Effect of Age and Arteriosclerosis on the Response of Parkinsonian Patients to Levodopa

Twenty-four patients with Parkinsonism were treated with levodopa for up to one year. Ten were aged under 65, 12 were aged 65 or over, and two were specifically included because they were considered to have arteriosclerotic Parkinsonism. These two patients showed no response to treatment. The 10 younger patients showed less clinical evidence of arteriosclerosis than the older ones, and responded significantly better to treatment with levodopa. Mean improvement was 61% in the younger group after 12 months'' treatment and 28% in the older group. Improvement was greatest within three months of starting treatment. Abnormal movements which resulted from treatment with levodopa could be reduced with only slight loss of therapeutic benefit by the addition of tetrabenazine.     

A Comparison of Nitrogen Mustard and Vinblastine Sulfate in the Treatment of Patients with Hodgkin's Disease

In a crossover study the effectiveness of intermittent maintenance doses of nitrogen mustard was compared to that of vinblastine sulfate in the treatment of 61 patients with advanced Hodgkin''s disease. Forty-five of the patients had had previous radiation therapy. Nine of 29 patients who received nitrogen mustard as the first drug had a complete response and five had a partial response. The comparative results in 32 patients receiving vinblastine sulfate first were nine complete responses and 13 partial responses. The median duration of the complete responses to each drug was 43 weeks. The partial responses were of shorter duration. When the second drug was given in adequate doses, almost as many patients responded with a similar median duration of response.It is concluded that nitrogen mustard and vinblastine sulfate are equally effective single agents in the treatment of patients with advanced Hodgkin''s disease and that patient preference would favour vinblastine sulfate because of its negligible side effects.     

Improved control of brittle Parkinsonism by separate administration of levodopa and benserazide.

A 59-year-old woman who had had Parkinsonism for 12 years was treated with orphenadrine and levodopa combined with a dopa carboxylase inhibitor. The initial response was good, but after several years'' treatment her condition alternated between severe bradykinesia and incapacitating, violent chorea, interspersed with short periods of mobility. A new regimen was devised, using levodopa in capsules of 40 mg and benserazide in separate capsules of 10 or 25 mg. Levodopa 40 mg was taken at intervals of half to two and a half hours, usually with benserazide 10 mg but alone in the late morning and evening. Additional benserazide was required one hour after lunch. With this regimen her condition was greatly improved, though she still had an abnormal gait and spells of bradykinesia and chorea. Separate, frequent small doses of levodopa and benserazide may give better control of brittle Parkinsonism.     

Treatment of Parkinsonism with Laevo-Dopa

Thirty-two patients with Parkinsonism were treated with L-dopa. Nine were markedly and 14 moderately improved. Twenty patients tolerated the drug well, derived definite improvement, and were treated for an average period of six months. Improvement was sustained during this period even though the average daily dosage of L-dopa was reduced. Dose-dependent side-effects occurred in 25 patients. It is suggested that dosage schedules should be flexible and tailored to the needs of each individual patient, and that treatment should be continued for six months before presuming it to be ineffective.It is concluded that L-dopa often ameliorates Parkinsonism for long periods, but its effect on the natural history of the disease is undertermined.     

Thiopropazate Hydrochloride in Persistent Dyskinesia

Thiopropazate (Dartalan) was found to be significantly more effective than a placebo in relieving dyskinesia in 23 patients with functional psychosis and persistent dyskinesia associated with prolonged phenothiazine therapy. Each patient whose dyskinesia had persisted unchanged for at least one month after phenothiazine withdrawal received thiopropazate by mouth for three weeks and the placebo for a similar period. Patients were evaluated before the trial, at three weeks, and at six weeks.The drug also improved psychotic behaviour. Possible side effects, which were generally mild, were noted in eight patients, of whom six had Parkinsonism and four drowsiness. None had side effects while on the placebo.The findings indicate that thiopropazate is of value in persistent dyskinesia associated with prolonged phenothiazine intake—a condition hitherto unresponsive to other treatment. Further research is required to determine the long-term effectiveness of the drug.     

