Reduction by inhibitors of mono(ADP-ribosyl)transferase of chemotaxis in human neutrophil leucocytes by inhibition of the assembly of filamentous actin.

1. Chemotaxis of human neutrophils is mediated by numerous agents [e.g. N-formyl-methionyl-leucyl-phenylalanine (FMLP) and platelet activating factor (PAF)] whose receptors are coupled to phospholipase C. However, the subsequent transduction pathway mediating cell movement remains obscure. We now propose involvement of mono(ADP-ribosyl)transferase activity in receptor-dependent chemotaxis. 2. Human neutrophils were isolated from whole blood and measurements were made of FMLP or PAF-dependent actin polymerization and chemotaxis. The activity of cell surface Arg-specific mono(ADP-ribosyl)transferase was also measured. Each of these activities was inhibited by vitamin K3 and similar IC50 values obtained (4.67 +/- 1.46 microM, 2.0 +/- 0.1 microM and 4.7 +/- 0.1 microM respectively). 3. There were similar close correlations between inhibition of (a) enzyme activity and (b) actin polymerization or chemotaxis by other known inhibitors of mono(ADP-ribosyl)transferase, namely vitamin K1, novobiocin, nicotinamide and the efficient pseudosubstrate, diethylamino(benzylidineamino)guanidine (DEA-BAG). 4. Intracellular Ca2+ was measured by laser scanning confocal microscopy with two fluorescent dyes (Fluo-3 and Fura-Red). Exposure of human neutrophils to FMLP or PAF was followed by transient increases in intracellular Ca2+ concentration, but the inhibitors of mono(ADP-ribosyl)transferase listed above had no effect on the magnitude of the response. 5. A panel of selective inhibitors of protein kinase C, tyrosine kinase, protein kinases A and G or phosphatases 1 and 2A showed no consistent inhibition of FMLP-dependent polymerization of actin. 6. We conclude that eukaryotic Arg-specific mono(ADP-ribosyl)transferase activity may be implicated in the transduction pathway mediating chemotaxis of human neutrophils, with involvement in the assembly of actin-containing cytoskeletal microfilaments.     

Impact direction from a fall influences the failure load of the proximal femur as much as age-related bone loss

Recent studies have shown that factors related to fall biomechanics may play as important a role in the etiology of hip fracture as age-related bone loss. Motivated by finite element analyses that showed failure of the proximal femur to be sensitive to loading direction, our objective with the current investigation was to determine experimentally if changes in impact direction affect the failure load of the elderly proximal femur. Thirty-three cadaveric femurs were assigned randomly to three groups of 11 and tested at one of three loading angles, 0°, 15°, or 30°, representing a fall on the hip rolled slightly forward, to the side, or rolled slightly backwards, respectively. Femurs were scanned using dualenergy X-ray absorptiometry (DXA) to assess bone mineral density (BMD) and tested to failure in a fall loading configuration at a displacement rate of 100 mm/second. Using an analysis of covariance to adjust for total hip BMD, we found that failure load decreased by 24% as the loading angle changed from 0° to 30°. This reduction in failure load is comparable to that associated with about 25 years of age-related bone loss after the age of 65. Therefore, the impact direction associated primarily with a fall is a critical determinant of hip fracture risk that is both independent of bone density and associated with fall biomechanics.     

Decreased serotonin2A receptors in Brodmann’s area 9 from schizophrenic subjects

There have been repeated reports of a decrease in serotonin_2A receptors in the frontal cortex from subjects with schizophrenia. Similarly, in rats treated with antipsychotic drugs, it has been shown that many antipsychotic drugs decrease cortical serotonin_2A receptors, an affect not seen with the antipsychotic drug haloperidol. We therefore compared the density of serotonin_2A receptors in frontals cortex from schizophrenic subjects treated with haloperidol, schizophrenic subjects treated with other antipsychotic drugs, and nonschizophrenic subjects. Independent of antipsychotic drug treatment, serotonin_2A receptors were decreased in the frontal cortex from schizophrenic subjects. Importantly, the density of serotonin_2A receptors was not different in schizophrenic subjects whether or not they had been treated with haloperidol. This study suggests that data obtained from treating rats with antipsychotic drugs cannot be simplistically extrapolated to studies on tissue obtained postmortem from schizophrenic subjects treated with the same drugs.     

Athetosis II: the syndrome of mild athetoid cerebral palsy.

