Lateralization of virtual sound sources with a binaural cochlear-implant sound coding strategy inspired by the medial olivocochlear reflex.

Many users of bilateral cochlear implants (BiCIs) localize sound sources less accurately than do people with normal hearing. This may be partly due to using two independently functioning CIs with fixed compression, which distorts and/or reduces interaural level differences (ILDs). Here, we investigate the potential benefits of using binaurally coupled, dynamic compression inspired by the medial olivocochlear reflex; an approach termed "the MOC strategy" (Lopez-Poveda et al., 2016, Ear Hear 37:e138-e148). Twelve BiCI users were asked to localize wideband (125-6000 Hz) noise tokens in a virtual horizontal plane. Stimuli were processed through a standard (STD) sound processing strategy (i.e., involving two independently functioning sound processors with fixed compression) and three different implementations of the MOC strategy: one with fast (MOC1) and two with slower contralateral control of compression (MOC2 and MOC3). The MOC1 and MOC2 strategies had effectively greater inhibition in the higher than in the lower frequency channels, while the MOC3 strategy had slightly greater inhibition in the lower than in the higher frequency channels. Localization was most accurate with the MOC1 strategy, presumably because it provided the largest and less ambiguous ILDs. The angle error improved slightly from 25.3° with the STD strategy to 22.7° with the MOC1 strategy. The improvement in localization ability over the STD strategy disappeared when the contralateral control of compression was made slower, presumably because stimuli were too short (200 ms) for the slower contralateral inhibition to enhance ILDs. Results suggest that some MOC implementations hold promise for improving not only speech-in-noise intelligibility, as shown elsewhere, but also sound source lateralization.

Effects of Electrical Stimulation in the Inferior Colliculus on Frequency Discrimination by Rhesus Monkeys and Implications for the Auditory Midbrain Implant.

UNLABELLED: Understanding the relationship between the auditory selectivity of neurons and their contribution to perception is critical to the design of effective auditory brain prosthetics. These prosthetics seek to mimic natural activity patterns to achieve desired perceptual outcomes. We measured the contribution of inferior colliculus (IC) sites to perception using combined recording and electrical stimulation. Monkeys performed a frequency-based discrimination task, reporting whether a probe sound was higher or lower in frequency than a reference sound. Stimulation pulses were paired with the probe sound on 50% of trials (0.5-80 µA, 100-300 Hz, n = 172 IC locations in 3 rhesus monkeys). Electrical stimulation tended to bias the animals' judgments in a fashion that was coarsely but significantly correlated with the best frequency of the stimulation site compared with the reference frequency used in the task. Although there was considerable variability in the effects of stimulation (including impairments in performance and shifts in performance away from the direction predicted based on the site's response properties), the results indicate that stimulation of the IC can evoke percepts correlated with the frequency-tuning properties of the IC. Consistent with the implications of recent human studies, the main avenue for improvement for the auditory midbrain implant suggested by our findings is to increase the number and spatial extent of electrodes, to increase the size of the region that can be electrically activated, and to provide a greater range of evoked percepts. SIGNIFICANCE STATEMENT: Patients with hearing loss stemming from causes that interrupt the auditory pathway after the cochlea need a brain prosthetic to restore hearing. Recently, prosthetic stimulation in the human inferior colliculus (IC) was evaluated in a clinical trial. Thus far, speech understanding was limited for the subjects and this limitation is thought to be partly due to challenges in harnessing the sound frequency representation in the IC. Here, we tested the effects of IC stimulation in monkeys trained to report the sound frequencies they heard. Our results indicate that the IC can be used to introduce a range of frequency percepts and suggest that placement of a greater number of electrode contacts may improve the effectiveness of such implants.

Cost Effectiveness of Childhood Cochlear Implantation and Deaf Education in Nicaragua: A Disability Adjusted Life Year Model.

