Mechanisms of neutrophil damage to human alveolar extracellular matrix: the role of serine and metalloproteases.

Many syndromes of lung injury are associated with accumulation of neutrophils within the pulmonary parenchyma. These neutrophils have the capacity to produce lung injury by products including proteases and reactive oxygen species (ROS). We examined the ability of activated neutrophils to solubilize human alveolar extracellular matrix (ECM), and by use of scavengers and inhibitors, evaluated the role of ROS and proteases in this process. Supernatants of phorbol myristate acetate-activated neutrophils routinely solubilized 10.2% +/- 0.8% (n = 30) of collagen in human alveolar ECM, as measured by hydroxyproline release. Scavengers of ROS had no significant effect on ECM solubilization. Inhibitors of metalloproteases partially inhibited ECM solubilization (38.5% +/- 4.6% inhibition by ethylenediaminetetraacetic acid [n = 6], and 37.0% +/- 14.7% by 1,10-phenanthroline [n = 6]; p less than 0.05). Inhibitors of the neutrophil serine proteases, elastase and cathepsin G, markedly inhibited ECM solubilization (100.9% +/- 3.7% by alpha 1-protease inhibitor [alpha 1-PI] [n = 6] and 81.9% +/- 0.1% by soybean trypsin inhibitor [n = 6]; p less than 0.01). Since alpha 1-PI completely inhibited solubilization, metalloprotease activity appeared to be related to serine protease activity. This finding was confirmed by the observation that addition of a metalloenzyme activator, p-aminophenylmercuric acetate, in the presence of alpha 1-PI, restored solubilization to the same level as that inhibited by metal chelators. We conclude that human neutrophil metalloproteases and serine proteases directly solubilize human alveolar ECM. Furthermore, neutrophil serine proteases activate latent metalloproteases. However, ROS were not demonstrated to play a major role in ECM solubilization in our system.     

Influence of factors before and during medical school on choice of psychiatry as a specialty

Prompted by the recruitment problem facing psychiatry, the authors investigated the influence of factors before and during medical school on choice of psychiatry. A questionnaire was completed by 392 of the 1982 graduates from 114 United States medical schools who entered a psychiatric training program in 1982. College courses, work experience, and experience with someone having a psychiatric disorder were the most positive "before" factors; the clinical psychiatric elective, the psychiatrist-patient relationship, inpatient experiences during the psychiatric clerkship, and control over practice hours were the most positive "during" factors.     

The nucleus "k" of Meessen and Olszewski efferents to the cerebellar paramedian lobule: a retrograde tracing histochemical (HRP) study in the rabbit and the cat

The group "k" of Meessen and Olszewski (1949) was identified in the brain stems of normal rabbits and cats. In the rabbit, a topographical subdivision of the group "k" into the well defined cell aggregations k1, k2 and k3 was found. In the cat, the nucleus corporis pontobulbaris was subdivised into a posterodorsal and a anteroventral part. The former was located ventrally to the motor and principal sensory trigeminal nuclei, the latter was wedgeshaped and situated more anteriorly at the lateroventral margin of the pons. In 9 rabbits and 7 cats the neurons of origin for cerebellar paramedian lobule afferents were identified with retrograde transport of horseradish peroxidase within the nucleus "k" and nucleus corporis pontobulbaris, respectively. In both species, most projections to the paramedian lobule were seen as originating ipsilaterally with only a small contralateral component. The study suggests that there are certain segregated projections of the nucleus "k" or the nucleus corporis pontobulbaris to the cortex of the anterior and posterior parts of the paramedian lobule, with some valid species differences. In the cat, the whole projection was found to originate in the more anterior and ventral parts of the nucleus "k" (nucleus corporis pontobulbaris). The posterior part of the paramedian lobule in the rabbit receives afferents from the homolateral subdivisions k3 and, to a minor degree, from k2; while in the cat, afferents are bilateral with an ipsilateral preponderance and originate from the posterior cellular group of the nucleus corporis pontobulbaris dispersed among and medially to the exiting motor root of the trigeminal nerve. The anterior part of the paramedian lobule afferents in the rabbit originates bilaterally within subdivision k1, to a minor degree ipsilaterally in the dorsal region of subdivision k3, and occasionally in subdivision k2, whereas in the cat afferents originate from the anterior and posterior levels of the corpus pontobulbaris. Additionally, some afferents for the rabbit anterior paramedian lobule originate within the homolateral nucleus "n". No evidence for a longitudinal zonal pattern of the projection onto the paramedian lobule was found. The study is discussed in the light of present information on the connections of the nucleus "k" (nucleus corporis pontobulbaris).     

