Subacute demyelinating polyneuropathy responding to corticosteroid treatment.

Ten patients with subacute demyelinating neuropathy responded satisfactorily to corticosteroid treatment. The most prominent features in these cases were (1) subacute progression of diffuse polyneuropathy over weeks and months, (2) high spinal fluid protein level, (3) marked nerve conduction abnormalities, and (4) high rate of relapse. The sural nerve biopsy specimen showed "demyelinating neuropathy." This subacute demyelination neuropathy appears to be a distinct and clinically identifiable entity in which corticosteroid treatment is indicated.


Periventricular leukomalacia in adults. Clinicopathological study of four cases.

The pathological findings in four patients with courses characterized by acute coma and respiratory insufficiency occurring in obscure circumstances are presented. Carbon monoxide intoxication was excluded. After an early partial recovery from coma, the patients remained in a persistent vegetative state, with a tetrapyramidal syndrome. Pathologic changes consisted of infarction and demyelination of periventricular white matter, with associated necrotic foci in the basal ganglia in some cases. We propose that the prolonged hypoxia and ischemia produce a "no reflow" phenomenon causing brain edema (more pronounced in the white matter); this resulted in infarctions of white matter in the periventricular arterial end and border zones.


Fink-Heimer/Nauta demonstration of regenerating axons in the rat spinal cord.

Six months after complete spinal cord transection, regenerated descending motor axons can be found by electrophysiologic testing and can also be demonstrated anatomically using the Fink-Heimer/Nauta technique. Regeneration was found in all animals, treated or control, but statistically significant increased regeneration as measured by the Fink-Heimer/Nauta technique was found in animals treated with a single injection of 75 mg/kg of cyclophosphamide 24 hours after the original spinal cord transection. This result is similar to those of another study using the orthograde axonal transport of tritiated proline as a measure of axonal regeneration. The mode of action of cyclophosphamide may be by its immunosuppressive properties because this drug is most effective when administered 24 hours after cord transection, a time when its effects as an immunosuppressant would be maximal.


Modulation of CSF production by alterations in cerebral perfusion pressure.

The rate of CSF production in cats was studied in relation to changes in intracranial pressure (ICP), systemic arterial pressure (SAP), and the resultant alterations in cerebral perfusion pressure (CPP). When ICP is raised to the point where CPP falls below 55 mm Hg, CSF production will diminish. Elevation of ICP does not appear to influence CSF production rate if CPP is maintained above 70 mm Hg.


Jamaica ginger paralysis. Forty-seven-year follow-up.

In 1930, thousands of Americans were poisoned by an illicit extract of Jamaica ginger ("jake") used to circumvent the Prohibition laws. A neurotoxic organophosphate compound, triorthocresyl phosphate (TOCP), had been used as an adulterant. The earliest reports were of peripheral neuritis, but later it was evident that an upper motor neuron syndrome had supervened. This TOCP poisoning apparently involved various cell groups and tracts in the spinal cord; the lesions was not peripheral at all. We interviewed 11 survivors of the illness residing in eastern Tennessee. Four were carefully examined. The principal findings showed the spasticity and abnormal reflexes of an upper motor neuron syndrome. One patient had mild disease, despite typical findings, and had lived a normal life.


Intracranial neoplasms in infants.

Fifty-four primary intracranial neoplasms occurred in infants (18 months of age or younger) in Connecticut during a 40-year period, 1935 to 1974. Thirty percent were medulloblastomas and 16% were ependymal neoplasms. An equal number of males and females were affected. Forty percent were located in the cerebellum, 37% in the cerebral hemispheres, and 17% in the brain stem. The most common symptom was vomiting. Abnormally large head circumference was the most common physical finding. Average survival was 43 months. Survival relative to histopathologic type and location of the neoplasm is discussed. Eighteen patients survived longer than one year and the level of neurological function of these longer survivors is presented.


Delayed cerebrovascular consequences of radiation to the neck. A clinicopathologic study of a case.

A man had a stroke 27 years after radiation therapy to the neck for treatment of laryngeal papillomas. There were premonitory symptoms suggesting cerebral ischemia. In contrast to many previously reported cases, in our patient there is a strong relationship between radiation therapy and stroke. Pathoanatomic study of the surgical vascular specimen strongly suggests that radiation is a potentially modifiable cause of delayed stroke.


External hydrocephalus. Early finding in congenital communicating hydrocephalus.

Dilation of the subarachnoid channels overlying the cerebral hemispheres, ie, external hydrocephalus, can be an early anatomic-radiologic finding in some infants with congenital communicating hydrocephalus. This structural change may progress to ventricular dilation or internal hydrocephalus. Enlargement of the subarachnoid channels appears to occur during the first stage in the development of congenital communicating hydrocephalus, which is to say that the subarachnoid compartment allows accumulation of CSF before there is significant ventricular distention, at least in some infants. When a pneumoencephalogram or a CT scan is performed at this stage, the findings may falsely suggest "cerebral atrophy." In six patients who received this grave neuroradiologic diagnosis, five subsequently developed normally and the sixth has static incoordination or clumsiness and mild intellectual deficiency.


Hemifacial spasm due to aneurysmal compression of the facial nerve.

Hemifacial spasm developed in a woman as the only symptom of an aneurysm of the posterior inferior cerebellar artery. Using microdissecting techniques, the aneurysm was clipped and moved from its distorting position at the brain stem exit zone of the seventh nerve. After surgery, she experienced immediate relief of her facial spasm of six years' duration. This case supports the finding that hemifacial spasm may be caused by vascular lesions of the seventh nerve at the brain stem junction. Recent surgical experience indicates that the majority of the hemifacial spasm cases may be due to normal but ectatic blood vessels that cross-compress the most proximal portion of the seventh nerve. Relief may be affected without facial paralysis by a retromastoid microvascular decompressive procedure.


Depletion of serum hemopexin in fulminant rhabdomyolysis. Evidence for an interaction of hemopexin with myoglobin-derived heme.

Hemopexin is a normal serum glycoprotein that functions as a carrier for intravascularly liberated free heme. Although its role is well established in the reutilization of hemoglobin-derived heme, there have been no previous clinical data to support its suspected interaction with heme released in the degradation of myoglobin. In a patient with fulminant rhabdomyolysis, we found depletion of serum hemopexin in the presence of high serum levels of myoglobin with normal levels of haptoglobin and hemoglobin. This combination of laboratory findings is evidence for an interaction between myoglobin-derived heme and hemopexin and implies a role for hemopexin in the catabolism of myoglobin. These findings support the proposed induction mechanism for observed increases of serum hemopexin in Duchenne muscular dystrophy and in polymyositis.


Progressive chorioretinopathy after receiving thioridazine.

A distinctive appearance of the ocular fundus as a late complication of high doses of orally administered thioridazine hydrochloride (Mellaril) is described. Discrete nummular areas of loss of retinal pigment epithelium (RPE) extended from the posterior pole to the midperiphery. Fluorescein angiography demonstrated loss of choriocapillaris in these zones. Atrophy of the remaining RPE was progressive, with advancement of the edges of the atrophic zones and breakdown of bridges of RPE separating them. Atrophy occurred after discontinuation of the drug and advanced without further exposure to it. Dark adaptation, the electroretinogram, and the electro-oculogram were abnormal in the late stages. Central visual acuity remained relatively good.


Reticular dystrophy of the retinal pigment epithelium. A clinical and electrophysiologic study of three generations.

Reticular dystrophy of the retinal pigment epithelium is characterized by a posterior pattern of pigment clumping like a "fishnet with knots." Four patients in three successive generations were seen with typical reticular dystrophy. A fifth patient had abnormal dark adaptation. In this family reticular dystrophy was characterized by the typical reticular pigmentary pattern, good visual acuity, normal electroretinographic findings, abnormal electro-oculographic findings, and abnormal dark adaptation. The pedigree indicates autosomal dominance as the inheritance pattern.


X-linked ocular albinism in Blacks. Ocular albinism cum pigmento.

X-linked ocular albinism can be an unsuspected cause of congenital nystagmus in blacks. In this study, eight of ten black ocular albinos from two kindreds had nonalbinotic, moderately pigmented fundi and no transillumination of the iris. We refer to this paradoxical condition as "ocular albinism cum pigmento." The only constant ophthalmoscopic feature was a foveal hypoplasia. Biopsy of clinically normal skin to demonstrate giant pigment granules is the most accurate means of diagnosis.


Heterogeneity in Waardenburg's syndrome. Report of a family with ocular albinism.

A family had the following manifestations of Waardenburg's syndrome (WS): prominent nasal root, white forelock, premature graying of the hair, freckled pigmentation of pale skin, hypoplastic heterochromia irides, heterochromia of the ocular fundi, congenital sensorineural hearing loss, and autosomal dominant heredity. This family differs from those previously reported in that none of its members showed dystopia of the inner canthi or lower puncta. In addition, four siblings had the combination of hyperopia-estropia-amblyopia, as well as ocular albinism, manifested by foveal hypoplasia and transilluminable irides. Observations on this family support prior suggestions of heterogeneity in WS.


Dysthyroid optic neuropathy. Clinical profile and rationale for management.

Dysthyroid optic neuropathy (DON) was diagnosed in 36 eyes of 21 patients with progressive visual loss and congestive ophthalmopathy. Systemic features in the patients with DON did not differ from those reported for Graves' disease patients except that patients with DON were older (mean age, 61 years) and did not show female preponderance. Congestive symptoms always preceded visual loss, which was gradual in onset and bilateral in most patients but acute and asymmetrical in several. Presenting acuities were poorer than 20/60 in 50% of cases; central scotomas, sometimes combined with inferior depression, were the predominant field defects. Congestive signs were of moderate intensity without severe proptosis or exposure keratopathy. Bilateral and symmetrical ductional restriction was the most common motility disturbance. Oral corticosteroids were effective in restoring visual function in ten of 21 eyes treated. Many steroid-unresponsive eyes were improved promptly by supervoltage orbital irradiation or surgical decompression. In general, therapeutic intervention appeared to hasten recovery and improve visual outcome.


Quantitative perimetry in compressive optic neuropathy and optic neuritis.

