Ethnic differences in family factors related to early drug initiation. The literature on family predictors of substance use for the general population is reviewed and compared to findings for three specific ethnic groups: black, white and Asian Americans. Rates of substance use initiation are examined in a sample of 919 urban 5th-grade students. Ethnic differences on measures of family predictors are examined and significant ethnic differences are found on several of these factors. Finally, separate regressions for black, white and Asian American youths of family factors on the variety of substances initiated examine ethnic similarities and differences in predictors. The results demonstrate significant differences by ethnicity in family management practices, involvement in family activity, sibling deviance, parental disapproval of children's drinking and family structure. The regression equations identified unique as well as common predictors of the variety of substances initiated by the end of 5th grade. Implications of the results are discussed.


Legal standards for an appropriate education in the post-Rowley era. In 1982 the U.S. Supreme Court held than an appropriate education under the Individuals with Disabilities Education Act was one that was formulated in accordance with the Act's procedures and that conferred some educational benefit on students with disabilities. Initially, the lower court applied this terminology strictly and approved any proposed individualized education program that conferred even minimal educational benefit. However, later courts began to take a more liberal approach and held that the educational program must confer some meaningful benefit. A careful reading of the Supreme Court's 1982 decision indicates that this recent approach is consistent with Congress's and the Court's intent. The Court never intended to establish one test of appropriateness since it recognized that some flexibility was needed to determine what would be appropriate for a diverse population of students with disabilities.


Comparative efficacy of alternative hand-washing agents in reducing nosocomial infections in intensive care units. Effective hand-washing can prevent nosocomial infections, particularly in high-risk areas of the hospital. There are few clinical studies of the efficacy of specific hand-cleansing agents in preventing the transmission of pathogens from health care workers to patients. For eight months, we conducted a prospective multiple-crossover trial involving 1894 adult patients in three intensive care units (ICUs). In a given month, the ICU used a hand-washing system involving either chlorhexidine, a broad-spectrum antimicrobial agent, or 60 percent isopropyl alcohol with the optional use of a nonmedicated soap; in alternate months the other system was used. Rates of nosocomial infection and hand-washing compliance were monitored prospectively. When chlorhexidine was used, there were 152 nosocomial infections, as compared with 202 when the combination of alcohol and soap was used (adjusted incidence-density ratio [IDR], 0.73; 95 percent confidence interval, 0.59 to 0.90). The largest reduction with chlorhexidine was in gastrointestinal infections (IDR, 0.19; 95 percent confidence interval, 0.05 to 0.64). When chlorhexidine was available, the rates of nosocomial infection declined in each of the ICUs, and health care workers washed their hands more often than when alcohol and soap were used (relative risk, 1.28; 95 percent confidence interval, 1.02 to 1.60). The total volume of alcohol and soap used was 46 percent that of chlorhexidine (P less than 0.001). A hand-disinfection system using an antimicrobial agent (chlorhexidine) reduces the rate of nosocomial infections more effectively than one using alcohol and soap. The improvement may be explained at least in part by better compliance with hand-washing instructions when chlorhexidine was used.


Retroclival arachnoid cyst.

Retroclival arachnoid cyst. Retroclival arachnoid cyst is a rare mass lesion, with only seven cases previously reported in literature. MR is the imaging modality of choice in its evaluation and in its differentiation from epidermoid cyst. The case reported here was surgically proved and had an uncharacteristic MR signal intensity that was higher than that of cerebrospinal fluid due to previous hemorrhage.


Histopathological changes in the coeliaco-mesenteric ganglia of horses with 'mal seco', a grass sickness-like syndrome, in Argentina. 'Mal seco' is a grass sickness-like syndrome of horses in Argentina. A histopathological study was made of the coeliaco-mesenteric ganglia of four horses with 'mal seco' and of four horses that died from other causes. The severity and extent of the lesions found in the horses with 'mal seco' was greatest in the two with the shortest clinical course. Degenerative changes consisted mainly in the loss of Nissl substance, cytoplasmic vacuoles, neuronophagia, intercellular and intracytoplasmic eosinophilic bodies, and pyknotic and eccentric nuclei. The coeliaco-mesenteric ganglia of the control horses had no histological lesions. The histological lesions in the horses with 'mal seco' were very similar to those described in the coeliaco-mesenteric ganglia of horses with grass sickness in Europe and it is suggested that 'mal seco' and grass sickness may be the same disease.


