknown source were observed in neutropenic patients with underlying leukemia. New syndromes of infection due to group C streptococci observed in our series included intra-abdominal abscess, epidural abscess, and dialysis-associated infection. Response to therapy and outcome was related to the underlying disease. While the literature suggests that patients with group C endocarditis respond better to synergistic penicillin-aminoglycoside regimens, patient numbers are too small to draw definite conclusions. The clinical significance of antibiotic tolerant group C streptococci remains uncertain. In patients with serious group C infections including endocarditis, meningitis, septic arthritis, or bacteremia in neutropenic hosts, we advocate the initial use of cell-wall-acting agents in combination with an aminoglycoside.

Left-sided endocarditis due to Pseudomonas aeruginosa. A report of 10 cases and review of the literature.

Ten confirmed cases of left-sided endocarditis due to Pseudomonas aeruginosa were reported in detail and the English literature was reviewed. In recent years, venous access (usually illicit) has been the major predisposing factor to this infection and abuse of pentazocine and tripelennamine has been particularly associated with endocarditis due to this organism. This infection involves previously damaged as well as normal valves. The development of congestive heart failure did not adversely affect the prognosis of this infection. However, the development of azotemia was associated with a greater likelihood of a fatal outcome. In the current series, deaths were due to uncontrolled infection. This often occurred despite inhibitory and bactericidal activity in serum generally considered adequate for treatment of endocarditis. Medical treatment alone rarely produced cure of infection. Our experience with a high frequency of major vessel embolization (4/10) and the improved survival after medical/surgical treatment suggests that prompt valve replacement combined with high doses of an aminoglycoside plus carbenicillin or ticarcillin provide the best opportunity for successful outcome in patients with left-sided endocarditis due to P. aeruginosa.

Haemophilus influenzae meningitis: the spectrum of disease in adults.

Fifteen cases of Haemophilus influenzae (HI) meningitis in adults occurring of Cleveland during the last 11 years are presented. The majority of patients had factors predisposing to infection such as otitis, pneumonia, diabetes or alcoholism. In addition, 7 of the 15 patients developed meningitis at various intervals following head trauma and neurosurgery, and 3 patients required dural repairs for CSF rhinorrhea. The diagnosis of meningitis may be difficult to establish resulting in delay in appropriate therapy in some cases. Nuchal rigidity was absent frequently; CSF lymphocytosis can be seen initially. The CSF Gram stain may be negative or the pleomorphic nature of the organism on Gram-stain may make distinction from other gram-negative organisms difficult. The majority of patients had meningitis due to non-Type B HI in contrast to previous reports of this illness in children and adults. One of our patients had beta-lactamase producing HI isolated from CSF. We believe that chloramphenicol should be included in the initial empiric therapy for adults with meningitis and gram-negative coccobacillary rods on Gram-stain or negative CSF Gram-stains.

Arteritis of the aged (giant cell arteritis) and fever of unexplained origin.

Arteritis of the aged (giant cell arteritis) masquerades as a degenerative, infectious, neoplastic or even functional disorder in the elderly. In the absence of obliterative vascular changes, the diagnosis is often overlooked when too rigid diagnostic criteria are employed. Four elderly women presented with fever of unexplained origin as the initial manifestation of this disease. The temporal arteries were conspicuously normal in all four, and other traditional clinical clues, such as visual disturbances, headache or manifestations of polymyalgia rheumatica were likewise infrequent of entirely absent. Influenza immunization and uncomplicated rectal surgery preceded the onset of illness in two. Anemia and an increased erythrocyte sedimentation rate are important diagnostic features, particularly in the face of spontaneous clinical improvement accompanied by defervescence and disappearance of nonspecific liver dysfunction. Occult intestinal perforation complicated steroid therapy in one case. Significant and sometimes hectic fever may be a common pattern for this arteritis in its earliest stages, when palpably abnormal temporal arteries, obliterative vascular changes and other traditional diagnostic clues are more likely to be absent.

Legionnaires' disease. Association with severe bronchospasm and hypoventilation.

A 31-year-old man with legionnaires' disease, who presented with severe pneumonia and hypoxemia, later developed severe bronchospasm and marked hypercapnia, a complication not previously reported in Legionella infection. He responded to therapy with erythromycin and a bronchodilator.

Capnocytophaga bacteremia in the compromised host.

Capnocytophaga, a CO2-requiring gram-negative bacillus, is a recently recognized pathogen in the immunocompromised host. The authors present two cases with granulocytopenia, oral disease and bacteremia with Capnocytophage ochracea. The microbiology of this genus, its clinical association with periodontal disease, granulocytopenia and oral ulceration, and its implications for the compromised host are reviewed.

The lumpy jaw. Cervicofacial actinomycosis.