The Goldmann perimetric defects in 20 cases of compressive optic neuropathy and 54 cases of optic neuritis were analyzed. While defects involving the papillomacular bundle were the rule in both compressive and neuritis cases, sparing of the fixational area occurred in 24% of neuritis eyes but in none of the eyes with compressive neuropathy. The most reliable differential perimetric sign was the presence of a hemianopic defect; at least one eye of 15 (75%) cases of compression showed such a defect, which was not found in any neuritis cases. The I2e was the largest kinetic isopter to demonstrate the hemianopic defect in a substantial proportion of cases. These defects were corroborated with sequential static presentation of the I2e to I4e stimuli to either side of the vertical meridan, and with similar techniques using 18/1,000 red test objects at the tangent screen.


Specular microscopy of epithelial downgrowth.

Specular microscopy in a case of pathologically proved epithelial downgrowth demonstrated a characteristic pattern of cell borders in the area of the epithelial downgrowth. This noninvasive clinical test may prove to be helpful in the early diagnosis of epithelial ingrowth following various intraocular surgical procedures.


Effect of long-term wear of hard contact lenses on corneal sensitivity.

The effect of years of wear of hard contact lenses on corneal sensitivity has been evaluated. By testing 91 subjects who had worn lenses for up to 22 years and a control group of 42 people, it was found that corneal sensitivity diminished exponetially. However, in five subjects who had abandoned use of their lenses, recovery occurred within four months, indicating that the process is reversible. The loss of corneal sensitivity with hard contact lens wear ought to be heeded, since the eye is thus at a greater risk of infection.


Acquired Brown's syndrome of inflammatory origin. Response to locally injected steroids.

In a recent large series of tendon sheath syndrome, Brown reported only five cases of the pure acquired type that were not intermittent and in which the patients did not undergo spontaneous recovery. The origin of acquired Brown's syndrome is varied and includes trauma of the orbit, direct trochlear trauma, orbital or muscle surgery, frontal sinusitis or sinus surgery, and inflammation of the superior oblique tendon and sheath, namely a stenosing tenosynovitis. The differential diagnosis and possible causes of the acquired Brown's syndrome were reviewed, and two cases of presumptive tenosynovitis of the superior oblique tendon and sheath are presented in detail. In both cases, the condition of each patient was notably improved by a series of direct injections of methylprednisolone acetate into the trochlear region. This form of treatment for acquired Brown's syndrome of inflammatory origin has never, to my knowledge, been reported in the literature.


Isolated oculomotor paralysis. The product of saccular and fusiform aneurysms of the basilar artery.

Isolated oculomotor paralysis was produced by an unsuspected saccular basilar aneurysm in one case and fusiform basilar aneurysm in another. The chronicity of symptoms and lack of pain were misleading features. The saccular basilar aneurysm, which has an untreated mortality of 50% to 80%, was visualized best with selective angiography and successfully clipped intracranially. The fusiform basilar aneurysm, part of a diffuse atherosclerotic ectasia of all basal intracranial arteries, indented and displaced the upper brain stem. A common ophthalmologic sign of posterior communicating aneurysms, oculomotor paralysis has not been documented frequently with basilar aneurysms.


Cysticercosis of the eyelid.

A 14-year-old girl had a four-month history of a painless, enlarging mass in the right upper eyelid. Histopathologic examination revealed the cystic mass to be Cysticercus cellulosae, the larval form of Taenia solium. This patient had been in Vietnam and Laos several years previously and, while there, developed a flu-like syndrome. Despite the fact that she was asymptomatic for the two years preceding her clinical examination, the histopathologic diagnosis of C cellulosae prompted an extensive medical and neurologic work-up to rule out the possibility that the patient harbored the adult tapeworm or other larval forms. Fortunately, the results of this survey were negative.


Ocular penetration of topical chloramphenicol in humans.

Commercial ophthalmic chloramphenicol solutions and ointments were applied to human eyes, and the concentrations of chloramphenicol in aqueous humor and tear samples were analyzed using gas-liquid chromatography. Within several minutes after a single application of 0.5% chloramphenicol solution, the tear concentrations of the drug had fallen below 1 mg/liter, the minimal bacteriostatic concentration for many ocular pathogens. Repeated drops of 0.5% chloramphenicol solutions during several hours were required to produce an aqueous humor concentration of 1 mg/liter. A single application of 1% chloramphenicol ointment gave prolonged drug concentrations in the tears and aqueous humor, falling to 1 mg/liter in two to four hours. The repeated use of chloramphenicol solution or ointment was well tolerated by the patients. We conclude that the penetration of chloramphenicol in the anterior segment of the eye is best carried out by the repeated application of chloramphenicol ointment.


Pediatric intraocular knife.

An intraocular knife was developed that is of fine sharpness and small size to permit easy use in the eyes of young children.


Indications for radical neck dissection following radiation therapy.

The recent trend has been away from elective neck dissection in the management of patients with cancer of the head and neck. In addition, improved techniques of radiation therapy have demonstrated their capacity to eliminate and sterilize occult and even frank neck metastases. An unselected series of 409 radical neck dissections performed in 357 patients in a period of eight years has been critically reviewed to determine the incidence of microscopically negative nodes in patients who were previously radiated for cure and in whom a neck dissection had been performed as a part of the surgical procedure. Findings and results support our current position that a neck dissection in the presence of clinically negative nodes, particularly when they were never previously present, need not be included in the surgical procedure designed to salvage patients following radiation failure. Because of the documented increase of postoperative complications following such surgery, the decrease in morbidity and mortality seems to justify this policy.


Human otoconia in surgical specimens.

The utricular otoconia of four patients, which were removed during surgical procedures (one for an eighth nerve section operation and three for removal of acoustic neuromas) with the use of the translabyrinthine approach, were observed with the scanning electron microscope. The otoconia of these patients showed some abnormal features. In three of the four patients, a number of otoconia were found to have cracked lines. One of these patients was a 14-year-old boy; the other patients were more than 40 years old. In the remaining case, the otoconial facet surfaces were rough, and a few otoconia were unusually shaped.


Double-sliding genioplasty for correction of severe micrognathia.

Profile correction of cosmetically deforming micrognathia in patients with functional occlusion may be attained by the foreshifting of multple horizontal oblique osteotomy segments of the anterior mandible. We discuss the development, limitations, advantages, preoperative evaluation, and surgical technique of this method.


Reliabilities of air and water caloric responses.

Air is a safer and more convenient caloric-irrigating medium than water, but many otologists are reluctant to use it because they suspect that it yields less reliable nystagmus responses. To compare reliabilities of air and water caloric responses, we subjected eight normal persons to 12 irrigations each of 50 degrees C air, 44 degrees C water, 24 degrees C air, and 30 degrees C water. Standard caloric-testing conditions were used, and nystagmus responses were recorded by the method of electronystagmography. We found that the reliabilities of air and water caloric responses were not significantly different. A single observation permitted estimation of response strength within approximalely +/- 5 degrees/sec (95% confidence level), regardless of whether air or water was used as the irrigating medium.


Intraoral augmentation mentoplasty with a hinged silastic implant.

Considerable concern has been expressed in the past ten years of bone resorption secondary to alloplastic chin implants. Therefore, I describe a modification of the surgical technique and a type of implant. Twenty-five patients underwent augmentation metoplasty for moderate to severe microgenia during the past three years. Surgery was performed with insertion of a modified type of Safian's solid silicone implant with triangular wedges that were removed on the posterior surface, and the spaces that were created were replaced with soft, pore-closed, whit silicone sponge. All implants were inserted intraorally, since the central body was supraperiosteal, and the lateral extensions were subperiosteal. Two implants of the 25 cases were removed postoperatively because of infection. Nine patients were followed up for one to three years postoperatively with serial xerographic analysis of the chin implants.


Stapedectomy for otosclerosis with malleus fixation.

Malleus fixation, in addition to stapes fixation, presents a perplexing surgical problem. Should the incus replacement prosthesis procedure be performed or only a stapedectomy? The hearing results of a stapedectomy alone in 45 cases with both stapes and malleus fixation are 70% within 10 dB and 84% within 20 dB of the preoperative bone conduction hearing level.


Effect of age on prediction of sensorineural hearing level from the acoustic reflex.

To study the effect of age on prediction of hearing level from the acoustic reflex, we compared reflex prediction with the actual hearing level in 505 patients. The following three age groups were defined: 130 children aged 2 to 12 years; 158 young adults aged 20 to 40 years; and 217 old adults aged 60 to 90 years. Prediction was substantially more accurate in the children's group than in either adult group.


Neuroblastoma of the head and neck.

We reviewed 105 cases of neuroblastoma, which were seen at the Buffalo Children's Hospital between 1936 and 1976. We describe seven patients with primary neuroblastoma of the head and neck. The results of postmortem examination in two of these patients proved without any doubt that the tumor was primarily in the head and neck region. Although metastasis of neuroblastomas to the head and neck from more common primary sites in the abdomen, pelvis, or thorax is common, to our knowledge, well-documented primary head and neck lesions are quite rare. The prognosis of invasive neuroblastoma of the head and neck is poor, with rapid and widespread metastasis being the rule. However, some success has been reported with early and massive therapy that involves surgery, chemotherapy, and radiation therapy.


Primary tumors of the external and middle ear. III. A clinicopathologic study of embryonal rhabdomyosarcoma.

Embryonal rhabdomyosarcoma of the middle ear-mastoid is a highly lethal neoplasm of childhood in most cases, which clinically simulates a chronic infection. Extensive hemorrhage and necrosis in the biopsy specimen may obscure and often delay the diagnosis. Two of the six embryonal rhabdomyosarcomas in this study showed histologic evidence of differentiation. These same two patients were the only long-term survivors. Similar examples of "differentiated" embryonal rhabdomyosarcomas of the middle ear-mastoid with prolonged survival have been recorded individually in the literature. Therapeutic implications of this finding have been discussed.


Auditory and vestibular damage in head injuries at work.

A series of 50 unselected patients who reported a head injury to the Workers' Compensation Board of British Columbia were referred to the AudioVestibular Unit of the Vancouver General Hospital for studies of auditory and vestibular function. All patients were interviewed and examined by a neuro-otology team during the course of their investigation. It was found that dizziness was the most common symptom of which they complained (60%), and bleeding from the ear was the least common (4%). Of the 50 patients studied, 32% showed evidence of either auditory and/or vestibular injury. Of the total number studied, 16% had auditory injuries and 26% had vestibular injuries. The most common auditory injury was unilateral partial loss of hearing. Central vestibular dysfunction was the most common vestibular injury. A study of the most effective means of selecting patients from the population with head injuries for referral for audiology and vestibular testing was undertaken. The most effective combination of symptoms for referral is the presence of one or more of the triad: hearing loss, unsteadiness, or loss of consciousness/amnesia.