INTRODUCTION: Cochlear implantation (CI) is a common intervention for severe-to-profound hearing loss in high-income countries, but is not commonly available to children in low resource environments. Owing in part to the device costs, CI has been assumed to be less economical than deaf education for low resource countries. The purpose of this study is to compare the cost effectiveness of the two interventions for children with severe-to-profound sensorineural hearing loss (SNHL) in a model using disability adjusted life years (DALYs). METHODS: Cost estimates were derived from published data, expert opinion, and known costs of services in Nicaragua. Individual costs and lifetime DALY estimates with a 3% discounting rate were applied to both two interventions. Sensitivity analysis was implemented to evaluate the effect on the discounted cost of five key components: implant cost, audiology salary, speech therapy salary, number of children implanted per year, and device failure probability. RESULTS: The costs per DALY averted are $5,898 and $5,529 for CI and deaf education, respectively. Using standards set by the WHO, both interventions are cost effective. Sensitivity analysis shows that when all costs set to maximum estimates, CI is still cost effective. CONCLUSION: Using a conservative DALY analysis, both CI and deaf education are cost-effective treatment alternatives for severe-to-profound SNHL. CI intervention costs are not only influenced by the initial surgery and device costs but also by rehabilitation costs and the lifetime maintenance, device replacement, and battery costs. The major CI cost differences in this low resource setting were increased initial training and infrastructure costs, but lower medical personnel and surgery costs.

Partial deafness cochlear implantation (PDCI) and electric-acoustic stimulation (EAS).

The purposes of this paper are to (1) review briefly the experience to date with combined EAS for patients with some residual, low-frequency hearing; and (2) describe the further results that have been obtained with this combination for patients with higher levels of residual hearing at low frequencies, termed 'PDCI'. In broad terms, PDCI and combined EAS have produced large improvements in the speech reception abilities of the treated patients, compared with preoperative scores or with postoperative scores for electric stimulation only or acoustic stimulation only. The benefits have been especially large for recognition of speech presented in competition with interfering sounds such as speech-spectrum noise. Although PDCI and combined EAS have been established as highly effective procedures, questions remain about optimal combinations of electric and acoustic stimuli; the ideal depth of insertion for the electrode array; whether the ideal depth may vary from patient to patient; and whether the reliability of hearing preservation in an implanted cochlea can be increased beyond the present high levels. The answers to these questions could lead to even better treatments for persons with little or no hearing at high frequencies and at least some remaining hearing at low frequencies.

Phosphatidylinositol mannoside ether analogues: syntheses and interleukin-12-inducing properties.

Phosphatidylinositol mannosides (PIMs) isolated from mycobacteria have been identified as an important class of glycolipids with significant immune modulating properties. We present here the syntheses of phosphatidylinositol dimannoside ether analogues 2 and 3 and evaluate their interleukin-12 (IL-12)-inducing properties along with dipalmitoyl PIM2 (1) in an in vitro bovine dendritic cell assay. Both synthetic PIM analogues and synthetic dipalmitoyl PIM2 (1) were effective at enhancing IL-12 production by immature bovine dendritic cells. Unexpectedly, ether analogue 2 was significantly more active than dipalmitoyl PIM2 (1) which indicates that modified PIM compounds can be strongly immunoactive and may have significant adjuvant activities.

Design for a simplified cochlear implant system.

A simplified cochlear implant (CI) system would be appropriate for widespread use in developing countries. Here, we describe a CI that we have designed to realize such a concept. The system implements 8 channels of processing and stimulation using the continuous interleaved sampling (CIS) strategy. A generic digital signal processing (DSP) chip is used for the processing, and the filtering functions are performed with a fast Fourier transform (FFT) of a microphone or other input. Data derived from the processing are transmitted through an inductive link using pulse width modulation (PWM) encoding and amplitude shift keying (ASK) modulation. The same link is used in the reverse direction for backward telemetry of electrode and system information. A custom receiver-stimulator chip has been developed that demodulates incoming data using pulse counting and produces charge balanced biphasic pulses at 1000 pulses/s/electrode. This chip is encased in a titanium package that is hermetically sealed using a simple but effective method. A low cost metal-silicon hybrid mold has been developed for fabricating an intracochlear electrode array with 16 ball-shaped stimulating contacts.

Increased osteoblastogenesis and decreased bone resorption protect against ovariectomy-induced bone loss in thrombospondin-2-null mice.