Selective decrease of immunoreactive tyrosine hydroxylase in nigrostriatum of adult male rats after N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment

Summary Several laboratories have reported that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine causes damage to the nigral dopamine neurons of man, monkey, and mouse. Controversial data suggest that a rat model of Parkinsonism may be possible. Although loss of dopamine cells has not been detected in the rat brain, our immunocytochemical studies show that immunoreactive tyrosine hydroxylase, the rate-limiting enzyme which synthesizes dopamine, is significantly reduced in concentration, or its antigenicity altered, in substantia nigra/pars compacta as well as the caudate nucleus. Optical density measurements demonstrate the reduction or alteration of immunoreactive tyrosine hydroxylase in nigro-striatal neurons, indicating that axonal terminals, as well as parent perikarya, may be sensitive to the drug. After treatment, abnormal morphological remodelling may result in the affected neuronal processes, perhaps indicating sublethal toxicity, followed by slow recovery. Despite the lack of nigral cell death, it is proposed that the present data support the use of the rat as a model to investigate the early effects of Parkinsonism induced by this agent, and the biological mechanisms of cellular recovery.     

Clinical course of untreated tonic-clonic seizures in childhood: prospective,hospital based study.

OBJECTIVE: To assess decleration and acceleration in the disease process in the initial phase of epilepsy in children with new onset tonic-clonic seizures. STUDY DESIGN: Hospital based follow up study. SETTING: Two university hospitals, a general hospital, and a children''s hospital in the Netherlands. PATIENTS: 204 children aged 1 month to 16 years with idiopathic or remote symptomatic, newly diagnosed, tonic-clonic seizures, of whom 123 were enrolled at time of their first ever seizure; all children were followed until the start of drug treatment (78 children), the occurrence of the fourth untreated seizure (41 children), or the end of the follow up period of two years (85 untreated children). MAIN OUTCOME MEASURES: Analysis of disease pattern from first ever seizure. The pattern was categorised as decelerating if the child became free of seizures despite treatment being withheld. In cases with four seizures, the pattern was categorised as decelerating if successive intervals increased or as accelerating if intervals decreased. Patterns in the remaining children were classified as uncertain. RESULTS: A decelerating pattern was found in 83 of 85 children who became free of seizures without treatment. Three of the 41 children with four or more untreated seizures showed a decelerating pattern and eight an accelerating pattern. In 110 children the disease process could not be classified, mostly because drug treatment was started after the first, second, or third seizure. The proportion of children with a decelerating pattern (42%, 95% confidence interval 35% to 49%) may be a minimum estimate because of the large number of patients with an uncertain disease pattern. CONCLUSIONS: Though untreated epilepsy is commonly considered to be a progressive disorder with decreasing intervals between seizures, a large proportion of children with newly diagnosed, unprovoked tonic-clonic seizures have a decelerating disease process. The fear that tonic-clonic seizures commonly evolve into a progressive disease should not be used as an argument in favour of early drug treatment in children with epilepsy.     

Dyspnoea,asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate the occurrence of asthma and dyspnoea precipitated or worsened by angiotensin converting enzyme inhibitors. DESIGN--Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation''s international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. SUBJECTS--Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. MAIN OUTCOME MEASURES--Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. RESULTS--In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had adverse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dyspnoea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. CONCLUSION--Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.     

Effect of new dopamine-blocking agent (oxiperomide) on drug-induced dyskinesias in Parkinson's disease and spontaneous dyskinesias.

Oxiperomide, a new dopamine-receptor antagonist, was found to decrease dyskinesias in patients with Parkinson''s disease receiving levodopa or other dopamine agonists without necessarily increasing Parkinsonian symptoms. Oxiperomide also decreased spontaneous dyskinesias in those with tics and chorea and to a less extent in those with torsion dystonia, without necessarily causing Parkinsonism. These results provide evidence that more than one population of dopamine receptors exist in the extra pyramidal system, and encourage the search for selective dopamine antagonists.     

Sj?rgren's syndrome treated with bromhexine: a randomised clinical study.

Existing treatment for Sjögren''s syndrome is unsatisfactory, and uncontrolled observations have suggested that bromhexine may be effective. Twenty-nine patients with Sjögren''s syndrome were therefore assigned to two randomised double-blind crossover trials with bromhexine and placebo, each comprising two two-week periods. In the first trial bromhexine 24 mg/day was given by mouth; in the second the dose was increased to 48 mg/day. After each treatment period the Schirmer test response, break-up time, Bijsterveld score, and the time taken for the patient to eat a dry biscuit were recorded, as well as the patient''s estimate of moistness in the eyes and mouth. In the second (higher-dose) trial values on the Schirmer test were significantly higher after bromhexine than after placebo and the break-up time was also increased after bromhexine, which suggested that the drug has a dose-dependent effect on lacrimal gland secretion in Sjögren''s syndrome. It had no effect on salivary gland function. Bromhexine is therefore valuable in the treatment of Sjögren''s syndrome.     