Impedance audiometry in serous otitis media.

The relationship between the results of impedance audiometry and middle ear effusion in serous otitis media was examined in 76 ears immediately prior to myringotomy. Tympanometry and acoustic reflex threshold showed the highest correlation with the operative findings relative to middle ear effusion. The combination of tympanometry and acoustic refex threshold was superior to the use of either component alone. Results are discussed in terms of clinical implications with specific consideration of hearing screening programs.


Papillomatosis of the respiratory tract. Upper airway obstruction and carcinoma.

Metastasizing squamous cell carcinoma of the lung developed in a patient who had juvenile papillomatosis but had had no previous radiation therapy. At the same time, a significant upper airway obstruction was present. All endobronchial lesions rapidly resolved with radiation therapy, and the carcinoma was resected.


Clinical rationale for using an overhead speaker in evaluation of hearing aids.

A variable that has received little attention in the psychoacoustic evaluation of the hearing aid is the position of loudspeakers with respect to the listener, particularly the azimuth of the loudspeaker, which is used for presenting the competing message. In the past, a variety of locations have been used, some of which can bias the outcome of the evaluation. For this reason, this article suggests the use of an overhead speaker to deliver the competing signal. The overhead placement provides a neutral location that is highly desirable for making reliable repeated speech performance comparisons. In addition, the overhead speaker can be easily adapted to the testing environment while it produces the effect of surrounding the listener with the competing signal.


Developmental changes of susceptibility to auditory fatigue in young hamsters.

Susceptibility to auditory fatigue was studied in young hamsters by using an evoked-potential criterion of sound-induced threshold shift. Animals aged 15, 28, 40, 54 and 85 days were anesthetized and stimulated with a continuous tone (3 kHz, 110 dB SPL) for 10 min. Threshold shifts 1 min post-exposure were highest in animals aged 40 days, and lowest in animals aged 15 or 85 days. Threshold shifts recovered within 100 min in 15- and 85-day-old animals, but required considerably longer to recover in the other age-groups. The data suggest that young hamsters pass through a critical period of susceptibility to auditory fatigue. Comparison of this critical period with various indices of the development of hearing in the hamster suggests that the developmental events underlying the critical period do not occur in the middle ear.


An immunologist's view of viral disease.

Immunologists see viral infection as a struggle between host defences and viral invasion. The outcome of such invasion may be sub-clinical or self limiting clinical infection or a less favourable outcome with chronicity, "slow virus" disease, autoimmunity or malignancy. A limited number of immune manipulations are possible in viral disease--immunization, immune enhancement with transfer factor or levamisole. An understanding of immune defences is vital at a time when antiviral chemotherapy is still so poorly developed.


Reverberation as a parameter in clinical testing.

Word identification was measured binaurally and monaurally using the Modified Rhyme Test under noise and reverberation. Normally hearing and hearing-impaired subjects were tested. A change in reverberation time from 0.25 to 0.50 s in a small audiometric room caused a significant change in word identification scores in both groups of subjects. A simulated reverberation composed of five distinct reflections did not affect word identification. The binaural advantage (difference between the binaural and monaural scores) was significant for normally hearing subjects, while it was not significant for hearing-impaired subjects.


Latency of brain stem responses to chirps (linear frequency-ramp bursts). Relationship between certain physical parameters of the stimulus and nervous activity.

The latency of Jewett wave V to 4-kHz tone (T) bursts was first studied on 55 normally hearing ears. In another group of 31 subjects, shift in latency was investigated as a function of certain physical parameters of the stimulus. Using T bursts and chirps--frequency-ramp (FR) bursts of 6 ms duration with an interstimulus interval of 33 ms and a constant attenuation, we noticed that (1) in all subjects, wave V latency was greater with ascending FR bursts than with descending ones; (2) in all subjects with even slight sensorineural hearing losses, the difference in latency between 1-kHz T bursts and 1- to 2-kHz FR bursts was less than that between 2-kHz T bursts and 2- to 4-kHz FR bursts, and (3) in subjects with normal internal ears on standard audiometry, the converse occurred, except in 4 subjects in a group of 6 who had been exposed to loud impact noises. Possible underlying mechanisms are discussed.


Surface-recorded cochlear microphonic potentials during temporary threshold shifts in man.

Cochlear microphonic potentials (CM) were recorded, by means of surface electrodes, before, during and after white-noise-induced temporary threshold shifts (TTS) in human volunteers. The behavioural threshold shift was not accompanied by a change in amplitude of CM. These findings indicate that in humans, the site affected by the noise exposure and which probably gives rise to the TTS is central to the site of generation of CM. In a previous study, the compound action potential generated in the auditory nerve was found to be of lower amplitude and longer latency during TTS, and it is thus proposed that the site affected is peripheral to the generation of conducted action potentials. The synapse between hair cells and the auditory nerve fibres is the most likely candidate to be the affected site.


Antibiotics: their true place in the treatment of viral disease.

The use of antibiotics in viral diseases of childhood is discussed. If bacterial infection is likely, either as superinfection or as part of the differential diagnosis, then antibiotics should be given. The antibiotic of choice for each illness is considered. Respiratory infections are common. The diagnosis and treatment of streptococcal pharyngitis is compared with viral pharyngitis. Penicillin is indicated if the bacterial infection is possible. If there is difficulty in distinguishing between croup and epiglottitis, then chloramphenicol or ampicillin should be given. Otitis media and pneumonia caused by viruses are difficult to differentiate from their bacterial counterparts, and antibiotics are indicated. By contrast, antibiotics are not used in bronchiolitis or asthma. Antibiotics are contraindicated in gastroenteritis even if caused by bacteria. Prolongation of the carrier state or superinfection may then occur. Interpretation of the biochemical and bacteriological findings of the cerebrospinal fluid is important in distinguishing viral meningitis and encephalitis from bacterial meningitis. If bacterial meningitis is possible, then antibiotics should be used. The indications for antibiotics in viral diseases of the skin, eye, joints, heart and parotid are also discussed.


[Impedancemetric study of the variations of the auditory reflex in man as a function of age (author's transl)].

The author has used the electroacoustic impedance bridge to study the variation of the auditory reflex in normally hearing subjects as a function of age. The parameters tested were essentially the rise time and the recovery time as well as the amplitude of the reflex response at frequencies of 1 000 and 2 000 Hz after ipsilateral and contralateral stimulation. The influence of age was found to be significant for the recovery time and the amplitude of response. The relationship between the rise time and the recovery time was found to be constant. These standards established as a function of age will facilitate the differentiation of normal from pathological responses.


Workload in rural practice: implications for education and health service structure.

In view of the reported maldistribution of medical manpower in Queensland, this study was undertaken to establish the effects of such a maldistribution on the workload and range of work performed by rural practioners. Rural practitioners were found to have a higher patient contact rate per week, and to perform more surgery and obstetrics than do their city counterparts.


Voluntary vacation attachments to rural general practitioners: experience with pre-clinical medical students.

In view of the continuing maldistribution of medical manpower away from rural practice, a voluntary vacation rural general practitioner attachment scheme was established for pre-clinical students. The responses of the students and preceptors to these attachments are discussed.


Protein and DNA levels in the submandibular salivary glands of isoproterenol stimulated mice.

The DNA and soluble and sedimental protein levels were studied in isoproterenol stimulated mouse submandibular salivary glands over a period of 200 h. Hypertrophy, the predominant cellular phenomenon following chronic isoproterenol treatment, was associated with a marked elevation of 14C-leucine incorporation into the buffer soluble protein fraction and a less pronounced isotope incorporation into the sedimental sub-cellular fraction as well as continued DNA synthesis. These findings are contrary to the accepted definitions of hypertrophy which preclude continued DNA synthesis. A suggestion is made, therefore, that in the system used the polyploidy associated with the hypertrophy involves.


The contribution of the acoustic reflex to the ascending-descending most comfortable loudness gap.

The contribution of the acoustic reflex (AR) contraction to the ascending-descending (A-D) gap was explored. 15 normal listeners traced ascending and descending most comfortable loudness (MCL) levels for continuous (C) and interrupted (I) tones at 250, 1000 and 4000 Hz. Reflex thresholds were obtained for each subject at the test frequencies. No evidence was found to implicate the AR as the causative agent in the A-D gap. Two important trends emerged: (1) an ordering of MCL conditions occurred which was consistent across frequencies and (2) there was a consistent difference between AR level and MCL for a given stimulus condition which was constant across frequencies. The findings suggest that a predictive relationship may exist between AR and pure-tone MCL.


The actions of vasoactive compounds in the foetus and the effect of perfusion through the placenta on their biological activity.

In acute experiments on the in utero foetal lamb, angiotensin II was a more potent pressor agent that either noradrenaline or adrenaline, and the response to angiotensin II was not consistently modified by the combined administration of alpha and beta-adrenergic blocking agents. A significant reduction in the pressor response of the foetus to angiotensin II and noradrenaline occurred with infusion of these compounds to the foetus by the umbilical artery when compared with the response obtained with infusions of the same doses of these drugs by the umbilical vein. Moreover, the concentration of angiotensin II (pg. ml-1) present in the foetal circulation was less following umbilical arterial infusions compared with umbilical vein infusions of the same doses. A similar reduction in the pressor activity of adrenaline and the cardio-stimulant effect of isoprenaline occurred when these drugs were infused by the umbilical artery. It is concluded that the foetus, like the adult  animal, is more sensitive to angiotensin II than to catecholamines and that the biological activities of noradrenaline, angiotensin II, adrenaline and isoprenaline are reduced by perfusion through the foetal placenta.


Studies on the brush border membrane on mouse duodenum: lipids.

Lipids were extracted from purified mouse duodenal brush border membranes. Lipid: protein ratios in different membrane preparations varied from 0.58 to 0.68. Both the chloroform and non-chloroform phases were quantitatively analysed for lipids. Chloroform extracts were composed of cholesterol, triglycerides and phospholipids. The major neutral lipid was cholesterol. Rechromatrography of the phospholipid spot showed sphingomyelin (7.9%), phosphatides of ethanolamine (61.7%), inositol (14.2%) and serine (16.2%). The average molar ratio of cholesterol to phospholipid was 1.39. Lipids in the non-chloroform phase were all glycosylated, being cerebrosides (69.3%), cerebroside sulphates (28.8%) and galgliosides (1.9%). Overal membrane lipid composition was neutral lipid 24%, phospholipid 33%, and glycolipid 43%.


