Apoptosis and its role in human disease

In a landmark paper published over two decades ago, Kerr et al. proposed the term apoptosis "for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations". In the ensuing years, this natural cell death process was studied at the basic science level, primarily with a view to understanding its roles in cancer and in the development and maintenance of the immune system. More recently, however, evidence has suggested a role for the failure of normal apoptosis control in many of the major diseases of the industrialized world. Though complex, apoptosis appears amenable to therapeutic intervention. The range of modern pharmaceutical strategies available to treat such disregulated gene-directed processes offers promise for advances in the control of cancer, immune system and neurodegenerative disorders, heart disease, and perhaps even the aging process itself.     

Fractures of the first rib in child abuse

PURPOSE: To evaluate the incidence and specificity of fracture of the first rib as an indicator of child abuse and to determine a mechanism of fracture. MATERIALS AND METHODS: All infants and young children with rib fractures who were seen at the radiology department of an academic medical center over a 2-year period were identified from the radiology data base. RESULTS: Rib fractures were attributed to child abuse in 12 of 35 children identified. Apart from a neonate with congenital osteogenesis imperfecta, only three children, all abused, had first-rib fracture, one bilaterally. Two additional children with first-rib fracture were identified from years prior to the study period. In four children, first-rib fractures were "isolated," without fractures of adjacent bones. CONCLUSION: Child abuse should be considered in cases of pediatric rib fracture, particularly fracture of the first rib. Possible mechanisms for first-rib fracture include impact force, compressive force, and shaking or acute axial load (slamming), which cause an indirect fracture.     

Brain stem integration of vocalization: role of the nucleus retroambigualis

1. The descending pathways that mediate the periaqueductal gray (PAG)-evoked coordination of respiratory, laryngeal, and orofacial activity for vocalization have yet to be delineated. Two hypotheses have been offered. One theory is that this activity is mediated by a diffuse descending projection to parvocellular reticular interneurons, adjacent to the relevant laryngeal and orofacial motoneuronal pools. The second hypothesis is that the motor activity for vocalization is integrated via a projection from the PAG to a caudal medullary column of neurons, the nucleus retroambigualis (NRA). These hypotheses were tested with the use of a series of medullary transections combined with PAG stimulation. Transections that eliminated, in a series of caudal-to-rostral steps, the NRA, also eliminated the PAG-evoked cricothyroid and most of the thyroarytenoid laryngeal motor activity. These results indicate that the final common pathway for much of the laryngeal activity in PAG-evoked vocalization includes un initial synapse in the caudal medulla, presumably in the NRA. 2. The electromyographic changes evoked by microinjection of D,L-homocysteic acid (DLH) in the NRA of the unanesthetized, precollicular decerebrate cat were analyzed in order to delineate the NRA contribution to the coordinated respiratory, laryngeal, and oral muscle changes in vocalization. A total of 415 DLH injection sites were located at or caudal to the level of the obex. Vocalization was evoked at 46 of these sites, which were all confined to a restricted region of the ventrolateral medulla 1-3 mm caudal to the obex. This region corresponded to the rostral half of the NRA and the immediately adjacent medullary tegmentum. 3. In all experiments evidence was obtained that variable muscle activation, rather than functional and integrated muscle patterns, was represented within the NRA. Vocalization evoked by DLH microinjection in the NRA was usually associated with excitation of the cricothyroid, thyroarytenoid, external oblique, internal oblique, internal intercostal, and diaphragm muscles that occurred in a different manner from site to site. That is, injection at sites separated by 0.3-0.5 mm evoked quite different responses. 4. NRA-evoked vocalization was compared with PAG-evoked vocalization using small injections (1.5-4.5 nl) into each region. As well, larger microinjections (15-120 nl) into NRA were made for comparison with previous results from the PAG using similar doses. Within the PAG, stereotyped and relatively "fixed" patterns of muscle activity are represented, whereas within the NRA there was no representation of specific muscle patterns, but rather a partial topographic separation of "premotor neurons" regulating different muscles. Correspondingly, stereotyped vocalizations were never evoked from the NRA. Further, most NRA-evoked vocalizations were unusual in quality and would not be identified generally as feline. 5. Evidence was obtained for a separation of pathways from the PAG regulating sound production and orofacial modulation of that sound. In contrast to the results from the PAG, excitation of NRA neurons rarely evoked activity in the oral muscles (genioglossus or anterior belly of digastric) or orofacial modulation of sound production. 6. Our finding suggests that the NRA serves as an important substrate for the generation of respiratory pressure and larynges adduction, which are two essential aspects of not only vocalization but also several behaviors involving Valsava maneuvers such as coughing, vomiting, and defecation.     