Disease-causing mutations in Parkin impair mitochondrial ubiquitination,aggregation, and HDAC6-dependent mitophagy

Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson''s disease (AR-JP). How parkin suppresses Parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these “mito-aggresome” structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP–causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of Parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson''s disease.     

Women's Access and Provider Practices for the Case Management of Malaria during Pregnancy: A Systematic Review and Meta-Analysis

Background

WHO recommends prompt diagnosis and quinine plus clindamycin for treatment of uncomplicated malaria in the first trimester and artemisinin-based combination therapies in subsequent trimesters. We undertook a systematic review of women''s access to and healthcare provider adherence to WHO case management policy for malaria in pregnant women.

Methods and Findings

We searched the Malaria in Pregnancy Library, the Global Health Database, and the International Network for the Rational Use of Drugs Bibliography from 1 January 2006 to 3 April 2014, without language restriction. Data were appraised for quality and content. Frequencies of women''s and healthcare providers'' practices were explored using narrative synthesis and random effect meta-analysis. Barriers to women''s access and providers'' adherence to policy were explored by content analysis using NVivo. Determinants of women''s access and providers'' case management practices were extracted and compared across studies. We did not perform a meta-ethnography. Thirty-seven studies were included, conducted in Africa (30), Asia (4), Yemen (1), and Brazil (2). One- to three-quarters of women reported malaria episodes during pregnancy, of whom treatment was sought by >85%. Barriers to access among women included poor knowledge of drug safety, prohibitive costs, and self-treatment practices, used by 5%–40% of women. Determinants of women''s treatment-seeking behaviour were education and previous experience of miscarriage and antenatal care. Healthcare provider reliance on clinical diagnosis and poor adherence to treatment policy, especially in first versus other trimesters (28%, 95% CI 14%–47%, versus 72%, 95% CI 39%–91%, p = 0.02), was consistently reported. Prescribing practices were driven by concerns over side effects and drug safety, patient preference, drug availability, and cost. Determinants of provider practices were access to training and facility type (public versus private). Findings were limited by the availability, quality, scope, and methodological inconsistencies of the included studies.

Conclusions

A systematic assessment of the extent of substandard case management practices of malaria in pregnancy is required, as well as quality improvement interventions that reach all providers administering antimalarial drugs in the community. Pregnant women need access to information on which anti-malarial drugs are safe to use at different stages of pregnancy. Please see later in the article for the Editors'' Summary     

Genitourinary tuberculosis: study of 20 patients.

In the past year 20 new cases of genitourinary tuberculosis were referred for treatment at Wrightington Hospital. Many of these patients had waited a long time between diagnosis and referral and the start of effective treatment. We suggest that a new short course of chemotherapy should be used, and surgery undertaken during the first three months of treatment, but after the patient has had at least four weeks'' drug treatment. After chemotherapy follow-up may be reduced to two years. Genitourinary tuberculosis remains a serious disease and should be managed by a urologist.     

Controlled Trial Comparing Effect of Two and Six Weeks' Treatment in Recurrent Urinary Tract Infection

Patients with recurrent urinary tract infection were allocated at random to two weeks'' or six weeks'' treatment with an appropriate antibacterial drug. There was no difference in the results achieved by the two different periods of treatment as judged by the presence of infection in the urine one week and six weeks after treatment was stopped.The urine was clear of infection in a higher percentage of patients following a course of nitrofurantoin than following a course of ampicillin, but the difference was not significant.     

Size and usage patterns of private TB drug markets in the high burden countries

Background

Tuberculosis (TB) control is considered primarily a public health concern, and private sector TB treatment has attracted less attention. Thus, the size and characteristics of private sector TB drug sales remain largely unknown.