Glucose-binding membrane proteins.

To identify glucose-binding proteins amongst the polypeptides of the mouse duodenal brush border membrane, three types of experiments are reported. The first involved the introduction of labelled glucose and its analogue phlorizin into the lumen of separate groups of ligatured duodenal segments. Several proteins were shown to have bound both labelled species in situ by liquid scintillation counting of slices from polyacrylamide gels on which solubilised membrane protein had been electrophoretically separated. The second type of experiment was designed to determine the competitive nature of the binding of both labelled and cold phlorizin to proteins which had already bound glucose. Only three bands could competitively bind phlorizin. Finally, gels on which solubilised protein from in situ glucose-binding experiments had been run were placed in solutions containing labelled phlorizin. The binding of phlorizin to proteins in the same three bands as above suggested a confirmation of the conclusion that there were three membrane protein types which appeared to be involved in phlorizin-sensitive glucose-binding.


Differential agglutination of particulate Vi and O antigens by the IgM and IgG class antibodies.

The IgG and IgM immunoglobulins were fractionated from pooled sera of typhoid patients and typhoid carriers and the agglutinin titres and weights of Vi and O antibodies in these immunoglobulin fractions determined. The O antigen particles were more effectively agglutinated than the Vi antigen particles by their corresponding antibodies of the IgM class. There was no such difference between IgG class Vi and O antibodies. Similar behaviour was found on indirect estimation of the agglutination capacity of the IgG and IgM class Vi and O antibodies in the sera of individual typhoid patients or carriers. The significance of such differential agglutinating capacity of the Vi and O antibodies of the IgM class is discussed.


Immune responses of sheep to the parasitic nematode Trichostrongylus colubriformis: infections in Thiry-Vella loops.

Some aspects of the local immune response to nematode infection were examined by introducing fourth-stage Trichostrongylus colubriformis larvae into Thiry-Vella loops in worm-free and T. colubriformis-resistant sheep. Approximately 15% of the larvae introduced into the worm-free sheep survived and matured into adult worms, whereas less than 1% survival in resistant sheep. The amount of IgG1, IgG2, IgM and albumin discharged from loops in worm-free but not resistant sheep all increased following infection with larvae. Secretions from resistant sheep contained approximately three times as much IgA as secretions from the worm-free group and, in addition, their plasma IgG1 level was significantly higher. Antibodies against T. columbriformis were found in both plasma and intestinal secretions, the highest titres being found in the resistant sheep. During worm expulsion from loops in the resistant sheep neither immunoglobulin levels nor antibody titres in the secretions increased significantly.


Carboxyhemoglobin levels during a submarine patrol.

One of the major contaminants from tobacco smoking aboard a nuclear submarine is carbon monoxide (CO). While this gas is controlled to 15 parts per million or lower by catalytic burners, there still remains a residual low level in the atmosphere. This study has shown that, on one submarine, the average ambient concentration was 7 ppm, which produced an average carboxyhemoglobin level in 15 nonsmokers of 2.1%, 1.7%, and 1.7% at the start, middle, and end of a 40-d patrol. Because submariners are generally healthy and young, it is concluded that CO exposures at these ambient levels do not constitute a major risk factor to the physiological well-being of these submariners, nor are they expected to cause any decrement in performance.


Effects of high ambient temperature on sleep in young men.

Each of 10 normal subjects had 4 nights of laboratory-monitored sleep, consisting of adjustment, baseline, high blanket temperature (HBT), and recovery nights. EEG-EOG recordings were made on each night; rectal temperature, heart rate, body weight, and ambient temperatures were monitored throughout the last 2 nights. On the HBT night, subjects had less total sleep time, more frequent and longer awakenings, greater shifting among sleep stages, decreased amounts of stage 1 REM and stages 3 + 4, and delayed onset of deep sleep (stages 3 and 4). Body temperature was elevated to a relatively constant level of 37 degrees C on the HBT night, but gradually decreased from 36 degrees C to 34.5 degrees C across the recovery night. Heart rate decreased at a linear rate on both the HBT and recovery nights, but was 15 beats/min faster on the former. Subjects experienced liquid loss of 1.25 kg on the HBT night, but had a full recovery by the following evening.


Persistence of lateral hypothalamic-mediated behaviors after a supralethal dose of ionizing radiation.

After exposure to 10 krad of high-energy electrons, rats experience an early transient incapacitation characterized by symptoms similar to those associated with lateral hypothalamic lesions: akinesia and decrements in various motivated behaviors. Experimenter-imposed electrical stimulation of the lateral hypothalamus in akinetic, irradiated animals produced a locomotor response similar to that seen in unexposed rats. Furthermore, when allowed to self-stimulate, the irradiated subjects persisted in vigorous self-stimulation of the lateral hypothalamus while self-stimulation rates of other subcortical sites showed marked attenuation. The lateral hypothalamus is apparently less sensitive to ionizing radiation than are the other subcortical structures sampled.


Effect of rewarming at various water bath temperatures in experimental frostbite.

Studies have been conducted on 72 rats to determine the most suitable temperature at which rapid rewarming should be done as an immediate treatment for frostbite. Animals were put in a harness containing arrangements for warming the body. Their hind limbs were left out of the harness. They were then exposed to -15 degrees +/- 1 degrees C in a deep freeze for 60 min, during which paw temperature was recorded every 5 min. After this, the animals were taken out, the left hind limb was rapidly rewarmed in a water bath maintained at 35 degrees, 37 degrees, 39 degrees, 41 degrees, 43 degrees, or 45 degrees C for different batches and the right hind limb was left free for slow rewarming at room temperature (27 degrees -29 degrees C). The severity of cold injury in the two limbs was compared. The paw temperature showed a drop on cold exposure, followed by a rapid rise and then a second fall. The degree of injury was related to the duration of exposure after the rise in the paw temperature. The rapid rewarming was effective only at water bath temperature of 37 degrees-39 degrees C and was harmful at 45 degrees C. This shows that rewarming at about body temperature is most effective as immediate treatment for frostbite.


Changes in the permeability of the blood-brain barrier under hyperbaric conditions.

Hyperbaric oxygen therapy (HBO) has been used in the treatment of cerebral edema with variable results. Two different actions of HBO, one decreasing and the other increasing cerebral edema, have been postulated. We examined the permeability of the blood-brain barrier (BBB) in rats and cats. Animals of each species were treated for 90 min/d with 100% oxygen at a pressure of 2.5 atm for 5 consecutive days. Following treatment, cadmium-free ferritin was injected intravenously. Sections of the brain were prepared for electron microscopic evaluation of the capillaries and their neighboring structures. Perivascular edematous zones were observed. Ferritin particles penetrated through the capillary endothelium and into the pericapillary structures. Hyperbaric oxygenation appears to increase the permeability of cerebral vessel walls in normal animals. Further work on this phenomenon may provide a more rational basis for the treatment of cerebral edema with HBO.


Body fluid compartments in rabbits on exposure to acute hypobaric hypoxia.

Body fluid compartments were studied in rabbits divided into three groups--control, exposed to acute hypoxia, and exposed to hypoxia after treatment with 2 mg frusemide intramuscularly. Total body water, extracellular body water, and plasma space were determined using the triple radiotracer technique. Total body water decreased insignificantly with no change in extracellular body space on exposure to hypoxia. Plasma volume and blood volume showed a significant decrease with a significant increase in haematocrit. In rabbits pretreated with frusemide, total body water, extracellular body water, plasma volume, blood volume, and interstitial fluid space decreased significantly on hypoxic exposure. This study suggested hypohydration on acute hypoxic exposure with a loss of intracellular water, while pretreatment with frusemide resulted in further hypohydration with a loss from both intracellular and extracellular compartments. The results have been discussed in relation to suggested use of diuretics on induction to high altitude.


Space colonization--some physiological perspectives.

While the establishment of large self-sustaining communities in free space is possible with present day technology, our understanding of the physiological design criteria determining habitat mass, structural configuration, cost, and ultimate feasibility, is inadequate. This paper briefly summarizes the biomedical findings of an engineering workshop cosponsored by the American Society of Engineering Education, Stanford University, and NASA's Ames Research Center (Summer, 1975). It is the conclusion of the study that a viable, economically productive space community of 10,000 people could be established with very conservative, centrifugally generated earth-normal gravity, general population maximum ionizing radiation dose standards (i.e. less than or equal to 0.5 rem/year, using passive shielding techniques), and a normoxic but reduced nitrogen partial pressure atmosphere. It is the conclusion of the author that although, in theory, some of the physiological constraints might in certain cases be partially relaxed, extensive research must be done to establish the degree of any such relaxation.


Concorde: ride quality and passenger reactions.

On four Concorde flights, recordings of environmental characteristics during flight were made and questionnaires were distributed to passengers to assess their reactions during and 24 h after their flight. The Concorde users were mostly traveling for business reasons. Most respondents were flying the Concorde for the first time. Passengers were satisfied with the Concorde, found it comfortable, and were able to perform a variety of activities in flight. On the day after their flight, respondents felt good, rested, and active. They reported less jet lag as a result of their Concorde flight than they had previously experienced on other transatlantic flights. Most respondents are likely to use the Concorde again.


Prevention of motion sickness in flight maneuvers, aided by transfer of adaptation effects acquired in the laboratory: ten consecutive referrals.

Ten flyers, grounded because of nausea and vomiting, were referred as potential candidates for adaptation to cross-coupled angular accelerations in a slow-rotation room; such adaptation has been shown to "transfer" to flight maneuvers. There was no opportunity to attempt treatment in two candidates. Among the remaining eight, five regained flight status (62.5%); follow-up periods of those five candidates ranged from 10 to 27 months. In one of the three remaining candidates, a satisfactory level of adaptation was achieved but more than 4 months elapsed before his assignment to a duty squadron. After becoming sick in his first flight (F-104), he submitted a request to be removed from duty involving flying. In the remaining two candidates, the rate of their acquisition of adaptation not only was very slow but also, after leveling off, actually declined. In other words, poor as well as good performance is demonstrable in the slow-rotation room.


Evaluation method of mental workload under flight conditions.

