Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24.

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

Pharmacologic treatment of essential tremor.

Essential tremor (ET) is a common movement disorder that often causes functional disability, potentially leading to physical and emotional difficulties. The paucity of data available regarding the underlying pathophysiologic mechanism of ET hinders the development of innovative approaches to pharmacotherapeutic treatments. Options for drug therapy include the use of primidone, beta-adrenergic blockers, such as propranolol, alcohol, and other drugs, such as benzodiazepines, gabapentin, carbonic anhydrase inhibitors, clozapine, flunarizine, clonidine, and the methylxanthine derivative theophylline. Chemodenervation with botulinum toxin type A may be a therapeutic option for selected patients with ET. Each drug is classified as to the quality of evidence for efficacy and the suggested strength of therapeutic recommendation. In general clinical practice, primidone and propranolol have proven efficacy in ET.

Early Parkinson's disease: what is the best approach to treatment.

Early and correct diagnosis and treatment of Parkinson's disease (PD) are crucial for the patient's well being. At the first visit, it is important to deal with the patient's misconceptions of the disease and its course, to offer sources of information and to suggest exercises. To make a correct initial diagnosis of PD we need to assess the course of the initial levodopa responsiveness. The most frequent challenges in diagnosing PD are the conditions of essential tremor and multiple system atrophy. PD has 3 stages of development: (i) early--from the onset of symptoms to the appearance of motor fluctuations; (ii) middle--from motor fluctuations to the appearance of moderate-to-severe disability; and (iii) advanced--when moderate-to-severe disability is present. The medical treatment of early PD should be started when functional disability appears, which is a different threshold for each patient. For patients below 65 years old, or above 65 years old but with preserved mental function and with no severe comorbidity, initial monotherapy with a dopamine agonist is advisable. This approach appears to delay the appearance and reduce the amount of late motor complications with subsequent levodopa treatment. All dopamine agonists have similar efficacy, which is less than that of levodopa. It is important to consider the adverse effect profile when a choice for initial or adjunctive therapy is made. When levodopa therapy is started as an adjunct in younger patients or as initial monotherapy in older patients, sustained-release levodopa preparations are preferred. They have a longer half-life and possibly stimulate the dopamine receptors more continuously. Anticholinergic drugs are appropriate for younger patients with tremor-dominant PD. Amantadine is mainly used for dyskinesia control. Catechol-O-methyl-transferase inhibitors and neurosurgery are not treatments of choice for early PD but can be very effective for more advanced disease. The presence of presymptomatic markers of PD, such as changes in odour detection, handwriting, speech, movement time of self-initiated motor acts, personality traits, presence of antibodies against dopaminergic neurons, pattern of positron emission tomography results, appearance of mitochondrial DNA mutation profiles, etc., appear to be very important in the light of the emerging neuroprotective therapies. Neuroprotection is aimed at slowing the rate of disease progression. Selegiline has been shown to cause a mild delay in the need for levodopa, possibly suggesting some protection. However, this initial benefit was not sustained in long term studies. Currently, there is no neuroprotective drug for PD.

Effect and time course of deep brain stimulation of the globus pallidus and subthalamus on motor features of Parkinson's disease.

We studied the effect and temporal profile of deep brain stimulation (DBS) of the globus pallidus and subthalamic nucleus on the motor signs of Parkinson's disease (PD). Four patients with bilateral deep brain stimulators of the globus pallidus and four patients with bilateral deep brain stimulators of the subthalamus were studied while taking no medication and at 15 and 30 minutes and 1, 2, 4, and 6 hours after turning stimulation on. An immediate (15 minutes) and sustained (6 hours) benefit was observed for all the motor manifestations of PD for both stimulation sites. Deep brain stimulation of the globus pallidus and subthalamus is highly effective in reducing all the cardinal motor features of PD.

Algorithm for assessment of the oxygen, acid-base and electrolyte status (ALBOA BEACH).

To achieve accurate interpretation of blood gas analysis data in intensive care units, the oxygen, acid-base and electrolyte-metabolite profile of arterial blood should be comprehensively and adequately monitored and assessed. A number of diagnostic software programmes have been developed to assist clinicians in this and to help improve instruction in this field. In the present study we describe an algorithm and a programme for assessment of the oxygen, acid-base and electrolyte status of the arterial blood. The algorithm, as well as the software programme, is named ALBOA BEACH, which is an acronym of the programme's full name--ALgorithm for Blood Oxygen, Acid-Base, Electrolyte And respective CHarts. The algorithm takes account of the latest achievements in blood-gas analysis; it can be used both in on-line and off-line modes and is useful in the laboratory and pathophysiological assessment of blood-gas disorders. The algorithm is based on a rigorous pathophysiological analysis and the interpretation achieved as a result is much more accurate than usual. Thus it provides a most reliable basis for taking the right clinical decision and making the proper prognosis of the possible critical conditions. The algorithm also provides additional bases for interpretations of data in the borderline zones, with due warnings in cases of absence of physiological coherence between the various parameters and modules. The programme is designed to be used with the modern multifunctional blood-gas analysers; it can be of assistance in making diagnoses, in the training and research activity in the intensive care units and specialised blood gas laboratories.