Validating the SF-36 health survey questionnaire: new outcome measure for primary care. To test the acceptability, validity, and reliability of the short form 36 health survey questionnaire (SF-36) and to compare it with the Nottingham health profile. Postal survey using a questionnaire booklet together with a letter from the general practitioner. Non-respondents received two reminders at two week intervals. The SF-36 questionnaire was retested on a subsample of respondents two weeks after the first mailing. Two general practices in Sheffield. 1980 patients aged 16-74 years randomly selected from the two practice lists. Scores for each health dimension on the SF-36 questionnaire and the Nottingham health profile. Response to questions on recent use of health services and sociodemographic characteristics. The response rate for the SF-36 questionnaire was high (83%) and the rate of completion for each dimension was over 95%. Considerable evidence was found for the reliability of the SF-36 (Cronbach's alpha greater than 0.85, reliability coefficient greater than 0.75 for all dimensions except social functioning) and for construct validity in terms of distinguishing between groups with expected health differences. The SF-36 was able to detect low levels of ill health in patients who had scored 0 (good health) on the Nottingham health profile. The SF-36 is a promising new instrument for measuring health perception in a general population. It is easy to use, acceptable to patients, and fulfils stringent criteria of reliability and validity. Its use in other contexts and with different disease groups requires further research.


If A-B does not predict heart disease, why bother with it? A clinician's view. Ray asks the question: 'If A-B does not predict heart disease, why bother with it?' (British Journal of Medical Psychology, 64 (1) 1991). Having worked for several years in prevention of heart attack recurrence, I am inclined to agree with his conclusion that the construct is a trail which should now be abandoned. Grief, hostility and social isolation, fear and work demands have each been implicated in heart disease independently of Type A.


Survival rates with coronary artery disease for black women compared with black men. To evaluate the influence of gender on the prognosis of coronary heart disease among black patients. Cohort study based on a consecutive sample from a hospital registry, with a mean follow-up of 4 years. An inner-city public hospital in Chicago, Ill. The study included 1719 consecutive black patients (780 men and 939 women) who had any one of the following events: cardiac catheterization for presumed coronary heart disease, hospitalization for acute myocardial infarction, or coronary artery bypass grafting. Hospital and operative mortality rates following acute myocardial infarction and coronary artery bypass grafting were similar between the two sexes. The relative risks for cardiac death in women vs men were 0.88 (95% confidence interval [CI], 0.60 to 1.28), 0.79 (95% CI, 0.53 to 1.17), and 0.79 (95% CI, 0.34 to 1.85) for coronary artery disease, acute myocardial infarction, and coronary artery bypass grafting, respectively, after adjusting for age, history of diabetes, hypertension, angina pectoris and myocardial infarction, number of diseased vessels, and ejection fraction. Compared with patients of the same sex with normal angiograms, relative risk estimates were 5.0, 10.1, and 6.3 for women and were 1.8, 4.0, and 2.0 for men in the same three groups of patients, respectively. Survival with coronary artery disease in black women is similar to that observed in black men, but relative to members of the same sex without the disease, the prognosis for women is considerably worse than for men.


Expression of a chimeric CaMV 35S Bacillus thuringiensis insecticidal protein gene in transgenic tobacco. Insecticidal transgenic tobacco plants containing a truncated Bacillus thuringiensis cryIA(b) crystal protein (ICP) gene expressed from the CaMV 35S promoter were analyzed for ICP gene expression under field and greenhouse conditions over the course of a growing season. We present new information on temporal and tissue-specific expression of a CaMV 35S/cryIA(b) gene. Levels of cryIA(b) protein and mRNA were compared in both homozygous and hemizygous lines throughout plant development. Levels of ICP mRNA and protein increased during plant development with a pronounced rise in expression at the time of flowering. Homozygous ICP lines produced higher levels of ICP than the corresponding hemizygous lines. ELISA analysis of different tissues in the tobacco plant showed ICP gene expression in most tissues with a predominance of ICP in older tissue. All transgenic ICP tobacco lines which were studied in the field and greenhouse contained 400 ng to 1 microgram ICP per gram fresh weight in leaves from the mid-section of the plant at flowering. The amounts of ICP produced by field lines were directly comparable to levels observed in greenhouse-grown plants.