In order to analyze the relationship between heart rate variability (HRV) and the flight tasks of pilots, HRV of various mental and physical work stresses were investigated. For the physical stress on the treadmill, S.D. of heart rate sequence showed a minimum value at medium stresses and remained there until the maximum stress. However, the centrifuge acceleration test presupposed special physical stresses, and S.D. was almost same as the resting findings. In the tracking tasks, which presupposed maximum interpretative actions, the increase in the mean heart rate (MHR) was small with the S.D. increased a greater amount than for resting results. Consequently, preflight checks and level flight phases presupposed medium interpretative actions and mental stress with reserve capacity. Takeoff and landing phases were considered as both high interpretative action and high emotional stress situations. Acrobatic and gunnery training flight phases were considered physical load, strong interpretative actions, and emotional stress tasks.


An epidemiological study of subacute sclerosing panencephalitis in Japan, 1976.

The National Registry for subacute sclerosing panencephalitis (SSPE) of Japan was established in 1976 at the Research Institute for Microbial Diseases, Osaka University, under the auspices of the Ministry of Health and Welfare. By March 1977, forty five clinically confirmed cases of SSPE were reported to the Registry, with onset of symptoms occurring between 1966 and 1976. Histories of measles were available in 42 of these cases. Thirty nine patients with known histories had measles prior to onset of SSPE and 3 had no history of measles illness. Twenty eight (71.7%) of the 39 patients had measles before the age of 2 years. All cases were 1 to 14 years old at the time of onset of SSPE and the mean interval between measles and SSPE was 6.1 years. One of the 3 cases with no history of measles was a recipient of measles killed vaccine, but no case of SSPE was reported among recipients of measles live, attenuated vaccine.


Rubella epidemic in an institution: protective value of live rubella vaccine and serological behavior of vaccinated, revaccinated and naturally immune groups.

A rubella epidemic occurred in an institutional population composed of 189 susceptible, 37 naturally immune, 35 previously vaccinated and 38 serologically uncharacterized children and nursing staff. The epidemic lasted 3.5 months and showed more than 5 waves. Detailed clinical and serological examinations of these subjects were made. A rash appeared in 156 (52%) of 299 persons, including 145 (87%) of 166 unvaccinated and serologically uncharacterized subjects, but not in the 72 immune persons. In the middle of the 3rd wave urgent vaccination of 61 children aged 0 to 2 years of the susceptible group reduced the rate of appearance of a rash to 11 of the children (18%), as compared with 126 (98%) of 128 subjects in the unvaccinated non-immune group. The epidemic only reached a 4th wave in the vaccinated group, but it extended to a 5th wave or more in unvaccinated subjects. None of the 35 subjects in a previously vaccinated group developed rubella, although the rate of subclinical reinfection in this previously vaccinated group was higher (35%) than that in the naturally immune group (17%). Three cases of subclinical reinfection were detected even among 6 previously revaccinated subjects.


What happens when data are fitted to the wrong equation?

In many problems of data analysis it is necessary to fit the data to a mathematical equation. Random errors of measurement will be responsible for deviations between the data and the equation, but superimposed on this there may be deviations that result from the equation being an inadequate description of the system from which the data were obtained. Plots of the residual (i.e. the difference between the experimental and calculated values of the dependent variable) against each of the experimental variables have been previously used to detect a misfit between the data and the equation. In the present paper, we show that the shape of the residual plots may be used as a guide in choosing a more appropriate equation. In addition, residual plots give useful information on the error structure of the data, and hence the weighting factors that should be used in the analysis.


Affinity chromatography of bacterial lactate dehydrogenases.

The affinity system used was the immobilized oxamate derivative previously used to purify mammalian lactate dehydrogenases. The bacterial dehydrogenases specific for the L-stereoisomer of lactate behaved in the same way as the mammalian enzymes, binding strongly in the presence of NADH. The D-lactate-specific enzymes, however, did not show any biospecific affinity for this gel. The L-specific enzymes could be purified to homogeneity in one affinity-chromatographic step. The D-specific enzymes could be efficiently separated from the L-specific ones and could then be further purified on an immobilized NAD derivative. The mechanism of activation of the lactate dehydrogenase from Streptococcus faecalis by fructose 1,6-bisphosphate was investigated by using the immobilized oxamate gel.


Surface behaviour of gangliosides and related glycosphingolipids.

1. The surface behaviour of six different gangliosides and eight chemically related glycosphingolipids was investigated in monolayers at the air-water interface. 2. Mono-, di-, tri and tetra-hexosylceramides had force-area isotherms showing similar limiting molecular areas on 145 mM-NaCl, pH 5.6. The increasing number of negatively charged sialosyl residues in mono-, di- and tri-sialogangliosides induced a progressive increase in the liquid-expanded character of the films and in the limiting area occupied per molecule, owing to electrostatic repulsions. When the ganglioside monolayers were spread on subphases at pH 1.2, the limiting area per molecule was similar to that found for neutral glycosphingolipids. 3. The monolayer collapse pressure at pH 5.6 increased with the number of uncharged carbohydrate units up to when the polar head group contained 3-4 residues. For gangliosides the collapse pressures were lower and decreased from mono- to tri-sialogangliosides. Ganglioside monolayers on subphases at pH 1.2 showed increases in their collapse pressure. 4. The glycosphingolipid monolayers studied had various surface in their collapse pressure. 4. The glycosphingolipid monolayers studied had various surface potentials according to the complexity of the polar head group of the lipid. Attempts to calculate the dipolar contributions to the surface potential from each carbohydrate residue suggest that the second and third sialosyl residues in di- and tri-sialogangliosides contributed with a vertical dipole moment opposite to that of the first sialosyl residue.


A simple procedure for the isolation and purification of protamine messenger ribonucleic acid from trout testis.

Preparation of milligram quantities of purified poly(A)+ (polyadenylated) protamine mRNA from trout testis tissue was accomplished by a simple procedure using gentle conditions. This involves chromatography of the total nucleic acids isolated by dissociation of polyribosomes with 25 mM-EDTA to release messenger ribonucleoprotein particles and deproteinization of the total postmitochondrial supernatant with 0.5% sodium dodecyl sulphate in 0.25 M-NaCl by binding it to a DEAE-cellulose column. Total RNA was bound under these conditions, and low-molecular-weight RNA, lacking 18S and 28S RNA, could be eluted with 0.5 M-NaCl and chromatographed on oligo(dT)-cellulose columns to select for poly(A)+ RNA. Further purification of both the unbound poly(A)- RNA and the bound poly(A)+ mRNA on sucrose density gradients showed that both 18S and 28S rRNA were absent, being removed during the DEAE-cellulose chromatography step. Poly(A)- RNA sedimented in the 4S region whereas the bound poly(A)+ RNA fraction showed a main peak at 6S [poly(A+) protamine mRNA] and a shoulder in the 3-4S region. Analysis of the main peak and the shoulder on a second gradient showed that most of the main peak sedimented at 6S, whereas the shoulder sedimented slower than 4S. The identity of the poly(A)+ protamine mRNA was established by the following criteria: (1) purified protamine mRNA migrated as a set of four bands on urea/polyacrylamide-gel electrophoresis; (2) analysis of the polypeptides synthesized in the wheat-germ extract by starch-gel electrophoresis showed a single band of radioactivity which co-migrated exactly with the carrier trout testis protamine standard; and (3) chromatography of the polypeptide products on CM-cellulose (CM-52) showed the presence of three or four radioactively labelled protamine components that were co-eluted with the unlabelled trout testis protamine components added as carrier. The availability of large quantities of purified protamine mRNA should now permit a more thorough analysis of its physical and chemical properties.


Effect of the protein-synthesis-initiation inhibitor 2-(4-methyl-2,6-dinitroanilino)-N-methylpropionamide on ribonucleic acid synthesis in radish seedlings.

2-(4-Methyl-2,6-dinitroanilino)-N-methylpropionamide, an inhibitor of initiation of protein synthesis in plants, selectively alters rRNA synthesis. Ribosomal genes are transcribed in the absence of protein synthesis, but processing of the transcripts is impaired. This results in an accumulation of the 2.3 X 10(6)-dalton pre-rRNA. Synthesis of polyadenylated RNA is not affected by the drug.


Properties of potato lectin and the nature of its glycoprotein linkages.

1. Potato lectin is a glycoprotein that contains about 47% (by weight) l-arabinose, 3% d-galactose and 11% hydroxyproline. It has a monomeric molecular weight of about 50000 and probably exists as a monomer-dimer system in aqueous solution, with the monomer predominating. It has a very high viscosity, which would indicate either that the molecule is very expanded or that it is an elongated ellipsoid. 2. After prolonged proteolytic digestion of a reduced and carboxymethylated derivative of the lectin, a glycopeptide was isolated (of mol.wt. 32000-34000) that included all the carbohydrate and hydroxyproline of the original glycoprotein but less than 30% of the total original amino acid residues. 3. The arabinose of the glycoprotein is present exclusively as the beta-arabinofuranoside and this includes those residues that are directly linked to the hydroxyproline residues of the polypeptide chain. All the arabinose of the glycoprotein is linked to the polypeptide chain through the hydroxyproline residues; the ratio of arabinose to hydroxyproline is 3.4:1. Although alpha-arabinofuranosides are known to be present in arabinans and arabinogalactans, the natural occurrence of beta-arabinofuranosides has not previously been reported. 4. Nine or ten serine residues of the polypeptide chain are substituted with single alpha-galactopyranoside residues that can be removed by the action of alpha-galactosidase from coffee beans but not by a beta-galactosidase. This is the first report of an alpha-galactoside linkage to serine. The effect of alpha-galactosidase is much greater on a glycopeptide from which the arabinose has been already removed, which indicates a steric hindrance of the galactosidase action by adjacent chains of arabinosides. 5. In 0.5m-NaOH (pH13.7), galactose residues were removed from the serine residues of the glycopeptide by a process of beta-elimination. This reaction took place very slowly in the intact glycopeptide but much more rapidly when the arabinofuranoside residues had been removed. This inhibitory effect of the arabinofuranoside residues on the beta-elimination reaction is likely to be due to a negative charge on the hydroxy groups of the adjacent arabinofuranoside residues, which would be ionized at this high pH value. 6. It is suggested that potato lectin may be representative of a class of soluble plant glycoproteins that would include precursors of the cell-wall glycoprotein extensin. If this is the case, extensin should also contain beta-l-arabinofuranosides linked to hydroxyproline and alpha-d-galactopyranosides linked to serine residues of the polypeptide chain.


A comparative study of the proteoglycan of growth cartilage of normal and rachitic chicks.

1. Proteoglycan was isolated from growth cartilage of normal and rachitic chicks. 2. The proteoglycan from normal cartilage showed differences in chemical composition and physical properties from a comparable fraction isolated from bovine nasal cartilage. 3. The proteoglycan from rachitic-chick cartilage was of smaller size than tis normal counterpart, though of similar average chemical composition. 4. Differences between proteoglycan from normal and rachitic cartilages can be explained in terms of limited proteolytic cleavage.


