ImuVert activation of natural killer cytotoxicity and interferon gamma production via CD16 triggering

The effect and mechanism of action of ImuVert, a new biological response modifier consisting of ribosomes and natural membrane vesicles of Serratia marcescens, on endogenous natural killer (NK) cells and activated NK activity has been analyzed. The studies showed that endogenous NK activity of peripheral blood mononuclear cells (PBMC) from normal cell donors was significantly increased (P less than 0.03) against K562, U937, and Molt-4 target cells. PBMC from cord blood of newborn infants lacking NK activity were upregulated (1.5-4 fold over endogenous NK activity) by ImuVert. Other studies showed that the abnormal NK activity of PBMC from patients with the human immunodeficiency virus (HIV) infection was significantly augmented in vitro (P less than 0.01) by ImuVert. ImuVert strongly stimulated interferon gamma production and in combination with interleukin 2 produced synergistically enhanced interferon gamma production and greater cytotoxicity than that induced by either alone. Studies on lymphocyte differentiation antigen expression following treatment with ImuVert indicated that ImuVert triggers interferon gamma production through binding the low affinity IgG Fc receptor, type III, CD16. The studies suggest that ImuVert may trigger interferon gamma production by binding to the Fc receptor and that the amplitude of the ensuing reaction and the ability of ImuVert to induce cytotoxicity in a setting where this activity has been down regulated is based on the absence of suppressor activation or direct contra suppressor activity.     

Brain regions and their dynamics in prospective memory retrieval: a MEG study.

We measured brain activity using magnetoencephalography in five participants during ongoing tasks that included prospective memory, retrospective memory, and oddball trials. Sources were identified in the hippocampal formation and posterior parietal and frontal lobes. Posterior parietal cortex activation had an earlier onset in the prospective memory condition than retrospective memory or oddball conditions, a higher level of theta activity in the retrospective condition, and higher levels of upper alpha in the prospective and oddball conditions. Activation of the hippocampal formation had a longer duration in the retrospective memory and prospective memory conditions than the oddball condition, but prominent alpha and theta band activity was present in all three conditions. We interpret the early (87 ms) onset of activity in parietal cortex as evidence for an initial noticing of appropriate conditions for a PM response. Hippocampal activity may reflect a subsequent memory search for the intended action.     

Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system

Chronic granulomatous disease, a syndrome of recurrent infections and failure of oxidative microbicidal activity in phagocytes, results from defects in the gene for one of several components of an oxidase system that can undergo activation. To determine the relative prevalence of certain of the genetic variants of this disorder, we used immunoblotting to detect two specific neutrophil cytosolic proteins of 47 and 67 kd recently shown to be required for oxidase activation. Chronic granulomatous disease is usually an X-linked disorder associated with the absence of membrane cytochrome b558. Of our 94 patients with chronic granulomatous disease, however, 36 had a phenotype characterized by autosomal inheritance, normal membrane oxidase components (including cytochrome b558), and functionally defective cytosolic activity in a cell-free oxidase system. We studied 25 of these 36 patients and found that 22 lacked the 47-kd cytosolic protein, and the remaining 3 were missing the 67-kd component. Patients with chronic granulomatous disease whose functional defect was localized to the neutrophil membrane (classic X-linked cytochrome b-negative type and two other rare variants) had normal amounts of both cytosolic components. We estimate that approximately 33 percent of all patients with chronic granulomatous disease are missing the 47-kd cytosolic oxidase component and about 5 percent of patients are missing the 67-kd component. Chronic granulomatous disease caused by a defect in any cytosolic factors other than the 47-kd and 67-kd proteins, if it exists, is apparently rare.     