We describe 8 patients who presented with continuous, irregular movements occurring independently in individual fingers and, in some cases, toes, in the setting of mild dystonia present since early childhood and not associated with major disability. The finger movements varied from low-amplitude quivering or wriggling to larger amplitude movements in the plane of abduction-adduction as well as flexion-extension; they were asymmetrical but not unilateral. Quivering or working of the facial muscles was seen in 5 patients. Most patients reported worsening of the movements over the years, but there was no other evidence of a progressive neurological disease. We classify the movement disorder as athetosis as described by Hammond and Shaw and the syndrome as mild athetoid cerebral palsy.     

The Effect of Trabecular Structure on DXA-based Predictions of Bovine Bone Failure

Bone-specific alkaline phosphatase (bone ALP) levels are considered to reflect osteoblastic activity and can therefore be used as a marker of bone formation. However, bone ALP is difficult to distinguish from other ALP isoforms since the kidney, liver, and bone isoenzymes are encoded by the same gene and only differ because of post-translational modification of their carbohydrate side chains. The aim of this study was to purify and separate bone ALP which could be used to raise specific antisera against human bone ALP, from Saos-2, a human osteogenic sarcoma cell line. The procedure involved two steps. The first step, cultivation of 10⁵ Saos-2 cells, yielded approximately 1 U ALP. Subsequent butanol extraction achieved 1.82-fold purification. For the second step, separating bone ALP, we used serial lectin affinity chromatography to distinguish between the carbohydrate side chains of the various ALP isoforms. A sample of the butanol extract was fractionated into three peaks (I, II, and III) by concanavalin A. Peaks II and III were subsequently identified as types IIa and IIIb bone ALP using pea lectin and wheat germ agglutinin columns, respectively. The specific activity of bone ALP was measured using commercial kits. Since bone ALP accounted for at least 84% of the total ALP activity after the final separation, this method appears more convenient and reproducible than others using bone or Pagetic sera. The bone ALP purified in this study could be used to raise monoclonal antibodies against bone-specific ALP. Received: 31 December 1996 / Accepted: 5 June 1997     

Idiopathic Pulmonary Arterial Hypertension Misdiagnosed as Asthma

Idiopathic pulmonary arterial hypertension (IPAH) is a rare disorder that is progressive and often leads to right heart failure if left untreated. Because of the vague nature of symptoms at presentation, IPAH may take several months to diagnose. The most common presenting complaint in patients with IPAH is dyspnea with exertion, which is also commonly seen with asthma. This report describes an adult female with refractory exertional dyspnea who was diagnosed with asthma 2 years earlier but was ultimately diagnosed with IPAH. Exclusion of other etiologies is a necessity for refractory dyspnea in the setting of asthma.     

Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors

To determine the subsequent evolution of neurologic, neuropsychologic, and intracranial anatomic findings in long-term survivors of small-cell cancer, we repeated an evaluation done 4 years previously in patients 6 to 13 years after treatment. Fifteen patients were reevaluated with a history and physical examination, mental status examination, neuropsychologic testing, computed cranial tomographic (CCT) scans, and magnetic resonance imaging (MRI). All but one was ambulatory and none were institutionalized. Thirteen of 15 had neurologic complaints, 10 of 15 had an abnormal neurologic examination, seven of 14 had an abnormal mental status examination, 12 of 14 had abnormal neuropsychologic testing, 12 of 15 had abnormal CCT scans, and seven of 15 had white-matter abnormalities on MRI scans. No dramatic decline in performance status, functional status, neurologic symptoms, or neurologic examination occurred in these patients with 4 years of additional follow-up. More patients showed a decline in mental status examinations and neuropsychologic testing than demonstrated improvement. Anatomic studies showed no dramatic changes in the CCT scans and MRI confirmed these findings. From these data we conclude that there is a slow decline in neuropsychologic function in some of the patients surviving more than 6 years from a diagnosis of small-cell lung cancer. The anatomic abnormalities documented by CCT scans and MRI are more frequent in patients with abnormal neuropsychologic function.     

Retinal magnification factor at the ora terminals: a structural study of human and animal eyes

A geometrical method of calculating retinal magnification factor at the limits of the retinal field, adjacent to the ora terminalis, is described. The method is applied to the eyes of 11 mammalian and avian species, using new anatomical measurements and data from the literature. In the human and monkey eye, magnification at the far periphery is substantially smaller than at the posterior pole; in cat, rabbit, rat and mouse there is lesser reduction; in pigeon, tawny owl and starling magnification is closely similar at the far periphery and posterior pole.