“Cerebral small vessel disease and other influential factors of cognitive impairment in the middle-aged: a long-term observational cohort PURE-MIND study in Poland”

GeroScience - A complex picture of factors influencing cognition is necessary to be drawn for a better understanding of the role of potentially modifiable factors in dementia. The aim was to assess...     

Success rate of radioiodine therapy in Graves' disease: the influence of thyrostatic medication

There is controversy whether simultaneous thyrostatic medication influences the outcome of radioiodine (131I) therapy in Graves' disease by reducing the absorbed energy dose of 131I when delivering a standard dose. We therefore sought to ascertain whether the outcome of ablative 131I therapy is in any way affected by simultaneous thyrostasis (carbimazole) by aiming for a constant absorbed dose of 200-250 Gy. We prospectively studied 207 patients with Graves' disease (106 with and 101 without simultaneous carbimazole at the time of 131I therapy). All patients were reexamined 3, 6, and 12 months after 131I therapy. The 101 nonthyrostatic patients showed a highly significantly greater success rate (93%) than the 106 thyrostatic patients (49%). Stepwise logistic regression demonstrated that failure was related to the administration of carbimazole during 131I therapy (P < 0.00005) and the absorbed dose (P < 0.025), but was not related to free T3, free T4, TSH receptor antibodies, or thyroid volume. The success rate was 100% in 93 nonthyrostatic patients with absorbed doses of 200 Gy or more, but was only 12.5% (1 of 8) for absorbed doses less than 200 Gy. Correlation between success and absorbed dose was significantly higher for nonthyrostatic than for thyrostatic patients (r = 0.93 vs. r = 0.24). Sixteen patients who discontinued thyrostasis 1-3 days before 131I therapy showed 94% successes. Simultaneous thyrostasis is the decisive factor against a successful 131I therapy even if the significantly reduced 131I uptake/half-life values under thyrostasis are compensated with a higher delivered dose to ensure a comparable absorbed dose, possibly due to the additionally effective radioprotective properties of carbimazole. Therefore, if clinically feasible, we recommend discontinuing thyrostasis at least 1 day before beginning 131I therapy, because even in hyperthyroid nonthyrostatic patients the success rate was 100%.     

Assessment of metabolic changes within normal appearing gray and white matter in children with growth hormone deficiency: Magnetic resonance spectroscopy and hormonal correlation

Objective: The pathogenesis of idiopathic growth hormone deficiency (GHD) in children, including possible cerebral metabolic alterations, remains unclear. The aim of the study was to evaluate metabolic changes within the normal appearing brain in children with GHD using MR spectroscopy (MRS) and to correlate MRS measurements with hormonal concentrations and with pituitary gland size. Methods: Seventy children with GHD (mean age 7.8 yrs) and 11 healthy controls (mean age 8.4 yrs) were enrolled in the study. The MRS examinations were performed on a 1.5T scanner. Voxels were located in the posterior cingulate gyrus (PCG) and the left parietal white matter (PWM). The NAA/Cr, Cho/Cr and mI/Cr ratios were analyzed. The metabolite ratios, pituitary gland size and hormonal concentrations: growth hormone (GH) in two stimulation tests and GH during the night, as well as IGF-1 (insulin-like growth factor) and IGFBP3 (insulin-like growth factor-binding protein) levels were also correlated. Results: There was a significant (p < 0.05) decrease of the NAA/Cr ratios in PCG and PWM in children with GHD compared to the normal subjects. Other metabolite ratios showed no significant differences. We also found significant positive correlations between NAA/Cr ratio in PWM and IGFBP3 level, as well as with GH concentration in a stimulation test with glucagon. Conclusions: The reduction of NAA/Cr ratios may suggest loss of neuronal activity within normal appearing gray and white matters in children with GHD. MRS could be a sensitive marker of cerebral metabolic disturbances associated with GHD and maybe used as an additional indicator for therapy with recombinant GH.