The crystal structure of a 3D domain-swapped dimer of RNase A at a 2.1-A resolution

The dimer of bovine pancreatic ribonuclease A (RNase A) discovered by Crestfield, Stein, and Moore in 1962 has been crystallized and its structure determined and refined to a 2.1-A resolution. The dimer is 3D domain-swapped. The N-terminal helix (residues 1-15) of each subunit is swapped into the major domain (residues 23-124) of the other subunit. The dimer of bull seminal ribonuclease (BS-RNase) is also known to be domain-swapped, but the relationship of the subunits within the two dimers is strikingly different. In the RNase A dimer, the 3-stranded beta sheets of the two subunits are hydrogen-bonded at their edges to form a continuous 6-stranded sheet across the dimer interface; in the BS-RNase dimer, it is instead the two helices that abut. Whereas the BS-RNase dimer has 2-fold molecular symmetry, the two subunits of the RNase A dimer are related by a rotation of approximately 160 degrees. Taken together, these structures show that intersubunit adhesion comes mainly from the swapped helical domain binding to the other subunit in the "closed interface" but that the overall architecture of the domain-swapped oligomer depends on the interactions in the second type of interface, the "open interface." The RNase A dimer crystals take up the dye Congo Red, but the structure of a Congo Red-stained crystal reveals no bound dye molecule. Dimer formation is inhibited by excess amounts of the swapped helical domain. The possible implications for amyloid formation are discussed.     

Effects of a startling acoustic stimulus on reaction time in different parkinsonian syndromes

BACKGROUND: The functional assessment of the startle circuit is usually done by analyzing the acoustic startle response (ASR). However, a startling acoustic stimulus (SAS) also induces changes in the excitability of neural structures that can be demonstrated by studying the SAS-induced change in the behavior of certain neurophysiologic responses. OBJECTIVE: To examine the effects induced by an SAS on voluntary reaction time in patients with parkinsonian syndromes (StartReact effect) and to compare the results with those obtained in a group of age-matched healthy volunteers. METHODS: Twelve patients with idiopathic PD (IPD), seven patients with progressive supranuclear palsy (PSP), seven patients with multisystem atrophy (MSA), and seven healthy age-matched control volunteers performed a simple visual reaction time task and received SAS together with the "go" signal in random trials. RESULTS: Baseline reaction time was significantly slower in PSP patients than in control subjects and MSA patients. The SAS induced a significant shortening of the reaction time in control subjects and in patients with IPD and MSA, but not in patients with PSP. The percentage of reaction time shortening with regard to the baseline values also differed significantly between PSP patients and the other groups of subjects. The StartReact effect was consistent throughout the experiment and showed reduced habituation with repeated testing. CONCLUSIONS: The results are consistent with an abnormal function of the startle circuit in patients with PSP and agree with previous studies using the ASR. The reduced habituation of the StartReact effect favors its clinical applicability in the assessment of differences between patients with parkinsonian syndromes.     

Treating achalasia: from whalebone to laparoscope

Reports of bile duct injuries are from tertiary care institutions and, therefore, may not report the spectrum of management that these patients receive in the care of these injuries. From June 14,1990 (the first operation) to June 30, 1995, 2654 laparoscopic cholecystectomies (LCs) were reviewed at this community hospital medical center to determine risk factors contributing to the etiology of these injuries, time and symptoms at presentation, duration of illness, and management of these injuries. None of the 13 general surgeons practicing during this time period had laparoscopic training in a general surgical residency. There were six major bile duct injuries (0.25%), of which five were available for further review. All occurred in women with cholelithiasis and chronic cholecystitis. Two operations were routine and two were associated with biliary tract anomalies. In two patients, the injuries were detected at LCs and definitive biliary-enteric anastomoses were performed immediately. Three patients presented at 2, 15, and 42 days after LC. In two patients, one or more operative procedures were performed before definitive repair and these patients were referred to tertiary care centers. One patient was managed with sequential CT-guided drainage catheters after attempted closure of the defect. The length of illness for these five patients was 8, 69, 348, 402, and 435 days with a follow-up of 245, 345, 531, 575, and 1088 days. Laparoscopic experience before injury by the operating surgeon was 3, 26, 35, 77, and 333 operations. Major biliary tract injuries occurred during routine cholecystectomy, length of illness was substantial for most patients, and biliary-enteric anastomosis was definitive for four of the five patients. The operating surgeons' "learning curve" did not seem as important as in other studies.     