Characteristics of tidal expiratory flow pattern in healthy people and patient with chronic obstructive pulmonary disease.

According to data reported in literature tidal breathing parameters and especially tidal expiratory flow pattern parameters can be useful in distinguishing airflow obstruction. The purpose of the present study was to investigate the parameters of the tidal breathing in healthy people and patients with chronic obstructive pulmonary disease. The study sample included 158 patients with COPD in clinically stable condition and different degree of functional disturbances (FEV1% pred. = 42% +/- 15%; ATS dyspnea scale = 2.5 +/- 0.9; mean +/- SD). The control group of healthy subjects consisted of 43 men and 37 women. The obtained results show that TPTEF/TE (the time necessary to reach the peak expiratory flow in tidal breathing over the total expiratory time) and VPTEF/VE (the volume necessary to reach the peak expiratory flow in tidal breathing over the total expiratory volume) are an independent aspect of tidal breathing. In healthy people these parameters show weak negative correlation with age and high variability. In COPD they are statistically significantly lower than those of healthy people but, since they are highly variable, they cannot be used for an individual assessment. The increase of the mean inspiratory flow (TV/Tin) and the shortening of VPTEF/VE, TPTEF/TE and Tin/Ttot, are indicative of the lung mechanics changes which have a bearing on dyspnea, too. According to factor analysis the parameters of tidal breathing are four separate dimensions: 1. Breathing frequency and respiratory times; 2. Relationship between the respiratory times; 3. Minute ventilation, mean expiratory flow, mean inspiratory flow and tidal volume; 4. Parameters of the expiratory flow VPTEF/VE and TPTEF/TE. The parameters of forced expiration and those of tidal breathing are separate dimensions of the functional profile of patients with COPD.

Studies on the plasma cholesterol and triacylglycerols in chronic methemoglobinemia in rats.

Plasma cholesterol and triacylglycerols were measured in rats with modelled chronic two-stage (mild and moderate) intermittent nitrite methemoglobinemia for 15 and 30 days. It was found that at the moment of methemoglobinemic peak (60 +/- 10 min) the experimental animals had mixed (hemtoxic, anemic and hypoxic) hypoxemia. The every day "pulse" decrease of the total oxygen concentration during the 30-day methemoglobinemia was accompanied with a significant rise (p < 0.05) of cholesterol concentrations in the high-density lipoproteins and the total cholesterol, as well as a decrease in the amount of triacylglycerols. These changes are considered to represent the side effects of adaptation for whose elucidation further research is needed.

Relationships between blood oxygen parameters in patients with chronic obstructive lung disease.

The hemoglobin-oxygen dissociation curve and the relationships between the parameters of tension, saturation, capacity, affinity and concentration of oxygen in the course of respiratory failure in chronic obstructive lung diseases (COLD) were studied. The study included 141 patients divided into four basic groups according to the value of pO2 (a): patients with normoxia, mild, moderate and severe arterial hypoxia. The blood-gas status was determined using the ABL-330 and OSM-3 analyzers (Radiometer A/S, Denmark). It is concluded that: 1. Presence of normoxia (pO2 and sO2 in norm) in COLD patients does not exclude abnormalities in their arterial blood oxygen transport and increased risk of tissue hypoxia. 2. Total oxygen concentration in respiratory failure is relatively stable and "independent" from the stepwise decrease of the arterial pO2, which results from the compensatory increase of the total and effective hemoglobin. 3. There are phase fluctuations of the ctO2/pO2 dissociation curve in the reference interval, expressed in the "lowering" of P50 and p90 in mild hypoxia and the "centering" or "raising" of their values in severe hypoxia. Such fluctuations are more pronounced in the p90 than in the p50. 4. The oxygen extraction tension lowers progressively (without reaching the anaerobic threshold) and the oxygen compensation factor elevates with the pO2 (a) reduction and the arising of hypercapnia and acidemia. 5. The calculated 2,3-diphosphoglycerate (2,3-DPG) concentration values are significantly higher in hypercapnics with COHb > 1% than in those with COHb < 1%. The relationships between hypoxia, oxygen affinity, hemoglobinemia and oxygen affinity as well as the dissociation curve properties in chronic respiratory failure are discussed.