Western blotting is a sensitive technique for the detection of anti-PlA1. Western (immuno-) blotting was evaluated as a technique for anti-PlA1 detection, using untreated and chloroquine or low pH-treated platelets. Chloroquine-treated platelet membranes generated the cleanest blots, giving end-point titres of 4000-16,000 for three different anti-PlA1 sera. These titres were between three and eight doubling dilutions higher than those obtained in solid phase, ELISA or indirect immunofluorescence tests. Nitrocellulose strips used for blotting could be stored for at least six months at room temperature without significant loss of PlA1 activity. However, immunoblotting still failed to detect anti-PlA1 in the sera of four of fivePl (A1-) women whose infants were born with neonatal thrombocytopenia of probable alloimmune origin.


Identification of region-specific yeast artificial chromosomes using pools of Alu element-mediated polymerase chain reaction probes labeled via linear amplification. The ability to identify large numbers of yeast artificial chromosomes (YACs) specific to any given genomic region rapidly and efficiently enhances both the construction of clone maps and the isolation of region-specific landmarks (e.g., polymorphic markers). We describe a method of preparing region-specific single-stranded hybridization probes from Alu element-mediated polymerase chain reaction (Alu-PCR) products of somatic cell hybrids for YAC library screening. Pools of up to 50 cloned Alu-PCR products from an irradiation-reduced hybrid containing 22q11.2-q13.1 were labeled to high specific activity by linear amplification using a single vector primer. The resulting single-stranded probes were extensively competed to remove repetitive sequences, while retaining the full complexity of the probe. Extensive coverage of the region by YACs using multiple probe pools was demonstrated as many YACs were detected more than once. In situ analysis using chosen YACs confirmed that the clones were specific for the region. Thus, this pooled probe approach constitutes a rapid method to identify large numbers of YACs relevant to a large chromosomal region.


(1-Sar, 8-Ile) angiotensin II in the treatment of inhalation injury: a pilot study. The patients were three men and two women with moderate to severe inhalation injury. Each patient received immediate fluid therapy and all required intubation for respiratory management. At some time between 24 and 72 hours after the injury, the synthetic angiotensin analogue (1-Sar, 8-Ile) angiotensin II was infused at a rate of 100 ng/kg/min for 10 minutes, 200 ng/kg/min for another 10 minutes, and 300 ng/kg/min for 30 minutes. The mean (+/- SD) PaO2 increased from 80.8 +/- 26.9 mmHg before to 89.8 +/- 27.3 mmHg after the infusion (P < 0.05) and the PaCO2 decreased from 42.4 +/- 8.3 to 39.6 +/- 7.9 mmHg (P < 0.05). A transient pressor response was noted in all patients. The results suggest that this angiotensin II analogue may be of benefit in the treatment of inhalation injury and other types of acute lung injury.


Distribution of filipin-sterol complexes in the bloodstream form of Trypanosoma brucei gambiense. The polyene antibiotic, filipin, was used as a probe for demonstrating sterols in the plasma membrane of Trypanosoma brucei gambiense. Three different regions of the continuous plasma membrane over the cell body proper, flagellar pocket, and flagellum, were compared as to density and distribution of the filipin-sterol complexes by freeze-fracture method. The density of the complexes was highest in the cell body membrane and lowest over the flagellar pocket. The filipin-sterol complexes in the cell body membrane were distributed homogeneously on both the protoplasmic and exoplasmic faces except in the zone of flagellar attachment. This junctional zone showed a linear, complex-poor region. In the flagellar membranes, a line of complex-poor regions was observed along the juncture of the flagellum to the cell body. At the neck of the flagellar pocket, the membranes of the flagellar pocket and flagellum were closely opposed, with few filipin-sterol complexes on either membrane. At the base of the flagellar shaft, the complexes were completely lacking on both faces. Based on these observations, the zones of juncture observed in T.b. gambiense seems to be similar in ultrastructure to mammalian cell junctions, such as tight, gap, septate junctions and desmosomes, which show a nearly complete absence of the filipin-sterol complexes.


