Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Loads applied tangential to a fingertip during an object restraint task can trigger short-latency as well as long-latency EMG responses in hand muscles

Electrical stimulation of the digital nerves can cause short- and long-latency increases in electromyographic activity (EMG) of the hand muscles, but mechanical stimulation of primarily tactile afferents in the digits generally evokes only a long-latency increase in EMG. To examine whether such stimuli can elicit short-latency reflex responses, we recorded EMG over the first dorsal interosseous muscle when subjects (n=13) used the tip of the right index finger to restrain a horizontally oriented plate from moving when very brisk tangential forces were applied in the distal direction. The plate was subjected to ramp-and-hold pulling loads at two intensities (a 1-N load applied at 32 N/s or a 2-N load applied at 64 N/s) at times unpredictable to the subjects (mean interval 2 s; trial duration 500 ms). The contact surface of the manipulandum was covered with rayon—a slippery material. For each load, EMG was averaged for 128 consecutive trials with reference to the ramp onset. In all subjects, an automatic increase in grip force was triggered by the loads applied at 32 N/s; the mean onset latency of the EMG response was 59.8±0.9 (mean ± SE) ms. In seven subjects (54%) this long-latency response was preceded by a weak short-latency excitation at 34.6±2.9 ms. With the loads applied at 64 N/s, the long-latency response occurred slightly earlier (58.9±1.7 ms) and, with one exception, all subjects generated a short-latency EMG response (34.9±1.3 ms). Despite the higher background grip force that subjects adopted during the stronger loads (4.9±0.3 N vs 2.5±0.2 N), the incidence of slips was higher—the manipulandum escaped from the grasp in 37±5% of trials with the 64 N/s ramps, but in only 18±4% with the 32-N/s ramps. The deformation of the fingertip caused by the tangential load, rather than incipient or overt slips, triggered the short-latency responses because such responses occurred even when the finger pad was fixed to the manipulandum with double-sided adhesive tape so that no slips occurred.     

Propranolol, a beta-adrenergic antagonist, retards response to MSH in skin of Anolis carolinensis

Lacking sympathetic innervation, the skin of A. carolinensis, an iguanid lizard, darkens within minutes in response to circulating melanocyte stimulating hormone (MSH) or beta adrenergic agonists such as epinephrine (EPI). This change is produced by dispersion of melanin from a perinculear position within dermal melanophores into superficial dendritic processes. These melanophores possess alpha-2 and beta-2 adrenergic as well as MSH receptors except in a patch of skin behind the eye, the eyespot, which lacks alpha receptors. Activation of beta or MSH receptors leads to stimulation of adenyl cyclase whereas alpha stimulation inhibits the enzyme to override the others. In a series of trials, injection of saline or propranolol was followed after 30 minutes by saline, EPI, or MSH. Propranolol inhibited chromatophore response to EPI. It also, unexpectedly, retarded the response to MSH, increasing latency to eyespot formation and body color change as well as the duration of darkening for both. Alteration of MSH response by a beta blocker could be explained by linkage of both adrenergic receptors and the MSH receptor to a common adenyl cyclase molecule to form a functional unit in the membrane of the melanophore.     

Staphylococcal toxin-induced T cell proliferation in atopic eczema correlates with increased use of superantigen-reactive Vbeta-chains in cutaneous lymphocyte-associated antigen (CLA)-positive lymphocytes

Staphylococcal superantigens have been implicated in the pathogenesis of atopic dermatitis (AD). This may occur through superantigenic activation of T lymphocytes and their subsequent induction of the skin homing receptor CLA on activated cells. We investigated the proliferative responses of peripheral blood mononuclear cells (PBMC) from 10 patients with an infective exacerbation of AD and six normal controls to the staphylococcal superantigens, staphylococcal enterotoxin A and B (SEA, SEB) and toxic shock syndrome toxin-1 (TSST-1), and the mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A). We also assessed CLA and T cell receptor (TCR) Vbeta-chain expression by immunofluorescence and flow cytometry before and after stimulation. PBMC from AD patients showed two-fold increased proliferation to SEA and SEB (P < 0.01) compared with normals, whereas the response to mitogenic stimulation was identical. Analysis of (TCR) Vbeta-chain expression demonstrated increased use of superantigen-reactive Vbeta families in freshly isolated PBMC in AD patients compared with controls. This pattern of Vbeta-chain expression was only observed in the CLA+ but not the total population of T cells. Furthermore, there was a positive correlation between the enhanced PBMC proliferative response and increased expression of superantigen-reactive Vbeta families in atopic patients. These data support the concept that superantigens are important in the pathogenesis of this common condition, and also provide evidence that the increased use of certain Vbeta families in circulating, CLA+, skin homing lymphocytes is of functional significance.     

The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection

We studied the development of respiratory syncytial virus (RSV)-specific IgE and the release of histamine in nasopharyngeal secretions from 79 infants with various forms of respiratory illness due to RSV. RSV-IgE was measured by an enzyme-linked immunosorbent assay; specificity was confirmed by appropriate blocking experiments. Histamine content in the secretions was determined by fluorimetric methods. RSV-IgE was detectable in only one of 19 patients with RSV infection without wheezing, but was detectable in the majority of 60 patients with wheezing (P less than 0.01). Titers of RSV-IgE were significantly higher in patients with wheezing (P less than 0.05). Histamine was detectable in secretions of some patients with all forms of illness but was detected significantly more often (P = 0.05) and in higher concentrations in patients with wheezing. Peak titers of RSV-IgE and concentrations of histamine correlated significantly with the degree of hypoxia (P less than 0.001). Formation of RSV-specific IgE and release of histamine may adversely affect the outcome of RSV infection.     