Isolation and hydroxylysine glycoside content of some cyanogen bromide-cleaved fragments of collagen from bovine corneal stroma.

Six CNBr-cleaved fragments of insoluble collagen from bovine cornea were isolated, characterized and examined for hydroxylysine glycosides. Thus the general distribution of most of the glycoside along the collagen molecule was determined. Collagen from bovine stroma is almost entirely type I. This work forms a basis for the pinpointing of glycoside-attachment sites along the collagen molecules of bovine cornea.


Chymotryptic and tryptic peptides of fragment alpha 1-CB3 from bovine corneal collagen. Pinpointing the sites of hexose attachment.

Tryptic peptides of citraconylated fragment alpha1-CB3 and chymotryptic peptides of fragment alpha1-CB3 of bovine corneal collagen were prepared, isolated and characterized. Their amino acid compositions were consistent with the amino acid sequence of fragment alpha1-CB3 from calf skin collagen. Two glycoside sites were identified in bovine corneal fragment alpha1-CB3, one of them being the first located in the overlap region of collagen. The results are related to the uniformly narrow collagen fibres found in cornea and essential for its transparency.


Determination of binding affinities of retinoids to retinoic acid-binding protein and serum albumin.

Binding affinities of retinoic acid and its synthetic analogues to intracellular retinoic acid-binding protein, which is a possible candidate for mediating their biological function, and to serum albumin, the plasma transport protein, were evaluated. A quantitative method involving elimination of interfering serum albumin by immunoprecipitation was developed to measure the binding efficiency of these retinoids, some of which are active in modifying epithelial differentiation and preventing tumorigenesis. Two cyclopentenyl analogues of retinoic acid and 13-cis-retinoic acid showed, like retinoic acid, a binding efficiency of 100% for the cellular binding protein. With the phenyl, dichlorophenyl and trimethylmethoxyphenyl analogues of retinoic acid, the binding efficiency increased as the substituents on the aromatic ring increased; thus the trimethylmethoxyphenyl analogue binds almost as efficiently as retinoic acid itself. However, the trimethylmethoxyphenyl analogue with a sulphur atom on the side chain has a much decreased binding affinity. The correlation noticed between the binding efficiency of these retinoids and their biological activity in differentiation and/or in the control of tumorigenesis particularly enhances the confidence in the present method of determining the relative binding efficiencies. None of the vitamins, hormones and cofactors tested, showed appreciable affinity for the retinoic acid-binding site. Studies on binding of retinoic acid and its analogues to serum albumin indicate that no correlation exists between binding affinity for albumin and their biological potency.


The specificity of cathepsin B. Hydrolysis of glucagon at the C-terminus by a peptidyldipeptidase mechanism.

The manner in which human liver cathepsin B (EC 3.4.22.1) digests glucagon was determined. After reaction of the proteinase with the substrate for 24h, more than 15 products were formed. During the first 7 h of reaction, eight products were formed; seven of these were dipeptides that originated from the C-terminal portion of the glucagon molecule, whereas the eighth peptide was the remaining large fragment of the hormone, consisting of residues 1-19. Measurement of the rate of formation of the products showed that cathepsin B degraded glucagon by a sequential cleavage of dipeptides from the C-terminal end of the molecule. Cathepsin B from both rat liver and bovine spleen was shown to hydrolyse glucagon by the same mechanism.


The reaction of amino-oxyacetate with pyridoxal phosphate-dependent enzymes.

The carbonyl reagent amino-oxyacetate is frequently used in metabolic studies to inhibit individual pyridoxal phosphate enzymes. The reaction of this compound with three such enzymes, aspartate transaminase, 4-aminobutyrate transaminase and dopa (3,4-dihydroxyphenylalanine) decarboxylase, was studied to determine the extent to which the inhibition is reversible and the rates at which it takes place. Reactions were followed by observing changes in the absorption spectra of the bound coenzyme and by measuring loss of enzyme activity. The reactions with aspartate transaminase and aminobutyrate transaminase were not rapidly reversible and had second-order rate constants (21 degrees C) of 400 M-1.s.1 and 1300 M-1.s-1 respectively and all all concentrations studied showed the kinetics of a simple bimolecular reaction. The reaction with 4-aminobutyrate transaminase could not be reversed and that with aspartate transaminase could only be reversed significantly by addition of cysteinesulphinate to convert the enzyme into its pyridoxamine form. The first-order rate constant (21 degrees C) for the reverse reaction was 4 X 10(-5)s-1. Dopa decarboxylase inhibition by amino-oxyacetate was more rapid and more readily reversible, but measurements of rate and equilibrium constants were not obtained for this enzyme.


The pseudouridine contents of the ribosomal ribonucleic acids of three vertebrate species. Numerical correspondence between pseudouridine residues and 2'-O-methyl groups is not always conserved.

The pseudouridine contents of the rRNA species of HeLa cells, mouse L-cells and Xenopus laevis cultured kidney cells were examined. Pseudouridine, like 2'-O-methylation, was found to occur relatively frequently in each of the high-molecular-weight rRNA species. However, the numerical data do not support the idea that there is a general one-to-one relationship between pseudoridine residues and 2'-O-methyl groups in vertebrate rRNA.


Effect of different compounds on 1-aspartamido-beta-N-acetylglucosamine amidohydrolase from human liver.

The effect of varous compounds on 1-aspartamido-beta-N-acetylglucosamine amidohydrolase (aspartylglucosylaminase, EC 3.5.1.26) was studied. N-Acetylcysteine inhibited the nezyme non-competitively (Ki 3.2 mM), whereas 3-hydroxybutanone inhibited competitively (Ki 4.1 mM). Methionine, isoleucine and cystathionine apparently enhanced the enzyme activity. The enzyme had a mol. wt. of 63000 as determined by gel filtration. The present studies differentiate between the aspartylglucosylaminase from human liver and that obtained from various other sources.


The contribution of serum triacylglycerol to hepatic triacylglycerol turnover in the starved rat.

The present study was undertaken to evaluate quantitatively the turnover of serum triacylglycerol (triglyceride) in the starved rat and to determine whether serum triacylglycerol recycled to liver contributes a significant fraction of the total hepatic triacylglycerol turnover. Serum was labelled in vitro with [3H]trioleoylglycerol (glycerol [3H]trioleate) to provide uniform labelling of all lipoprotein species. By using the curves describing disappearance of isotope from serum and its appearance in liver, rate constants for movement of triacylglycerol out of serum (0.29 min-1) and the uptake of serum triacylglycerol by liver (0.22 min-1) were calculated. The total rate of movement (flux) of triacylglycerol in these processes, the product of rate constant and serum pool size, was calculated to be 0.39 and 0.29 mg/min per 100 g body wt. respectively. A model is postulated for whole-body triacylglycerol metabolism consistent with the present data as well as most observations in the literature. From the model it can be predicted that: (1) the entire turnover of liver triacylglycerol in the starved rat can be accounted for on the basis of contributions from serum non-esterified fatty acid and serum triacylglycerol; (2) the entire turnover of the serum triacylglycerol pool can be accounted for quantitatively on the basis of contributions from intestine and liver; (3) the release rate for triacylglycerol from liver should be 0.34 to 0.35 mg/min per 100 g body wt.; (4) triacylglycerol synthesized by liver from non-esterified fatty acid of serum and by intestine can account quantitatively for the irreversible disposal rate of triacylglycerol from serum.


Rate of release of hepatic triacylglycerol into serum in the starved rat.

After an intravenous injection of a pulse of [U-14C]palmitate to starved rats, the time-dependent radioactivity profiles were determined in the triacylglycerol (triglyceride) of hepatic microsomal fractions, floating fat, mitochondria and nuclei. The profile of activity in serum gave a value of 0.08 mg/min per 100 g body wt. for the irreversible disposal rate of triacylglycerol from serum. This value, combined with the previously estimated rate of movement of triacylglycerol from serum to liver, and the reported rate from intestine to serum, gave a calculated value of 0.35 mg/min per 100 g body wt. for release rate of triacylglycerol from liver to serum. The rate of release of hepatic triacylglycerol into serum was also measured by the widely used Triton WR-1339 method. The rate obtained with this technique (0.15 mg of triacylglycerol/min per 100 g body wt.) was identical with that reported previously. During the interval from 45 min to 3h after ethanol administration this rate increased to 0.18 mg/min per 100 g body wt. It was concluded that the use of Triton underestimates the true rate of movement of triacylglyerol from liver to serum.


An energy requirement for the degradation of intravenously injected 125I-labeled albumin in mouse liver and kidney slices.

Liver and kidney slices prepared 30min after intravenous injections of formaldehyde-treated 125I-labelled bovine serum albumin into mice degrade approx. 25-40% of the protein to a trichloroacetic acid-soluble form during 60min incubation at 37 degrees C. The presence of bicarbonate in Krebs-Ringer phosphate medium inhibited intracellular proteolysis, and similar results were obtained at pH5 or pH7 in kidney or liver slices. Cellular integrity was required to obtain substantial rates of proteolysis. This intralysosomal intracellular degradation of an exogenous protein was partially inhibited by inhibitors of oxidative ATP formation, such as cyanide, azide, 2,4-dinitrophenol and absence of oxygen. Arsenite and iodoacetamide were also effective inhibitors, but the effects of fluoride were variable. These results suggest that an energy requirement exists for intralysosomal proteolysis in intact cells and are consistent with the hypothesis that energy may be required to maintain intralysosomal acidity.


Effect of nutrition on subcellular localization of rat fat-cell lipoprotein lipase.

This study supports the possibility for multiple subcellular forms of lipoprotein lipase. 1. The total activity of lipoprotein lipase per g of intact epididymal adipose tissue from fed rats is much higher than that from starved rats. 2. The isolated fat-cells of fed and of starved rats have lipoprotein lipase of almost the same activity per g of fat-pads. The isolated fat-cells of starved rats have a much higher proportion of total activity per g of the intact tissue than do those of fed rats. 3. Under the conditions of homogenization used, only a small proportion of the total activity per g of intact tissue from fed rats was associated with the fat layer which floated to the top of the homogenate during low-speed centrifugation. The different proportions of the specific enzyme activity found in each subcellular fraction are described. 4. Lipoprotein lipase from plasma membranes and microsomal fractions from starved and fed rats was purified by affinity chromatography. 5. The total activity of microsomal lipoprotein lipase per g of intact adipose tissue is enhanced by a normal diet. 6. In intact epididymal adipose tissue from fed rats, the activity per g of tissue of lipoprotein lipase of plasma membranes is much higher than that in the same fraction from starved rats. By contrast, the activities per g of tissue in plasma membranes obtained from starved or from fed rats by collagenase treatment were similar.