[Collection of anti-HBs hyperimmune plasma: stimulation by Genhevac B in weakly immunized donors]. The need for anti HBs globulin is still important in spite of the development of the HBs vaccination. Twenty-two plasma donors, immunized against Hepatitis B virus (HBV) with titers of anti HBs between 100 and 6,000 milli International Units per ml (mUI/ml), received two injections of Genhevac B Pasteur at a one-month interval, and a third injection two months later whenever the answer was still under 6,000 mUI/ml, which is the minimum necessary in order to obtain a specific globulin compatible with the National Standard (100 UI/ml) from plasma fractions. In this programme, no severe adverse reaction was documented, and the mean rate of anti HBs rose from 1,322 to 35,173 mUI/ml, with a mean multiplying factor of 20.2. This result was reached after the first injection in "responders"; the third injection did not increase the titer in "non responders". The titer was still above 6,000 mUI/ml after six months in all the donors with more than 1,500 mUI/ml before vaccination. This limit is suggested to select plasma donors for vaccination, and a booster injection could be proposed every six months.


[Role of the ABO system in transplants and grafts]. The structures and locations of the glucidic molecules in the ABO system vary according to the tissues, ontogenesis and individuals. Although their physiological role is not well established, they are considered as very important factors in transplantations. When the ABO identity is not taken into account, hyperacute, acute, and chronic rejections, or hemolysis and tolerance phenomenon may occur but the incidence of these problems varies according to the tissues. In ABO minor mismatch, the transplantation is always possible, but is associated with worse long term graft survival, except for bone marrow. In ABO major mismatch, the frequency of hyperacute rejections remains the main problem, although the frequency is nil for bone marrow, very low for the liver, quite important for the kidney, and high for heart transplantations. Thus, the ABO group barrier is not absolute but must still be taken into account for allogenic transplantations.


Classification of accidents in the Arctic. A suggestion for adaptation of the Nordic classification for accident monitoring. Since 1980 the Nordic Medico-Statistical Committee (NOMESCO) has supported the development of the Classification for Accident Monitoring. The objective of the Classification is to provide the foundation for accident prevention. In agreement with the purpose of NOMESCO to establish comparable medical statistics in the Nordic countries, it is considered how the Nordic Classification might be adapted to conditions in Arctic areas, in order also to facilitate accident prevention in these areas. The Classification is multiaxial and describes place of occurrence, injury mechanism, activity (of victim), products involved in accidents, and information of special relevance to traffic accidents and occupational accidents. The hierarchical build-up of the coding system allows subspecification of the variables mentioned above, thus enabling the system to contain such information which is suggested for Arctic areas, and at the same time preserving the comparability of data at an aggregated level. Further development is suggested in a plan of work.


Fatal non-intentional injuries in Greenland. Accidents are one of the main killers in Greenland, responsible for 16% of deaths but 34% of potential years of life lost (PYLL). During 1968-89, 1310 deaths from accidents were recorded, equivalent to a mortality rate of 118 per 100,000 person-years-more than six times higher than in Denmark. There was a decreasing secular trend but only for certain types of accidents. Mortality rates were considerably higher in indigenous Greenlanders than in Danes, higher in males than in females and higher in settlements than in towns. Most accidents were related to the Greenlandic life style with drowning and boat accidents responsible for 45% of all fatal accidents, and injuries due to fire, cold, firearms or bites of dogs responsible for 23%. In certain age groups and in particular in females, at least 60% of the fatal accidents were alcohol related.