Cervicofacial actinomycosis is a unique polymicrobic infection of endogenous origin, displaying a highly variable clinical course, ranging from an acute, suppurative lesion to a chronic fibrotic process more suggestive of a malignancy. Lesions advance with total disregard for tissue planes, producing burrowing sinus tracts to the skin or mucosal surfaces, which often discharge sulfur granules, colonies of Actinomyces species cemented together by host phosphatase activity. The diagnosis is quite elusive when proper studies (anaerobic culture, careful tissue examination and fluorescent antibody stains) are not undertaken in a timely fashion. Most cases respond well to a prolonged course of antimicrobial therapy. Some patients require excision of fibrotic lesions or persistent sinus tracts. Penicillin G is considered the agent of choice on the basis of extensive clinical experience; tetracycline, erythromycin, and clindamycin are effective as alternative agents.

Dopamine-beta-hydroxylase in cerebrospinal fluid and plasma: effects of alpha-adrenergic agents.

Dopamine-beta-hydroxylase (DBH) and norepinephrine are both localized in noradrenergic storage vesicles. When noradrenergic nerves fire, both norepinephrine and DBH are released by exocytosis. DBH released from the peripheral nervous system and the adrenal medullae is found in blood, while DBH in cerebrospinal fluid (CSF) is presumably of central origin. This study was designed to: (1) investigate the effect of drugs which alter central noradrenergic activity on DBH activity in CSF; and (2) compare the effects of these drugs on DBH in CSF and plasma in cats. Phenoxybenzamine was given subcutaneously at 6 mg/kg and DBH was measured 8 h later. This treatment significantly increased DBH activity in CSF (n = 10,P less than 0.005). There were no consistent changes in plasma DBH, although there was a tendency for DBH to increase from low basal levels and to decrease from high basal levels. Clonidine was administered in 4 subcutaneous injections (100, 50, 50, 50 microgram/kg) over a 19-h period, and blood and CSF were taken 5 h after the last injection. This treatment caused a significant decrease in CSF DBH activity (P less than 0.05, n = 8). The effect of clonidine on plasma DBH was strongly dependent on the basal enzyme level. The 3 lowest DBH values increased and the 5 highest DBH values decreased on drug treatment. These results are discussed with respect to the theory that changes in CSF DBH may reflect central noradrenergic activity.

Differential effects of DL-propranolol on norepinephrine in cerebrospinal fluid and plasma.

Acute administration of DL-propranolol (5 mg/kg, subcutaneous) to cats caused a significant increase in cerebrospinal fluid (CSF) norepinephrine and a significant decrease in plasma norepinephrine. This increase in CSF norepinephrine is probably due to a reflex increase in central noradrenergic firing after beta blockade. The decrease in plasma norepinephrine reflects decreased sympathetic outflow. These results are consistent with the centrally mediated hypotensive effects of the drug.

Central noradrenergic adaptation to long-term treatment with imipramine in rhesus monkeys.

Rhesus monkeys were treated with the antidepressant drug imipramine; cerebrospinal fluid norepinephrine and dopamine-beta-hydroxylase were measured to assess central noradrenergic activity. Large changes occurred after short-term, but not long-term, treatment. Biochemical stabilization occurs at the time when therapeutic effects are seen in patients.

Neurologic complications of infective endocarditis.

Neurologic complications continue to occur in approximately 30 per cent of all patients with infective endocarditis and represent a major factor associated with an increased mortality rate in that disease. Of these complications, cerebral embolism is the most common and the most important, occurring in as many as 30 per cent of all patients, most of whom ultimately die. Emboli that are infected also account for all the other complications (mycotic aneurysm, meningitis or meningoencephalitis, brain abscess) that may develop. Emboli are more common in patients with mitral valve infection and in those infected with more virulent organisms. Mycotic aneurysms (often preceded by an embolic event) occur more frequently and earlier in the course of acute endocarditis, rather than later, which is more common in the course of subacute disease. The management of a cerebral mycotic aneurysm depends on the presence or absence of hemorrhage, its anatomic location and the clinical course. Healing can occur during the course of effective antimicrobial therapy and thus will preclude the need for automatic surgery in all angiographically demonstrated aneurysms. The indication for surgical intervention must be evaluated on an individual basis. Meningitis is usually purulent when associated with virulent organisms, but the CSF may present an aseptic formula when associated with subarachnoid hemorrhage or multiple microscopic embolic lesions, infected or otherwise. Macroscopic brain abscesses are rare, but multiple microscopic abscesses are not uncommon in patients with acute endocarditis due to virulent organisms. Seizures are not uncommon in patients with infective endocarditis. Focal seizures are more commonly associated with acute emboli, whereas generalized seizures are more commonly associated with systemic metabolic factors. Penicillin neurotoxicity should be considered in seizure patients with compromised renal function who are receiving high doses of penicillin. The CSF tends to reflect the nature of the infecting organism rather than the nature of the neurologic complication, except when hemorrhage is present. Endocarditis due to virulent organisms, such as Staphylococcus aureus, is usually associated with a purulent CSF formula, whereas non-virulent organisms, such as "viridans" streptococci, usually have aseptic or normal CSF formulas.