Although bone is composed primarily of extracellular matrix (ECM), the dynamic role that the ECM plays in regulating bone remodeling secondary to estrogen loss is relatively unexplored. Previous studies have shown that mice deficient in the matricellular protein thrombospondin-2 (TSP2-null) form excess endocortical bone; thus, we postulated that enhanced bone formation in TSP2-null mice could protect against ovariectomy (OVX)-induced bone loss. Wild-type (WT) OVX mice showed a significant loss of both midfemoral endocortical and proximal tibial trabecular bone, but OVX did not significantly alter TSP2-null bone. TSP2-null mice showed an increase in bone formation, as indicated by a 70% increase in serum osteocalcin two weeks post OVX and a two-fold increase in bone formation rate (BFR) five weeks post OVX as measured by dynamic histomorphometry. WT animals showed only a 20% increase in serum osteocalcin at two weeks and no change in BFR at five weeks. This increase in bone formation in TSP2-null OVX mice was accompanied by a three-fold increase in osteoprogenitor number. Although these results provide a partial explanation for the maintenance of bone geometry post-OVX, TSP2-null mice five weeks post-OVX also showed a significantly lower level of bone resorption than OVX WT mice, as determined by serum levels of the amino-terminal telopeptide of type I collagen (NTx). We conclude that the absence of TSP2 protects against OVX-induced bone loss by two complementary processes: increased formation and decreased resorption.

Cochlear implants: some likely next steps.

The history of cochlear implants is marked by large improvements in performance, especially over the past two decades and especially due to the development of ever-better processing strategies. Although the progress to date has been substantial, present devices still do not restore normal speech reception, even for top performers and particularly for listening to speech in competition with noise or other talkers. In addition, a wide range of outcomes persists, with some patients receiving little benefit using the same devices that support high levels of speech reception for others. The purpose of this review is to describe some likely possibilities for further improvement, including (a) combined electric and acoustic stimulation of the auditory system for patients with significant residual hearing, (b) use of bilateral implants, (c) a closer replication with implants of the processing steps in the normal cochlea, and (d) applications of knowledge about factors that are correlated with outcomes to help patients presently at the low end of the performance scale.

Three-month results with bilateral cochlear implants.

OBJECTIVES: To evaluate possible binaural listening advantages for speech in quiet, speech in noise, and for localization in a group of postlingually deafened adults with two cochlear implants functioning independently after 3 mo experience. DESIGN: Nine postlingually deafened subjects who had received a Cochlear Corporation CI24M implant in each ear were evaluated on a number of tasks. The subjects all had audiometric or biographical (e.g., duration of deafness) differences between the ears. Word and sentence materials were presented to the subjects in quiet and in noise with the signal always in the front and the noise from the front or either side. Results are reported for each ear and for both ears with the noise on either side. This allowed evaluation of head shadow and squelch effects. Additionally, localization ability was assessed for broadband noise presented either to the right or left of center at 45 degrees azimuth. Localization was assessed for each ear and for both ears. RESULTS: Results of speech testing in quiet showed a significant advantage for the binaural condition over the better ear in four subjects. In noise, with both signal and noise in front of the subject, a significant advantage of two ears over the better ear was found for four subjects. For noise to one side of the head, when the ear opposite the noise source was added to the ear ipsilateral to the noise, a significant advantage was demonstrated for seven of seven tested subjects. When the ear ipsilateral to the noise was added to the ear contralateral to the noise, a significant advantage was shown for only one of seven (noise on right) and three of seven (noise on left) tested subjects. The localization task showed that all seven tested subjects could discriminate 45 degrees left from 45 degrees right above chance with bilateral stimulation. Three subjects could perform the discrimination above chance with only one ear. However, performance with both ears was significantly better than performance with one ear for two of these latter subjects. CONCLUSIONS: We conclude that bilateral cochlear implants can provide real advantages, particularly when it is possible to utilize the ear that is away from a noise source, thus taking advantage of the head shadow effect. In addition, localization ability was generally better with two implants than with one.

Orbital forcing of the marine isotope stage 9 interglacial.

Milankovitch orbital forcing theory has been used to assign time scales to many paleoclimate records. However, the validity of this theory remains uncertain, and independent sea-level chronologies used to test its applicability have been restricted largely to the past approximately 135,000 years. Here, we report U-series ages for coral reefs formed on Henderson Island during sea-level high-stands occurring at approximately 630,000 and approximately 330,000 years ago. These data are consistent with the hypothesis that interglacial climates are forced by Northern Hemisphere summer solar insolation centered at 65 degrees N latitude, as predicted by Milankovitch theory.

Disease-modifying activity of SB 273005, an orally active, nonpeptide alphavbeta3 (vitronectin receptor) antagonist, in rat adjuvant-induced arthritis.