Accident toll in a Norwegian Spitsbergen mining community. The coal mining community of Longyearbyen suffered a total loss of 84 persons in fatal accidents during the 40-year period from 1950 to 1989. Up to the beginning of the 1970's the great majority of injuries causing death were related to coal mining. In the 20-year period from 1970-1989 14 people died in occupational accidents. 24 were killed during off-work hours. The male population, averaging, 776 individuals through the observation period, run a risk of being involved in a fatal leisure-time accident nearly 3 times that of age-matched groups on the Norwegian mainland. Potential years of life lost for the Spitsbergen group were estimated to be of a magnitude 2.6 times that of the mainland. The females are even worse off with a risk of having a fatal accident which is 18 times higher. Occupational deaths in the mines were nearly 2 times as frequent as in the mines on the Norwegian mainland. We have moved a long way towards the control of fatal occupational accidents. The rise in non-occupational fatal injuries means, however, that the overall safety gain is meagre.


National registration of accidents in Iceland. Community based registration of accidents has been employed in Iceland from 1987. A form developed in the emergency ward at the city Hospital of Reykjavik has been used for the registration. The following issues have been registered: the type and the seriousness of the injury, treatment, place of accident and time of accident. Health centres in Iceland have been computerized from 1976. At the time being about half of the health centres participate in the registration with the information included in the form as the source. Every health center has its well defined district. The accidents among the inhabitants in each district is registered, while accidents among other people, e.g. tourists, is registered separately. At this moment 183,000 out of a total number of 259,000 inhabitants are covered by the registration, i.e. 71% of the population. In 1989 the frequency of accidents was 198 per 100,000 inhabitants. 26% of the accidents occurred at home, 11% at work, 9% during physical activity, 6% was traffic accidents, whereas the same proportion occurred at school. This registration system has been created as a result of annual conferences on accidents arranged by the Director General of public health since 1984. Representatives for the following parties have been invited; medical doctors working in hospitals and health centres, clinical nurses, physiotherapists, the National Insurance Service, other insurance companies, rescue and ambulance personal, fire departments, the Automobile Association, the communication Council. Local communities members of the parliament, voluntary organizations, e.g. Red Cross, the Sea Rescue Service and the Aviation Board. This activity has stimulated measures aiming at preventing accidents in several local communities.(ABSTRACT TRUNCATED AT 250 WORDS)


Injuries in the Alaskan Arctic.

Injuries in the Alaskan Arctic. In recent years, the State of Alaska has developed a Trauma Registry data collection system on injuries which result in hospitalization or death. All 25 acute care hospitals in Alaska have agreed to participate in this Trauma Registry. Data are presented from this registry on injuries which occurred between March 1988 and December 31, 1990 in the North Slope Borough, the Northwest Arctic Borough, and the Norton Sound Region. Causes of death and serious injury are presented and comparisons made among regions and between Natives (primarily Inupiat Eskimos) and non-Natives. Use of firearms accounted for the majority of fatalities (32%), while falls were the most reported injury (19%). Trauma Registry Data can be used to target high risk groups and activities for the development and evaluation of prevention programs. This database also is used for quality assurance reviews of patient care and outcomes.


Epidemiology of injuries in northern areas. Traumatic injuries are among the leading causes of death in Alaska and the arctic. Intentional injuries (homicide and suicide) and unintentional injuries (motor vehicle crashes, drowning, aviation crashes, alcohol and other drugs) cause 29% of all deaths and 53% of all years of potential life lost (YPLL) in Alaskans. Mortality and morbidity rates due to injuries remain higher among Alaska Natives than other racial groups. The occupational fatality rate in Alaska (33 deaths per 100,000 workers) is the highest in the United States and is largely due to the large number of deaths among commercial fishermen, airplane pilots, sailors, truck drivers, and loggers. Effective injury control and prevention efforts are hampered by lack of adequate surveillance systems. Injury research and public health control measures are unfocused, lack continuity, and are undersupported.