A factor analysis of dyspnea indexes and lung function parameters in patients with chronic obstructive pulmonary disease.

The purpose of the present study was to investigate the correlation between dyspnea ratings and a large group of lung function parameters, and extract those factors that best reflect the functional profile of patients with COPD using factor analysis. Ninety nine patients with COPD in stable clinical condition (age 60 +/- 8 years, ATS score = 2.5 +/- 0.9, FEV1% pred. = 33 +/- 13%) were included in the study. The factor analysis of the results yielded 5 factors which accounted for 80.1% of the total variance of the changes. The highest coefficients found between the factors and the original group of variables after Varimax rotation are given in the following table: Factor 1: Oxygen-cost diagram: 0.92; ATS dyspnea score: -0.80; TL,CO/VA: 0.78; Factor 2: FEV1% pred.: 0.87; FEV1/VC%: 0.86; FEV1L: 0.79; Factor 3: MIF50% pred.: 0.85; FIV1% pred.: 0.76; PImax: 0.67; Factor 4: PaCO2: -0.81; SaO2: 0.77; Mean pulmonary arterial pressure: -0.67 Factor 5: Age: 0.88; Six minutes walk distance: -0.72 The factor analysis showed that the functional profile of COPD patients has several dimensions. Therefore, in order to have COPD comprehensively evaluated, assessment of dyspnea and the respective set of lung function parameters (exercise capacity, forced inspiration and pulmonary hemodynamics), should be included in the battery of tests, besides the conventional tests.

Comparison of estimated energy requirements in severely burned patients with measurements by using indirect calorimetry.

Severe burn injuries give rise to an extreme state of physiological stress. No other trauma results in such an accelerated rate of tissue catabolism, loss of lean body mass, and depletion of energy and protein reserves. A heightened attention to energy needs is essential, and the significance of adequate nutritional support in the complex management of patients with major burns is very important. The purpose of this study is to compare the results obtained by three of the most popular methods of estimating energy requirements in severely burned adult patients with the measurements of resting energy (REE) expenditure by indirect calorimetry (IC). A prospective study was carried out of 20 patients (male/female ratio, 17/3; mean age, 37.83 ± 10.86 yr), without accompanying morbidities, with burn injuries covering a mean body surface area of 34.27 ± 11.55% and a mean abbreviated burn severity index of 7.44 ± 1.58. During the first 30 days after trauma, the energy requirements were estimated using the Curreri, Long, and Toronto formulas. Twice weekly measurements of REE by IC were obtained. It was found that the Curreri and Long formulas overestimated the energy requirements in severely burned patients, as found by other investigators. However, no significant difference was found between the daily energy requirements calculated by the Toronto formula and the measured REE values by IC. It is concluded that the Toronto formula can be used as an alternative method for estimating the energy requirements of patients with major burns in cases where IC is not available or not applicable.

Mapping of a distal form of spinal muscular atrophy with upper limb predominance to chromosome 7p.

An autosomal dominant distal form of spinal muscular atrophy mainly affecting the upper limbs with a mean age of onset of 17 years has been identified in a large Bulgarian family. Linkage of the above family to the spinal muscular atrophy type I, II and III locus on chromosome 5 has been excluded. In an attempt to map this disease gene we have analysed individuals of this family, with more than 140 microsatellite polymorphic markers of the human genome. A maximum lod score of 5.99 at theta = 0.007 has been obtained with locus D7S795. We have thus mapped the gene for this hereditary form of distal spinal muscular atrophy to chromosome 7p.

Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings.

A previously unrecognized neuropathy was identified in Bulgarian gypsies, and was designated hereditary motor and sensory neuropathy-Lom (HMSNL) after the town where the initial cases were found. It was subsequently identified in other gypsy communities. The disorder, which is of autosomal recessive inheritance, was mapped to chromosome 8q24. It begins consistently in the first decade of life with gait disorder followed by upper limb weakness in the second decade and, in most subjects, by deafness which is most often first noticed in the third decade. Sensory loss affecting all modalities is present, both this and the motor involvement predominating distally in the limbs. Skeletal deformity, particularly foot deformity, is frequent. Severely reduced motor nerve conduction velocity indicates a demyelinating basis, which was confirmed by nerve biopsy. The three younger patients biopsied showed a hypertrophic 'onion bulb' neuropathy. The hypertrophic changes were not evident in the oldest individual biopsied and it is likely that they had regressed secondarily to axon loss. In the eight cases in which brainstem auditory evoked potentials could be recorded, the results suggested demyelination in the eighth cranial nerve and also abnormal conduction in the central auditory pathways in the brainstem. As no myelin genes are known to be located at chromosome 8q24, the disorder may involve a gene for a novel myelin protein or be due to an abnormality of axon-Schwann cell signalling.