OBJECTIVE: To evaluate the effects of SB 273005, a potent, orally active nonpeptide antagonist of the integrin avbeta3 vitronectin receptor, on joint integrity in rats with adjuvant-induced arthritis (AIA). METHODS: Male Lewis rats with AIA were orally dosed either prophylactically (days 0-20) or therapeutically (days 10-20) with SB 273005. Efficacy was determined by measurement of paw inflammation, assessment of bone mineral density using dual-energy x-ray absorptiometry (DEXA), magnetic resonance imaging (MRI), and histologic evaluation. RESULTS: SB 273005 is a potent antagonist of the closely related integrins, avbeta3 (Ki = 1.2 nM) and alphavbeta5 (Ki = 0.3 nM). When SB 273005 was administered prophylactically to AIA rats twice per day, it inhibited paw edema at doses of 10, 30, and 60 mg/kg, by 40%, 50%, and 52%, respectively. Therapeutic administration twice daily was also effective, and a reduction in paw edema was observed at 30 mg/kg and 60 mg/kg of the antagonist (by 36% and 48%, respectively). SB 273005 was also effective when administered once per day, both prophylactically and therapeutically. Significant improvement in joint integrity in treated rats was shown using DEXA and MRI analyses. These findings were confirmed histologically, and significant protection of bone, cartilage, and soft tissue was observed within the joint. CONCLUSION: Symptoms of AIA in rats were significantly reduced by either prophylactic or therapeutic treatment with the alphavbeta3 antagonist, SB 273005. Measurements of paw inflammation and of bone, cartilage, and soft tissue structure indicated that this compound exerts a protective effect on joint integrity and thus appears to have disease-modifying properties.

Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis.

OBJECTIVE: To evaluate the effects of SB 242235, a potent and selective inhibitor of p38 mitogen-activated protein (MAP) kinase, on joint integrity in rats with adjuvant-induced arthritis (AIA). METHODS: Male Lewis rats with AIA were orally treated either prophylactically (days 0-20) or therapeutically (days 10-20) with SB 242235. Efficacy was determined by measurements of paw inflammation, dual-energy x-ray absorptiometry for bone-mineral density (BMD), magnetic resonance imaging (MRI), microcomputed tomography (CT), and histologic evaluation. Serum tumor necrosis factor alpha (TNFalpha) in normal (non-AIA) rats and serum interleukin-6 (IL-6) levels in rats with AIA were measured as markers of the antiinflammatory effects of the compound. RESULTS: SB 242235 inhibited lipopolysaccharide-stimulated serum levels of TNFalpha in normal rats, with a median effective dose of 3.99 mg/kg. When SB 242235 was administered to AIA rats prophylactically on days 0-20, it inhibited paw edema at 30 mg/kg and 10 mg/kg per day by 56% and 33%, respectively. Therapeutic administration on days 10-20 was also effective, and inhibition of paw edema was observed at 60, 30, and 10 mg/kg (73%, 51%, and 19%, respectively). Significant improvement in joint integrity was demonstrated by showing normalization of BMD and also by MRI and micro-CT analysis. Protection of bone, cartilage, and soft tissues was also shown histologically. Serum IL-6 levels were decreased in AIA rats treated with the 60 mg/kg dose of compound. CONCLUSION: Symptoms of AIA in rats were significantly reduced by both prophylactic and therapeutic treatment with the p38 MAP kinase inhibitor, SB 242235. Results from measurements of paw inflammation, assessment of BMD, MRI, and micro-CT indicate that this compound exerts a protective effect on joint integrity, and thus appears to have disease-modifying properties.

Idoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvant-induced arthritis.

Idoxifene, a selective estrogen receptor modulator, was evaluated in male and female rats with adjuvant-induced arthritis (AA). AA was induced in Lewis rats with Mycobacterium butyricum in paraffin oil injected into the base of the tail, and the animals were treated with idoxifene prophylactically (days 0-21) or therapeutically (days 10-21). Efficacy was determined by measurements of paw inflammation, bone mineral content, and bone mineral density (BMD) with dual X-ray absorptiometry and by histological evaluation. Serum interleukin-6 levels were measured as a marker of the anti-inflammatory effects of the compound. Estrogen was included for comparison and was administered at 5 mg/kg, three times a week s.c. Prophylactic treatment of male AA rats with idoxifene at 10, 3, and 1 mg/kg and estrogen at 5 mg/kg significantly inhibited paw inflammation. There was improved joint integrity measured by BMD and reduced serum interleukin-6 levels in animals treated with 10 mg/kg/day idoxifene. Idoxifene and estrogen were as effective for AA in female Lewis rats as in male rats, significantly inhibiting paw inflammation and improving BMD. Histological evaluation of the tibiotarsal joints of female rats treated with 10 mg/kg showed protection of bone, cartilage, and soft tissue. Therapeutic treatment with either idoxifene or estrogen (starting on day 10 of disease) of male and female Lewis rats also was effective in reducing paw inflammation in these animals, although the effect was much less than that observed with the prophylactic dosing protocol.