The availability of inorganic sulphate in blood for sulphate conjugation of drugs in rat liver in vivo. (35S)Sulphate incorporation into harmol sulphate.

1. When Na235SO4 is injected intravenously in rats, it is immediately available for sulphate conjugation of the phenolic drug harmol (7-hydroxyl-1-methyl-9H-pyrido[3,4-b]indole) in the liver. This was established by following the time course of the biliary excretion of the sulphate conjugate of harmol, and the incorporation of [35S]sulphate into harmol sulphate. 2. During the 10min immediately after injection of Na235SO4 re-distribution of [35S]sulphate took place, which resulted in a rapid initial decrease in the plasma concentration of [35S]sulphate; a concomitant decrease in the amount of [35S]sulphate incorporated into harmol sulphate was observed, indicating that the co-substrate of sulphation, adenosine 3'-phosphate 5'-sulphatophosphate, equilibrates rapidly with [35S]sulphate in plasma. 3. The results suggest that the pool size of adenosine 3'-phosphate 5'-sulphatophosphate is very small; therefore the specific radioactivity of [35S]sulphate in plasma determines the specific radioactivity incorporated into sulphate esters at any time.


Degradation of cartilage proteoglycans by a neutral proteinase secreted by rabbit bone-marrow macrophages in culture.

When cultivated together with pieces of cartilage biosynthetically labelled with 35S in their proteoglycans, rabbit macrophages, differentiated in vitro from bone-marrow cells, cause the release of soluble 35S-labelled material into the culture medium. This process is inhibited by killing the macrophages or by cycloheximide treatment, and is due to the secretion by the cells of a metal-dependent neutral proteinase capable of degrading cartilage proteoglycan subunits into fragments of high molecular weight. Enzyme activity is optimum at about pH7, and is inhibited by EDTA, o-phenanthroline, cysteine or serum, but not by di-isopropyl phosphorofluoridate nor by 4-hydroxymercuribenzoate. The effect of EDTA is partially reversed by Co2+ or Zn2+ ions. The enzyme is eluted from Sephadex G-150 columns as a single peak of material (apparent mol.wt. 17000) that contains also most of the proteolytic activity exerted by culture media on Azocoll (denatured collagen) or on casein. The possible role of this metalloproteinase in chronic inflammatory processes is discussed, particularly in connection with joint erosions in rheumatoid arthritis.


A radiochemical assay for glycine N-acyltransferase activity. Some properties of the enzyme in rat and rabbit.

We have developed a sensitive radiochemical assay of glycine N-acyltransferase activity, using phenylacetyl-CoA as the acyl donor and glycine as the acceptor. This assay measures formation of the product, phenylacetylglycine, instead of disappearance of the substrate, phenylacetyl-CoA, as did earlier assays. The subcellular location and some properties of the conjugating activity were determined in liver and kidney of the rabbit and the rat. Rabbit lung and intestine were also tested for activity.


Perinatal development of, and effect of chemical pretreatment on, glycine N-acyltransferase activities in liver and kidney of rabbit and rat.

The ontogenic development of glycine N-acyltransferase activity was studied in preparations of hepatic and renal mitochondria from the New Zealand White rabbit and the Sprague-Dawley rat. Preparations of hepatic mitochondria from the rat and the rabbit attain adult glycine N-acyltransferase specific activities by birth and 4 weeks of age respectively, whereas mitochondrial preparations from rabbit kidney do not attain adult activity until 4 months of age. Pretreatment of adult rats or immature rabbits with salicylic acid, benzoic acid or phenobarbital had little effect on glycine N-acyltransferase activity in vitro in liver or kidney.


Calcium-dependent Golgi-vesicle fusion and cathepsin B in the conversion of proalbumin into albumin in rat liver.

1. An enzyme from rat liver that converts proalbumin into albumin is described. Partial purification, inhibitor studies and the conditions for maximum activity suggest that the enzyme is cathepsin B. 2. A membrane-bound enzyme, located mainly in lysosomes, also converts proalbumin into albumin. This appears to be a membrane-bound form of cathepsin B. 3. Isolated Golgi vesicles, incubated under conditions suitable for cathepsin B, convert endogenous proalbumin into albumin. 4. This conversion in Golgi vesicles has an absolute requirement for Ca2+ at micromolar concentrations. Mg2+ does not affect or substitute for Ca2+. Both the proalbumin and the albumin formed from it are intravesicular. 5. Converting activity is enhanced by pretreatment with the known chemical fusogen, poly(ethyleneglycol). 6. Vesicles preincubated at pH above 7 in the presence of dithiothreitol show a marked fall in converting activity. This can be partially restored by incubation with native vesicles. These results suggest that vesicle fusion is a requirement for conversion of proalbumin into albumin.


Rapid stimulation by vasopressin, oxytocin and angiotensin II of glycogen degradation in hepatocyte suspensions.

1. The hormonal control of glycogen breakdown was studied in hepatocytes isolated from livers of fed rats. 2. Glucose release was stimulated by [8-arginine]vasopressin (10pm-10nm), oxytocin (1nm-1mum), and angiotensin II (1nm-0.1mum). These responses are all at least as sensitive to hormone as is glucose output in the perfused rat liver. 3. The effect of these three hormones on glucose release was critically dependent on extracellular Ca(2+), unlike that of glucagon. Half-maximal restoration of the vasopressin response occurred if 0.3mm-Ca(2+) was added back to the incubation medium. 4. Glycogen breakdown was more than sufficient to account for the glucose released into the medium, in the absence or presence of hormones. Lactate release by hepatocytes was not affected by vasopressin, but was inhibited by glucagon. 5. If Ca(2+) was omitted from the extracellular medium, vasopressin stimulated glycogenolysis, but not glucose release. 6. The phosphorylase a content of hepatocytes was increased by vasopressin, oxytocin and angiotensin II; minimum effective concentrations were 0.1pm, 0.1nm and 10pm respectively. This response was also dependent on Ca(2+). 7. These results demonstrate that hepatocytes can respond to low concentrations of vasopressin and angiotensin II, i.e. these effects are likely to be relevant in the intact animal. The role of extracellular Ca(2+) in the effects of these hormones on hepatic glycogenolysis and glucose release is discussed.


Changes in the lipoprotein lipase (clearing-factor lipase) activity of white adipose tissue during development of the rat.

The lipoprotein lipase (clearing-factor lipase) activity of the white adipose tissue from rats aged between 1 and 145 days was determined. Five adipose-tissue sites (epididymal, uterine, subcutaneous, perirenal and intramuscular) together with serum concentrations of triacylglycerol, cholesterol and glucose were studied. The pattern of enzyme-activity change was remarkably similar in all the sites studied, although the growth of the tissues proceeded non-uniformly. After a peak of activity early in suckling, lipoprotein lipase activity fell to low values by 20 days of age. At weaning (21 days) the activity increased sharply and within 5 days high values were regained. The serum triacylglycerol and cholesterol concentrations were low at birth and reached peaks of concentration coincidentally with the minima of white-adipose-tissue lipoprotein lipase activities, seen late in suckling. The changes in enzyme activity were related to other metabolic changes in adipose tissue and with the known changes in plasma insulin concentrations occurring during development.


Effects of chronic hyperinsulinaemia on hepatic enzymes involved in lipogenesis and carbohydrate metabolism in the young rat.

Chronic (6 days) hyperinsulinaemia in young rats produced lower blood glucose concentrations and augmented body- and liver-weight gain. The insulin-treated rats had increased hepatic activities of citrate-cleavage enzyme, 'malic' enzyme and high-substrate (6.6 mM-phosphoenolpyruvate) pyruvate kinase, and decreased glucose 6-phosphatase. There were no changes in activities of phosphoenolpyruvate carboxykinase, phosphofructokinase, low-substrate (1.3 mM-phosphoenolpyruvate) pyruvate kinase, glucokinase and hexokinase.


Is the adenine nucleotide translocator rate-limiting for oxidative phosphorylation?

1. The effects of atractyloside and carboxyatractyloside (between 5 and 40mum) on O(2) uptake, glucose synthesis, urea synthesis, the adenine nucleotide content and the intracellular K(+) concentration were measured in isolated hepatocytes. 2. Urea synthesis was much less inhibited than glucose synthesis by both atractylosides. Measurements of intermediary metabolites of carbohydrate metabolism in freeze-clamped liver after injection of atractyloside into rats indicate that inhibition of gluconeogenesis is due to interference at the cytosolic reactions requiring ATP (phosphoenolpyruvate carboxykinase and 3-phosphoglycerate kinase). 3. The decrease in [ATP]/[ADP]x[P(i)] after addition of atractyloside or carboxyatractyloside was restricted to the cytosol. 4. Dihydroxyacetone can be converted either into glucose with the consumption of 2mol of ATP (per mol of glucose) or into lactate with the production of 2mol of ATP. In the presence of high concentrations of atractyloside and carboxyatractyloside more ATP was produced than was used for the synthesis of glucose from dihydroxyacetone, probably for the maintenance of intracellular [K(+)]. 5. When the rates of respiration were altered by changing substrates, the degrees of inhibition of respiration and translocation by a given concentration of the atractylosides were the same, whereas at a given concentration of HCN the degree of inhibition was high at higher initial rates, and low at lower initial rates. 6. Inhibition of a complex series of reactions by atractyloside does not necessarily indicate that the translocator is a rate-limiting step in that sequence as Th. P. M. Akerboom, H. Bookelman & J. M. Tager [(1977) FEBS. Lett.74, 50-54] assume. This point is discussed.


Evidence that the coproporphyrinogen oxidase activity of rat liver is situated in the intermembrane space of mitochondria.

Preferential rupture of the outer membrane of mitochondria from rat liver releases coproporphyrinogen oxidase in parallel with components of the intermembrane space. Coproporphyrinogen III enters the mitochondrion through the freely-permeable outer membrane. Either protoporphyrinogen IX or protoporphyrin IX must then cross the inner membrane before haem synthesis can be completed.


Phospholipase A2 of rat liver mitochondria in vitamin E deficiency.