Prognosis of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer by immunological urinary measurements: statistically weighted syndrome analysis

PURPOSE: The goal of this research was to discover new biological indicators in urine which could be used for short-term prognosis of local Bacillus Calmette-Guerin (BCG) therapy outcome in patients with superficial bladder cancer. PATIENTS AND METHODS: We measured and statistically evaluated soluble immunological molecules in urine from bladder cancer patients (n = 34) receiving BCG intravesically. Urine was collected following each of 6 weekly treatments, processed and assayed. The data base included measurements of interleukin-1 (IL-2, IL-4, IL-6, IL-10, IL-12, soluble intercellular adhesion molecule-1 (sICAM-1), tumour necrosis factor-alpha (TNF alpha), soluble CD14 (sCD14), interferon-gamma (IFN gamma), GM-CSF, volume of urine and its pH. The clinical response was evaluated by urine histology and random quadrant biopsy 3 months after the start of therapy. Patients were divided into 2 groups, with good and poor therapeutic effect. The initial complete response rate was 62% (21/34). The data base was analyzed using traditional multivariate statistical methods and a pattern recognition method which deals with combinatorial-statistical analysis (statistically weighted syndromes (SWS) method) of the gradated features. The SWS method is capable of identifying robust patterns in small "fuzzy" sets with high dimensional objects and some missing values. RESULTS: Only one parameter gave significant differences at p < 0.05, GM-CSF at instillation 6. Repeated measurement analysis of variance, backward stepwise multiple logistic regression and linear discriminant analysis failed to show any significance. However, significant differences in the structure of correlation between features in the groups with and without therapeutic effect were observed and four highly informative variables (the masses of sICAM-1, TNF alpha, sCD14 and pH) relating to 5th-6th installations were selected by SWS. These features provided accurate individual prediction of therapeutic outcome for all our patients. Cross-validation analysis and computer simulation showed the statistically significant stability of the prediction. CONCLUSION: We have selected a set of urinary variables that could be considered as a perspective combination of indicators (syndromes) of outcome of pre-operation BCG therapy of patients with superficial bladder cancer. A larger patient database will provide testing and evaluation of the biological and clinical significance of selected features. The computational syndrome-disease approach should be applicable for the solution of decision-making problems for management of cancer.     

Gender-related differences in susceptibility of A/J mouse to benzo[a]pyrene-induced pulmonary and forestomach tumorigenesis

A commercial patient dose verification system utilizing non-invasive metal oxide semiconductor field effect transistor (MOSFET) dosimeters originally designed for radiotherapy applications has been evaluated for use at diagnostic energy levels. The system features multiple dosimeters that may be used to monitor entrance or exit skin dose and intracavity doses in phantoms in real time. We have characterized both the standard MOSFET dosimeter designed for radiotherapy dose verification and a newly developed "high sensitivity" MOSFET dosimeter designed for lower dose measurements. The sensitivity, linearity, angular response, post-exposure response, and physical characteristics were evaluated. The average sensitivity (free in air, including backscatter) of the radiotherapy MOSFET dosimeters ranged from 3.55 x 10(4) mV per C kg(-1) (9.2 mV R(-1)) to 4.87 x 10(4) mV per C kg(-1) (12.6 mV R(-1)) depending on the energy of the x-ray field. The sensitivity of the "high sensitivity" MOSFET dosimeters ranged from 1.15 x 10(5) mV per C kg(-1) (29.7 mV R(-1)) to 1.38 x 10(5) mV per C kg(-1) (35.7 mV R(-1)) depending on the energy of the x-ray field. The high sensitivity dosimeters demonstrated excellent linearity at high energies (90 and 120 kVp) and acceptable linearity at lower energies (60 kVp). The angular response was significant for free-in-air exposures, as illustrated by the sensitivity differences between the two sides of the dosimeter, but was excellent for measurements within a tissue equivalent cylinder. The post-exposure drift response is a complicated but reproducible function of time. Real-time monitoring requires little if any corrections for the post-exposure drift response. The MOSFET dosimeter system brings some unique capabilities to diagnostic radiology dosimetry including small size, real-time capabilities, nondestructive measurement, good linearity, and a predictable angular response.