Acetaminophen effects on behavioral thermoregulation in albino rats.

Acetaminophen (N-Acetyl-p-aminophenol) was administered intraperitoneally to 15 Sprague-Dawley rats partitioned into 3 studies (5 rats per study) using a within subjects, repeated-measures reversal design. Behavioral thermoregulation was assessed in a cold Skinner Box using 5-sec. exposures of microwave radiation [Specific Absorption Rate = 0.34 Watts/kg/(mW/cm2)] as reinforcing stimuli under a fixed-interval 2-min. schedule of positive reinforcement. Doses of 10, 20, 30, 40, and 50 mg/kg (in solutions of 1%, 2%, 3%, 4%, and 5%) acetaminophen showed stable rates of operant responding for heat compared with significant changes in rates for comparable doses of aspirin in a 1993 study by Vitulli, et al. Weight reductions and temperature increases varied significantly with before-session and after-session measures, respectively. 1994-95 biochemical data of Murphy, et al. from humans following aspirin or acetaminophen ingestion which affect thermoregulation and sleep patterns are discussed in conjunction with behavioral data from rats.

The shape up challenge: a community-based worksite exercise competition.

PURPOSE: To assess organizational and employee participation during three community-wide worksite exercise competitions in two communities. DESIGN: A one-group, posttest-only design was used. Lack of controls, exercise baseline, and the short-term nature of the interventions were limitations. SETTING: The Minnesota Heart Health Program conducted annual exercise campaigns between 1982 and 1989 within three intervention communities to reduce behavioral risk for cardiovascular disease. The Shape Up Challenge was a worksite exercise competition designed, in conjunction with other campaign activities, to increase levels of physical activity. SUBJECTS: A total of 119 participating companies in two Minnesota communities, and 17,626 employees within these worksites, composed the subjects in this study. INTERVENTION: Eligible worksites were invited to participate in a month-long competition during which employees recorded minutes spent daily in aerobic activities. Incentives were established to promote intragroup cooperation and intergroup competition. Companies competed for awards that were based on average minutes of exercise per employee versus per participant. MEASURES: Numbers of companies recruited and participating, campaign activities, minutes of exercise, and costs were recorded on implementation logs. Companies completed surveys describing business type, number and sex of employees, existing health promotion programs, and perceived benefits of participation. RESULTS: Of the 365 companies invited to participate, 33% participated (range 15% to 50%). Participating companies were more likely than nonparticipating companies to offer other health promotion programs and perceived greater benefits from participation. Women and smaller companies had significantly greater participation rates than men and larger companies. Average employee participation rates ranged from as high as 84% in smaller organizations to as low as 16% as organization size increased. CONCLUSIONS: Community-based worksite exercise competitions appear to be a viable strategy for promoting employee exercise, particularly in smaller companies. Group-based contingencies applied in natural work units may facilitate employee participation. Further research is needed to assess the relative efficacy of this approach, compare alternative incentives, and identify strategies to enhance exercise maintenance after the intervention has ceased.

Role of TNF alpha in the induction of antigen induced arthritis in the rabbit and the anti-arthritic effect of species specific TNF alpha neutralising monoclonal antibodies.