Accidents in the north. Some aspects on snowmobile accidents and moose-car collisions. Snowmobile accidents and moose-car crashes are typical accidents in Northern Sweden. In this region there is about 1 snowmobile/10 inhabitants. The present paper combines previously published studies. The studies on snowmobile accidents are based on a material comprising all 61 fatally injured snowmobile drivers from the four northern counties of Sweden during the period 1973-1987. The helmet usage was analyzed in two clinical study populations including 200 injured from the county of Västerbotten from two periods 1979-1980 and 1985-86. Of the fatally injured (median age 32 years) 86% were driving under the influence of alcohol with a mean blood alcohol concentration of 0.17 g/ml. Serious head injuries were uncommon among persons driving without a helmet in the clinical material. Only in about 6% of the cases an open face helmet would probably have had an injury reducing effect. Drunken driving is an important etiological factor for fatal snowmobile accidents. Preventive measures must include information that the Traffic Temperance Law also applies to snowmobile riding. A helmet law for snowmobile riders does not seem to be motivated from the injury reduction point of view. According to official Swedish police statistics more than 400 car occupants are injured annually in crashes with a moose. The crash mechanism is special. Because of its long legs the body of the moose hits directly against the windshield, windshield pillars and front roof. During a period of three years 154 injured passenger car occupants were treated in the hospitals in Umeå and Skellefteå. Of both the front and rear seat occupants 80% suffered laceration injuries from glass or glass splinters.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevention of accidents in reindeer herding work. In the northern part of Finland we have about 450,000 reindeer and their raising gives work to about 3,500 reindeer herders. In this study data on the occupational accidents of herders were collected by two questionnaires with an interval of 2 years. Based on the surveys of accident risks in various work phases 34 preventive measures were developed and information about them was passed on to the herders between the questionnaires. Most of the accidents occurred in the late autumn during slaughtering, gathering for separation and during separation work. The main causes of accidents were the slaughtering knife (30%) and the reindeer itself (25%). The most serious accidents were caused by snowmobiles and other terrain vehicles. The recommended preventive measures mostly dealt with the environment of permanent working places, personal protection and working habits. The follow-up questionnaire showed that the herders had implemented on an average 5.8 preventive measures. The incidence rate of accidents also decreased during the 2 years from 21 to 12 accidents/1000 working days. In conclusion these results show that it is possible to develop measures preventing accidents and to improve the safety in reindeer herders' work.


Snowmobile accidents in Lapland.

Snowmobile accidents in Lapland. It is assumed that there are about 30,000 snowmobiles in Lapland. In 12 health centers and in all three hospitals the snowmobile accidents were analyzed in 1990. There were 290 accidents reported. Seventy-two percent were leisure time accidents. The accidents occurred typically in the afternoon during the weekend in the spring. Most accidents took place in the woods by driving into a barrier. Half of the injuries were on extremities, especially on legs. Eighteen % were head injuries and 11% thorax injuries. According to the Abbreviated Injury Scale classification most injuries were of class 1 and 2. There were 5 deaths. Thirty-one % of the injured persons had a helmet. From 1991 the use of the helmet is compulsory. The registration of snowmobiles is important and it should be implemented in Finland. The snowmobile is a significant cause of accidents in Lapland today and preventive measures are urgent.


Accidents in the Arctic. A psychological point of view. The aim of this paper is to discuss the influence of arctic conditions on the occurrence of accidents especially from the point of view of the interaction between environment, activity and man. Special attention is paid to risk assessment, risk taking and risk compensation. According to the danger factor theory frostbites should be extremely common in arctic regions, but in reality serious frostbites appear rarely in accident statistics. This finding supports the interactive accident theories. Instead cold can be a contributing factor in accident and injury causation and the effect of cold is most often indirect. Frostbites can occur e.g. as a result of an accident, losing one's way because of darkness, snow storm etc., wet clothes, unexpected temperature changes, disease attack, alcohol-induced reasons such as immobility or excess risk taking etc. Temperatures below and above +20 degrees C increase unsafe behavior. In the Arctic it is impossible to remove all the potentially dangerous factors, because many typical features of working and living conditions are regulated by natural forces, the seasons etc. This makes accurate risk assessment and prediction especially important in accident prevention. If the person does not recognize the situations in which the risk factors exist, he/she cannot implement precautionary steps at the right moment and hence cannot avoid risks. Moreover, if better and safer machines, equipment and tools get people to take greater risks, the accident situation can even become worse.