Methodology/Principal Findings

We used IMS Health data to analyze private TB drug consumption in 10 high burden countries (HBCs), after first mapping how well IMS data coverage overlapped with private markets. We defined private markets as any channels not used or influenced by national TB programs. Private markets in four countries – Pakistan, the Philippines, Indonesia and India – had the largest relative sales volumes; annually, they sold enough first line TB drugs to provide 65–117% of the respective countries'' estimated annual incident cases with a standard 6–8 month regimen. First line drug volumes in five countries were predominantly fixed dose combinations (FDCs), but predominantly loose drugs in the other five. Across 10 countries, these drugs were available in 37 (loose drug) plus 74 (FDCs) distinct strengths. There were 54 distinct, significant first line manufacturers (range 2–11 per country), and most companies sold TB drugs in only a single study country. FDC markets were, however, more concentrated, with 4 companies capturing 69% of FDC volume across the ten countries. Among second line drugs, fluoroquinolones were widely available, with significant volumes used for TB in India, Pakistan and Indonesia. However, certain WHO-recommended drugs were not available and in general there were insufficient drug volumes to cover the majority of the expected burden of multidrug-resistant TB (MDR-TB).

Conclusions/Significance

Private TB drug markets in several HBCs are substantial, stable, and complicated. This calls for appropriate policy and market responses, including expansion of Public-Private Mix (PPM) programs, greater reach, flexibility and appeal of public programs, regulatory and quality enforcement, and expansion of public MDR-TB treatment programs.     

Clínica de la demencia con cuerpos de Lewy y evolución frente a la enfermedad de Alzheimer

Lewy body dementia (LBD) is a neurodegenerative disease with well-defined symptoms and established clinical criteria, characterized by the presence of cortical and subcortical dementia, accompanied by some characteristic features such as Parkinsonism, visual hallucinations and fluctuations in alertness and attention, as well as hypersensitivity to neuroleptics. Compared with Alzheimer's disease, LBD seems to have a more rapid clinical course and greater mortality. The differences with Alzheimer's disease may be more apparent in the initial stages of the disease but tend to disappear with disease progression. Because of the greater presence of neuropsychiatric symptoms and the higher degree of dependency in LBD, there is greater caregiver overload and probably greater resource use.     

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson''s disease by optimizing stimulation in real time according to fluctuating disease and medication state. In the present realization of adaptive DBS we record and stimulate from the DBS electrodes implanted in the subthalamic nucleus of patients with Parkinson''s disease in the early post-operative period. Local field potentials are analogue filtered between 3 and 47 Hz before being passed to a data acquisition unit where they are digitally filtered again around the patient specific beta peak, rectified and smoothed to give an online reading of the beta amplitude. A threshold for beta amplitude is set heuristically, which, if crossed, passes a trigger signal to the stimulator. The stimulator then ramps up stimulation to a pre-determined clinically effective voltage over 250 msec and continues to stimulate until the beta amplitude again falls down below threshold. Stimulation continues in this manner with brief episodes of ramped DBS during periods of heightened beta power.Clinical efficacy is assessed after a minimum period of stabilization (5 min) through the unblinded and blinded video assessment of motor function using a selection of scores from the Unified Parkinson''s Rating Scale (UPDRS). Recent work has demonstrated a reduction in power consumption with aDBS as well as an improvement in clinical scores compared to conventional DBS. Chronic aDBS could now be trialed in Parkinsonism.     

Spin-Lattice Distribution MRI Maps Nigral Pathology in Progressive Supranuclear Palsy (PSP) during Life: A Pilot Study

An MRI biomarker for Parkinsonism has long been sought, but almost all attempts at conventional field strengths have proved unsatisfactory, since patients and controls are not separated. The exception is Spin-Lattice Distribution MRI (SLD-MRI), a technique which detects changes in the substantia nigra (SN) due to changes in the spin-lattice relaxation time, T₁. This easily separates patients with Parkinson''s disease (PD) from control subjects at 1.5 Tesla, suggesting that it may be sensitive to presymptomatic disease. SLD-MRI demonstrates a topography of signal change within the SN which is the same as the known topography of pathological change, where the lateral portions of the nucleus are more affected than the medial. In a further step towards its validation, we apply SLD-MRI to a disease control, Progressive Supranuclear Palsy (PSP), the most common of the atypical forms of Parkinsonism. In PSP the topography of pathological change in the SN is reversed. We therefore hypothesized that PSP would show a topography of SLD-MRI signal change in the SN that is the reverse of PD (i.e. the medial portion is more affected than the lateral). All 7 patients showed such a topography of MR signal, and all patients were separated from control subjects. Although this is a step toward validation of SLD-MRI with respect to sensitivity and disease specificity, nevertheless we stress that this is a pilot project only. Validation will only be possible when comparing larger cohorts of PSP, PD and control subjects.