OBJECTIVE: To investigate the role of tumour necrosis factor alpha (TNF alpha) in the development of antigen induced arthritis (AIA) in rabbits. METHODS: Monoclonal antibodies to rabbit TNF alpha were developed in rats and were used to detect TNF alpha in synovial fluid by enzyme linked immunosorbent assay and to localise it in tissue sections of synovium and cartilage from rabbits up to 21 days after induction of AIA. An antibody which neutralised TNF alpha activity in vitro was injected into rabbits to block TNF alpha action in vivo in AIA. Joint swelling, leucocyte infiltration into synovium and proteoglycan loss from cartilage were measured and compared with a control group, which were injected with sterile saline. RESULTS: Monoclonal antibodies to purified rabbit TNF alpha were prepared in rats and two were selected which were able to neutralise rabbit TNF alpha in a cytotoxicity bioassay. TNF alpha was detected in significant concentrations (21.7 (SE 0.5) pg/ml) in the arthritic joint fluid of rabbits with AIA only at one day after induction and it was then also sparsely localised in cells of the synovium, but from day 3 onwards it was localised more strongly in the deep zone of articular cartilage. Injection of anti-TNF monoclonal antibody R6 over three days into rabbits with AIA reduced joint swelling and leucocyte infiltration into joint fluid and decreased the expression of CD11b and CD18 on cells in the joint fluid. However, there was no significant reduction in the loss of proteoglycan from articular cartilage, although the joint fluid at three days contained a lower glycosaminoglycan content. The antibody R6 gave most effect at a dose of 0.6 mg/kg and there was no increase in its effectiveness at a fivefold greater dose (3.0 mg/kg). Treatment over 10 days gave a more complete suppression of joint swelling, but did not result in any less proteoglycan loss from cartilage. Treatment for five days with a 16 day follow up gave a significant reduction in swelling for several days beyond the treatment, but the swelling then slowly returned, until by day 21 there was no significant difference in joint swelling and there was also no recovery of cartilage proteoglycan content. A rabbit anti-rat immunoglobulin response was detected at 21 days, which may have limited the long term effectiveness of the antibody. CONCLUSIONS: In AIA in rabbits, TNF alpha was only detected in synovial fluid at one day after induction and there was only limited cellular localisation of TNF alpha in synovium and cartilage from three days. However, neutralising TNF alpha with a monoclonal antibody was effective in suppressing inflammatory changes in the joint during the acute onset of AIA, but it had little effect on the loss of proteoglycan from cartilage. The results suggest that blocking inflammation and synovitis with anti-TNF alpha may be more easily achieved than preventing damage to articular cartilage.

The effect of menadione epoxide on the experimental immune arthritis in the rabbit.

It was shown previously that the experimentally induced arthritis in the rabbit can be largely nullified by subsequent treatment with menadione (by gavage). It is now shown that menadione epoxide, as is produced in the vitamin K cycle, also exerts a beneficial effect histologically and biochemically. Such treatment decreased both the glucose 6-phosphate dehydrogenase and the 6-phosphogluconolactonase activities in the synovial lining cells of the challenged joints towards values found in the unchallenged joints; it had only equivocal effects on the 6-phosphogluconate dehydrogenase activity. The results indicated that the epoxide might be interfering primarily with the lactonase activity.

Amelioration by menadione of the experimental chronic immune arthritis in the rabbit.

The immunological induction of arthritis in the knee of the rabbit is well established as a model for human rheumatoid arthritis. It has the special advantage of allowing the development of the condition, and the effect of disease-modifying agents, to be followed. Attention has been focussed on the activity of glucose 6-phosphate dehydrogenase in the synovial lining cells since the fourfold elevation of this activity was shown to be fundamental in the human condition. An equal elevation of this activity has now been demonstrated in the rabbit model. Furthermore, it has been shown that the oral administration of menadione decreases this activity towards normality with a concomitant decrease in the degree of inflammation.

Nifedipine in the treatment of hypertension.

Nifedipine, a calcium antagonist with a predominant vasodilator action, was evaluated for the treatment of hypertension. A 20 mg-tablet, with a slower absorption and a more sustained blood-level than provided by the 10 mg-capsule was administered to 20 patients. The duration of the trial was 20 weeks. All patients achieved a significant reduction in both systolic (p less than 0.05) and diastolic (p less than 0.001) blood-pressure (B.P.), but 10 patients were withdrawn before completion of the trial period. Two patients, although achieving a fall in B.P. which was significant, did not reach to target level (less than 160/90) on maximal dosage, one patient suffered a stroke due to a cerebral infarct, and seven patients were withdrawn because of side-effects due mainly to vasodilatation. The remaining 10 patients obtained a satisfactory response. In nine patients, who had achieved a satisfactory result, there was no change in plasma renin activity (P.R.A.) during chronic nifedipine administration.