1. There is a more than 2-fold increase in phospholipase A(2) activity (EC 3.1.1.4) of liver mitochondria isolated from vitamin E-deficient rats compared with that in normal rats. 2. alpha-Tocopherol in lipoprotein-bound form is more effective than free alpha-tocopherol in restoring the enzyme activity to normal.


Clinical features of the arthritis of mixed connective tissue disease.

Seventeen of 19 patients with mixed connective tissue disease (MCTD) had arthritis as a significant initial feature of their disease; 8 were given an initial diagnosis of rheumatoid arthritis (RA) and 4 received chrysotherapy. RA-like hand deformities were present in 35% and contractures and/or persistent loss of joint motion in 47%. Joint radiographs showed abnormalities in 41% and included erosions and/or cysts in 30%. The arthritis of MCTD may be both erosive and deforming and this disease should be considered in patients presenting as RA with unusual features.


Autoimmune neutropenia in systemic lupus erythematosus.

The mechanism of granulocyte depletion in a patient with systemic lupus erythematosus and neutropenia was investigated. Neutrophil kinetic studies showed a shortened intravascular survival (t1/2 of 1.6 hours) in the face of an increased marrow neutrophil pool. IgG bound to the patient's neutrophils, measured by the Fab antiF(ab')2 assay, was nearly three times normal. The IgG neutrophil-binding activity of the patient's serum was elevated in serial samples obtained over two years. In addition, his serum was able to opsonize normal neutrophils for ingestion by other neutrophils as detected by 14C-1-glucose oxidation. Enhanced IgG PMN-binding activity was observed with sucrose density gradient fractions of the patient's serum containing either large complexes (19S or greater in size), intermediate complexes (between 7S and 19S), or monomeric IgG. Only the momomeric IgG fraction from the patient's serum, however, opsonized normal neutrophils for ingestion by other neutrophils. These results support the hypothesis that anti-cell antibodies were responsible for the neutropenia in this patient by opsonizing neutrophils for ingestion by other phagocytic cells.


Electron microscopic morphology of immunoglobulin aggregates and their interactions in rheumatoid articular collagenous tissues.

Immunoelectron microscopy for IgG and IgA was combined with plain electron microscopy and light microscopy to study a variety of articular collagenous tissues from 14 cases of classic rheumatoid arthritis. Numerous extensive aggregates of IgG and IgA positive material were found widely spread in locations that coincided with immunofluorescent staining for these immunoglobulins and B1c. This Ig positive material is thought to represent deposits of immune complexes. As great and greater amounts were seen in fibrocartilage menisci as in hyaline cartilage. A single specimen of disease tendon was also positive. Severe pathologic changes of the matrix characterized by loss of normal morphology, alterations in collagen, and overall reduced density were observed in regions of aggregate deposition with a consistent replacement and disappearance of collagen in the locale of the aggregates themselves. Polymorphonuclear cells in regions of degraded hyaline and tendon matrix were seen to have phagocytosed aggregates. These data give some credence to a direct role of immune aggregates in rheumatoid arthritis articular collagenous tissues in disease pathogenesis.


A subgroup of ankylosing spondylitis associated with HLA-B7 in American blacks.

In a study of 34 American black patients with primary ankylosing spondylitis, 18 were found to be HLA-B27-negative. Of these, 10 possessed HLA-B7 (55.6%) compared to 23.7% of 59 B27-negative black controls (P less than 0.025, relative risk = 4). On comparing these 10 B7-positive patients (group I) with 16 B27-positive black patients (group II), a difference in mean age at onset of disease was found: 33.6 years in group I and 22.2 years in group II (P less than 0.005). In addition, a family history of ankylosing spondylitis was absent in group I patients but present in 6 patients in group II (P = 0.034). These findings indicate an association between HLA-B7 and ankylosing spondylitis in American blacks and suggest that these patients who lack B27 but possess B7 represent a subgroup of patients with this disease.


The infectious etiology of rheumatoid arthritis. New considerations.

Several possible mechanisms of chronic inflammatory arthritis that might be initiated by infectious agents are discussed. Some recent information on mycoplasma infections, long-term virus infections, and shed bacterial components provides the bases for new experimental approaches. Currently, evidence of involvement of mycoplasma or viral agents in rheumatoid arthritis is tenuous. Chronic peptidoglycan-immune-complex formation is a consideration that has been discussed, but only recently pursued in depth. It may well be that experimental studies on the infectious etiology of rheumatoid arthritis will be revitalized through an appreciation of the bacterial antigen load in the gastrointestinal tract. The perimental vehicles for testing this possibility are available and should be directly applicable at the clinical level.


The specific suppression of contact sensitivity.

The ability of 2,4,6 trinitrobenzenesulfonic acid (TNBS)-induced regulatory cells to modulate the generation of contact sensitivity (CS) to picryl chloride has been studied. We have confirmed that such suppressor cells can modulate CS and have extended these observations to demonstrate that suppressor factors, liberated by suppressor cells in supernatants, can limit the generation of CS. We have also confirmed that hapten-coupled membrane products can induce tolerance to PCl. The investigation of the properties of the suppressor factors has revealed that they are hapten-specific and bear H2 coded specificities.


Association of systemic lupus erythematosus and SLE-like syndromes with hereditary and acquired complement deficiency states.

The most prominent association of rheumatic diseases with hereditary complement deficiency is systemic lupus erythematosus (SLE) and discoid lupus erythematosus with homozygous C2 deficiency in females. The lupus disease in these patients differ from classic lupus in 1) the increased incidence of discoid lesions, 2) the low incidence of renal disease, 3) the low or absent titers of antibodies to native DNA, and 4) the infrequent finding of immunoglobulin and complement in skin lesions. The strong positive linkage disequilibrium between C2 deficiency and HLA genes raises the possibility that genes other than those determining C2 levels may have the primary role in determining predisposition to disease in these patients. However, the finding of similar diseases in certain patients with hereditary angioedema and SLE-related syndrome who have acquired deficiency of the early components of complement supports a primary role of the C2 deficiency gene in predisposing to lupus disease in these patients.


Epidemiology of anti-lymphocyte antibodies in systemic lupus erythematosus.

Lymphocytotoxic antibodies (LCTA) occur in 80% of SLE patients and 40% to 60% of their asymptomatic relatives. They occur equally in consanguineous and nonconsanguineous relatives, are more common with close proband contact, and vary directly with LCTA activity in the proband. LCTA are also increased in laboratory personnel handling SLE blood. Anti-RNA antibodies are found in SLE patients and consanguineous relatives. Both antibodies are primarily IgM in relatives but are IgM and IgG in SLE patients.


Effect of clofibrate on in vivo triglyceride production and clearance in genetically hyperlipemic rats.

Seventeen hyperlipemic and 17 normolipemic littermate Zucker rats were treated with clofibrate or normal saline to determine the effect of this drug upon hepatic triglyceride (TG) production and peripheral TG disposal. Peripheral Intralipid clearance was not different in hyperlipemic rats relative to control animals. Hyperlipemic animals demonstrated abnormally elevated TG production in the fasted state which was not corrected with clofibrate administration. Following treatment, peripheral Intralipid clearance was increased 100% in hyperlipemic rats, but unchanged in normolipemic animals. These observations provide further evidence that the predominant lipid reducing action of clofibrate is manifested only in the hyperlipemic state, and predominantly upon peripheral lipid disposal.


Incorporation of labelled glucose and glycerol into phospholipids and triglycerides by rat and rabbit aorta.

[1-14C]Glycerol and [U1-14C]glucose were incorporated into aortic phospholipids and triglycerides by isolated rat and rabbit aorta. The major portion of radioactivity was found in the glycerol moiety of triglycerides and phospholipids. Within the range of concentrations studied the rate of incorporation of [1-14C]glycerol was dependent on substrate concentration, whereas the rate of incorporation of [U1-14C]glucose was not. The distribution of radioactivity in the glycerophosphatides was found mainly in phosphatidylserine and phosphatidic acid when [1-14C]glycerol was used as substrate. On the other hand, the major portion of radioactivity was found in phosphatidylcholine when [U1-14C]glucose was the substrate. The incorporation of [1-14C]glycerol and [U1-14C]glucose into aortic triglycerides and phospholipids was markedly increased by aortae obtained from rabbits fed an atherogenic diet as compared to aortae from control animals. Results from double-labeled glycerol containing both [2-3H]glycerol and [1-14C]glycerol indicated that the biosynthesis of triglycerides and phospholipids in the rat aorta did not use phosphatidic acid from the same pool.


Clofibrate retardation of naturally-occurring arteriosclerosis in repeatedly-bred male and female rats.

Repeatedly-bred, male and female Sprague-Dawley rats which develop hyperglycemia, hyperlipidemia, hypertension, and arteriosclerosis spontaneously were killed at sequential time intervals, i.e., when the females had completed 1, 2, 3 and 4 pregnancies. The control breeders received no treatment; the experimental animals were given 113 mg of clofibrate/100 g of b.w., subcutaneously, daily, 5 times per week. Clofibrate-treated breeders manifested reduction in blood pressure and in the incidence and severity of arterial disease characteristic of repeatedly-bred rats. The aortic lesions of the clofibrate-treated breeders showed attenuation of the usual severe ground substance alterations, the degenerative changes in connective tissue elements, e.g., fibrosis and elastosis, and absence of calcification and cartilaginous metaplasia. Clofibrate-treated breeders did not show any unusual elevation in serum enzymes, e.g., CPK, SGOT, SGPT and LDH, or significant reduction of their hyperlipidemia. They manifested a definite reduction in adrenocortical and medullary histopathology and their circulating corticosterone levels were subnormal compared to non-treated breeders. It is suggested that the protective effect of clofibrate was mediated through its ability to block normal adrenal steroidogenic pathways rather than through its antilipemic action.


The role of hemodynamic factors in arterial wall thickening in the rat.

In a study on the pathogenesis of arterial wall thickening, hemodynamic factors in the common carotid artery of the rat were experimentally altered with an autograft. The relationship between flow pattern and wall-thickening was examined in a half-ring bypass model with an induced stenosis, using both flow-visualization in a corresponding in vitro model circuit and observation of the wall by microscopy. Wall-thickening was found in the neighborhood of bifurcations, junctions and curved segments, which corresponded to regions of low-shear in the flow-field. Marked histologic changes in the wall were observed in the post-stenotic segments where the flow field was very disturbed. Histologic changes in the arterial wall correlated well with flow patterns.