A reappraisal of frog muscle chloride conductance-voltage relations at pH 9

Voltage clamp experiments in muscle show that the steady state chloride conductance at pH 9 remains rather independent of [Cl^–]_o, for [Cl^–]_o in the range 165–265 mM. The steady state conductance-voltage relation has a maximum near V _rest — 20 mV. The initial-conductance — voltage relation obtained when the voltage is stepped away from a constant conditioning value (e.g. the resting potential) approaches an asymptotic maximum for hyperpolarizing steps and a minimum for depolarizing steps. The conductance declines with time if the test voltage is more negative than the resting potential, but remains constant if it is more positive. When the conditioning voltage is varied and the test kept constant the initial conductance at the step is also seen to be sigmoidal, if the test step is hyperpolarizing: for large negative conditioning steps the conductance at the test potential approaches the same asymptotic value as does the steady state relation, independent of the test voltage. At positive conditioning voltages it approaches a maximum asymptote which is dependent on the test voltage. When the test step is positive-going the initial conductance at the step is weakly dependent on the conditioning voltage and for large negative conditioning potentials is larger than predicted from the steady state relation. In summary, during hyperpolarizing voltage steps the chloride conductance seems to decline due to a gating phenomenon, but openstate conductance seems to be voltage-dependent, and at membrane potentials more positive than the resting it rapidly (within the settling time of the clamp) assumes a value almost independent of any preceding (conditioning) voltage.     

Effect of therapeutic dosages of prednisone on human immunoglobulin G metabolism

In order to evaluate factors possibly responsible for the increased incidence of infections in patients treated with corticosteroids, immunoglobulin G (IgG) metabolism was studied in 8 patients before and during the administration of prednisone in a therapeutic range (30 mg. per day). The survival of intravenously administered IgG was determined, and total circulating IgG, fractional catabolic rate, and synthetic rate were calculated. There was no significant decrease in the measured levels of circulating IgG, but all patients had a shortened half-time (5 to 45 percent) and an increased fractional catabolic rate (p < 0.01). Since corticosteroid therapy was the only variable in these paired studies, it appears that corticosteroids can cause a hypercatabolism of IgG in some patients. Therefore, the maintenance of normal levels of IgG must be the result of an increased synthetic rate.     

The role of the autonomic innervation in the control of glucagon release during hypoglycaemia in the calf

1. The extent to which the autonomic innervation to the pancreas is implicated in the control of glucagon release during hypoglycaemia has been investigated in calves 3-6 weeks after birth.2. A pronounced rise in plasma glucagon concentration occurred in normal conscious calves in response to hypoglycaemia following administration of insulin (0.1 u./kg). Prior treatment with atropine caused no significant change in the hypoglycaemic response to insulin in these animals but the rise in plasma glucagon concentration was delayed.3. Section of both splanchnic nerves produced no significant change in the tolerance of conscious calves to this small dose of insulin and the changes in plasma glucagon concentration in these animals were within the normal range.4. In contrast, the same dose of insulin produced severe hypoglycaemia, accompanied by convulsions, in atropinized calves with cut splanchnic nerves. In spite of the intensity of the hypoglycaemic stimulus the rise in plasma glucagon concentration was both delayed and diminished in these animals.5. Administration of atropine alone (0.2 mg/kg) to normal fasting calves produced a significant fall in the mean plasma concentrations of both glucose and glucagon (P < 0.01) within 30 min, without affecting that of insulin.6. A significant increase in plasma glucagon concentration also occurred in response to stimulation of the peripheral ends of the thoracic vagi in adrenalectomized calves with cut splanchnic nerves under barbiturate anaesthesia. A rise in mean plasma glucose concentration was also observed in these experiments and found to be significantly correlated with the glucagon response.7. It is concluded that changes in either sympathetic or parasympathetic efferent activity may modify plasma glucagon concentration in the conscious calf, but that only the latter mechanism is likely to be implicated in the response to changes in plasma glucose concentration within the physiological range.     

Promoting dietary change: demonstrating reduction of dietary fat

This short demonstration accomplishes several goals. People see where fat comes from and learn amounts needed to be removed. They practice substituting complex carbohydrate foods for fat. Most important, they learn that changing is not an "all-or-nothing" proposition. They can reduce dietary fat and still eat many of their favorite foods. This demonstration is a useful tool for nutrition educators who want to promote dietary change.     

Return to alertness after brain-stem hemorrhage. A case with evoked potential and roentgenographic evidence of bilateral tegmental damage

After a 65-year-old man had received anticoagulation therapy for brain-stem ischemia, a large, bilateral pontomesencephalic hemorrhage developed in the ischemic region. He survived a period of being "locked in" to attain a limited functional recovery. When he first became alert, brain-stem auditory evoked potentials and short-latency somatosensory evoked potentials (SEPs) demonstrated bilateral brain-stem damage; computed tomography revealed a bilateral tegmental hematoma. Results of repeated studies changed little as clinical improvement occurred. Recovery from brain-stem hemorrhage is rare, and return of consciousness with bilateral tegmental involvement is even more rare. The short-latency SEPs are useful in defining the extent of brain-stem damage, but they evaluate structures distinct from those regulating consciousness and cannot predict a return to alertness.