Safety in the use of four-wheeled all-terrain vehicles in Finland. The aim of this study was to ascertain the use of four-wheeled all-terrain vehicles in Finland and estimate the safety in driving a four-wheeler. According to the importers there are about 3,000 four-wheelers in use in Finland. A questionnaire was sent to the owners of four-wheelers (n = 185), in which questions were asked about their use, protection used when driving, accidents that had occurred and suggestions for developing four-wheelers. One hundred three answers (response rate 56%) were received. The respondents reported minor injuries (15%) and dangerous situations: the four-wheeler had fallen over (35%) and the driver had fallen off the four-wheeler (20%). The accidents and dangerous situations were concentrated to occupational users who drove a lot in poor terrain. Four-wheeler driving was estimated to be more dangerous than snowmobile driving. According to the answers the most efficient measures to improve safety would be the use of a safety helmet and high boots when driving as well as the enforcement of an age limit for the driver. The technical properties of the four-wheelers could also be developed e.g. the leg room, foot board and protective roll bar.


Occupational safety and health training in Alaska. We have eleven years of experience delivering a wide variety of worker education programs in cross-cultural settings to reduce the levels of occupational fatalities and injuries in Alaska. We published an instructional manual and informational poster for workers, on Alaska's "Right-To-Know" law regarding chemical and physical hazards. The "Job Hazard Recognition Program" curriculum for high school students has received national acclaim for being proactive in dealing with worker safety education before the student becomes a member of the work force. Adult educational programs and materials have been designed to include less lecture and formal presentation, and more practical "hands on" and on-the-job experience for specific trades and hazards. New industry specific manuals deal with hazardous waste reduction as a method to reduce harm to the employee. Difficulty in getting instructors and training equipment to rural locations is dealt with by becoming creative in scheduling classes, using locally available equipment, and finding regional contacts who support the overall program. Alternative approaches to funding sources include building on regional long-term plans and establishing complementary program objectives.


Ergonomic design of machinery for use in the cold. A review based on the literature and original research. The main purpose of this paper is to identify some important problems associated with ergonomics of the human-machine-task-environment system under cold conditions. Practical examples of stress, strain and accident risks based on the literature and original research are given, and needs and possibilities for improving the ergonomic design of machinery are described. The awareness of designers to the demands set by cold conditions should be increased. Both the need for better operability and the need for better maintainability of machinery in the cold argue for the development of a new, systematic engineering design methodology.


Work in the cold--an information and research program in occupational health. Hundreds of thousands of employees work in the cold. The problems concerning cold are, to a great extent, well known. There are also good suggestions about how to deal with these problems. This project deals with: Cold stress, as an important risk factor for medical illness; the problems concerning clothing and equipment; how to change the snowmobile into a modern low risk piece of equipment: international standardization usable in the field; different approaches for information to reach and be used by the workers and their chiefs.


Protective clothing against cold--performance standards as method for preventive measures. Survival, function and comfort in the cold are dependent on a rational and cautious use of protective measures to reduce and control heat losses. International standards are now available for establishing a basis for the rational assessment of protection requirements and the subsequent selection of appropriate clothing. Protection requirements may be readily calculated by the IREQ-index (ISO/TR-11079), which specifies required resultant clothing insulation for given conditions. Performance of selected clothing ensemble can be tested by measuring the insulation value on a moveable, thermal manikin according to prEN-342. Similarly, performance of protective gloves against cold may be tested with a heated hand model (prEN-511). It is important to emphasize that the outlined procedure should only be applied as a guide-line for action. Due to considerable individual variation in capacities, preference and demand, room must be available for behavioral adjustments, as well as clothing must be flexible enough to accommodate these adjustments.


Purification and characterization of CeqI restriction endonuclease. CeqI, a type II restriction endonuclease, an isoschizomer of EcoRV was purified to apparent homogeneity by a combination of salt precipitation, ion exchange, dye affinity and hydrophobic interaction chromatographies. The crude enzyme was present in the form of large aggregates that could be pelleted by high speed centrifugation. The enzyme was not associated with cellular membranes, though non-ionic detergents lowered the apparent size of the aggregates. The purified enzyme also showed a tendency to form large molecular mass (66-600 kDa) complexes under physiological conditions, in the absence of cleavable DNA. The enzyme formed smaller complexes in the presence of DNA and non-ionic detergents and dissociated into subunits (and undergoes reversible loss of activity) in the presence of high concentrations of salts. According to SDS gel electrophoresis and sedimentation analysis the molecular mass of the monomer 32 +/- 2 kDa. The enzyme had a rather broad PH optimum, extending into the alkaline range and lost specificity and activity in buffers below pH 6.