Proprioceptive input patterns elevator activity in the locust flight system

1. In the locust, Locusta migratoria, the roles of two groups of wing sense organs, hind wing tegulae and wing-hinge stretch receptors, in the generation of the flight motor pattern were investigated. A preparation was employed that allowed the intracellular recording of neural activity in almost intact tethered flying locusts or after selective manipulations of sensory input. The functions of the two sets of receptors were assessed 1) by studying the phases of their discharges in the wingbeat cycle (Fig. 3), 2) by the selective ablation of input from the receptors (Figs. 4-7), and 3) by the selective stimulation of the receptor afferents (Figs. 8-12). 2. Input from the tegulae was found to be responsible for the initiation of elevator activity (Figs. 9 and 10) and for the generation of a distinct initial rapid depolarization (Figs. 4, 5, and 8) characteristic of elevator motor neuron activity in intact locusts (Figs. 1 and 16). 3. Input from the wing-hinge stretch receptors was found to control the duration of elevator depolarizations by the graded suppression of a second late component of the elevator depolarizations as wingbeat frequency increased (Figs. 6, 7, 11, and 12). The characteristics of this late component of elevator activity suggested that it is generated by the same (central nervous) mechanism that produces the elevator depolarizations recorded in deafferented animals (Fig. 2). Apparently this late component contributes to the intact pattern of elevator depolarizations only at lower wingbeat frequencies and is abolished by the action of stretch-receptor input at frequencies above approximately 15 Hz (Figs. 1, 2, and 4). At these high wingbeat frequencies elevator activity is dominated by the rapid depolarizations generated as a result of tegula input. 4. The present study demonstrates 1) that the timing of elevator motor neuron activity is determined by phasic afferent input from tegulae and stretch receptors and 2) that input from the stretch receptors controls the duration of elevator activity in the wingbeat cycle following the wing movement that was responsible for the generation of the receptor discharge.     

Triggering of locust jump by multimodal inhibitory interneurons

1. The locust jump is triggered by a sudden inhibition of activity in hindleg flexor tibiae motoneurons following cocontraction of the hindleg flexor and extensor tibiae muscles. The main result of this investigation was the identification of two interneurons (one for each hindleg) that monosynaptically inhibit flexor tibiae motoneurons and whose properties are all consistent with them being the trigger interneurons for initiating a jump. 2. These interneurons receive strong excitatory input from many sensory modalities (visual, auditory, tactile, and proprioceptive). Because of their multimodal response characteristics, we designated them M-neurons. A particularly strong excitatory input to each M-neuron is from both descending contralateral movement detector (DCMD) interneurons. 3. The threshold for spike initiation in the M-neurons is high (approximately 14 mV). As a consequence, input from any one sensory modality alone rarely initiates action potentials. 4. Each M-neuron is depolarized by sensory input from leg proprioceptors. We propose that proprioceptive feedback during the cocontraction phase depolarizes the M-neurons to decrease their threshold, thus enabling extrinsic sensory stimuli to generate action potentials in both M-neurons and in so doing trigger a jump. The function of the proprioceptive gating of inhibitory transmission from the various sensory systems to the flexor motoneurons (via the M-neurons) is to ensure the development of a strong isometric contraction of the extensor tibiae muscle, and thus a powerful jump in response to external stimuli. 5. Insofar as the initiation of the locust jump depends on sensory convergence onto large identified interneurons, this behavior is similar to ballistic movements in some other animals such as the crayfish tail flip and the startle response in fish. The unique feature of the locust jump is that the trigger interneurons initiate the jump only after a preceding phase (cocontraction) has been accomplished.     

Relapsing diabetes can result from moderately activating mutations in KCNJ11

Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.     

Remitting seronegative symmetrical synovitis with pitting edema. RS3PE syndrome

Eight elderly men and two elderly women presented with symmetrical polysynovitis of acute onset involving most of their appendicular joints and flexor digitorum tendons associated with pitting edema of the dorsum of both hands and both feet. Onset of seven of the ten cases could be pinpointed almost to the hour. Rheumatoid factors were absent from serum samples in all, and no radiologically evident erosions developed. Clinical and laboratory signs of inflammation and the edema disappeared gradually in each case. Treatment consisted of aspirin or other nonsteroidal anti-inflammatory drugs. Hydroxychloroquine, 200 to 400 mg/day, was given in six and gold therapy in two cases. Painless limitation of motion of the wrists and/or fingers persisted in all, although the patients were both unaware of and unhampered by this abnormality. Six of eight cases where typing was possible were positive for HLA-B7, CW7, and DQW2 (relative risk for B7, 9.5). Three cases of this syndrome were found in a consecutive series of 52 men diagnosed as having definite "rheumatoid arthritis," and thus represent a distinctive condition with an excellent prognosis.     

Absolute electronegativity and hardness correlated with molecular orbital theory

The concepts of absolute electronegativity, χ, and absolute hardness, η, are incorporated into molecular orbital theory. A graphic and concise definition of hardness is given as twice the energy gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital. Useful correlations can now be made between chemical behavior, visible-UV absorption spectra, optical polarizability, ionization potentials, and electron affinities.     

Does spaced education improve clinical knowledge among Family Medicine residents? A cluster randomized controlled trial

Advances in Health Sciences Education - Spaced education is a learning strategy to improve knowledge acquisition and retention. To date, no robust evidence exists to support the utility of spaced...