Modulating luminol-dependent chemiluminescence of neutrophils by flavones. The effect of 14 flavones on luminol-dependent chemiluminescence of neutrophils was studied in vitro. Chemiluminescence was used in this study as an indicator for the production of a reactive oxygen species by neutrophils, stimulated by phorbol myristate acetate. While flavone-8-acetic acid, and most of the compounds tested, inhibited chemiluminescence, flavone and its 5-hydroxy-7-methoxy derivatives enhanced it by up to 150%. The most active inhibitors of photon emission were the glycosides. These results indicate that lipophilicity and some structural determinants modulate the chemiluminescent capacity of neutrophils.


Acid DNase activities in peripheral, mononuclear blood cells: a possible parameter to detect proliferating cell populations. After electrophoresis in DNA-containing polyacrylamide gels, two acid DNase activities can be detected in peripheral, mononuclear cells of the human blood. One of these acid DNase activities correlates with cell proliferation; its isoelectrical point is at pI 7.4. By means of this DNase activity, a quantity of less than 1% leukemic cells can be detected. The increased acid DNase activity can indicate the proliferation of malignant cell populations and possibly the proliferation of cell populations during immunological reactions.


Disturbing GTP-binding protein function through microinjection into the visual cell of Limulus. We have tested the action of three agents microinjected into the ventral nerve photoreceptor of Limulus on the electrical response to dim light. 1. A monoclonal antibody (mAb 4A) against the G alpha subunit of frog transducin reduces the size of the receptor current to 60%, suggesting an interaction with G alpha in the Limulus photoreceptor. 2. Injection of Clostridium botulinum ADP-ribosyltransferase C3 reduces the size to 46%; latency is not affected. The results imply that small GTP-binding proteins play a functional role in photoreception of invertebrates. 3. Injection of GDP-beta-S reduces dose-dependently the size of the receptor current to 15% and prolongs the latency to 200%, presumably by reducing number and rate of G-protein activations.


Two phases of ferricyanide reductase activity in Ehrlich cell plasma membranes. Ehrlich cell plasma membrane vesicles have a ferricyanide reductase activity that shows two phases. These two phases were kinetically characterized. Evidence is presented for a differential effect of trypsin on both phases.


The biology of wound healing.

The biology of wound healing. Wound healing is a complex biological process. A thorough knowledge of normal wound healing is of utmost importance for the clinicians who are involved in the care of patients with open wounds. It is imperative for every clinician who is involved in wound care to know the process which prevents, minimizes and eliminates those factors which adversely affect wound healing.


Case study: traumatic pressure sore of the left lateral malleolus. JB, a 62 year old male, was facing potential amputation of his lower left leg following traumatic injury in the left malleolar area. Previous treatments over an approximate six week period had not improved the wound condition. A sodium chloride impregnated dressing, Mesalt Sterile Sodium Chloride Impregnated Dressing, was tried as a last resort prior to amputation of the lower leg. Three weeks of therapy with this dressing documented dramatic improvements in wound size, odor, amount of drainage, type of drainage, surrounding skin condition and appearance of the wound bed. The simplicity of the treatment regimen facilitated care of the wound by nursing home staff, home care personnel and JB's son. After 17 weeks of therapy, the wound was completely healed and amputation avoided.


Structural studies on bio-active compounds. Part 21. Acid-promoted debenzylations in antitumour 2,4-diamino-5-[4-(N-alkylbenzylamino)-3-nitrophenyl]-6-ethylp yrimidines. Methylbenzoprim and ethylbenzoprim undergo debenzylation in hydrochloric acid. Two reaction mechanisms are proposed to explain this reaction, both of which involve a neighbouring group participation by the nitro group ortho to the tertiary amine fragment. The physical stability of dihydrofolate reductase inhibitors in the benzoprim class may influence the choice of a clinical candidate.


Crystal structure determination at 2.3 A of recombinant human dihydrofolate reductase ternary complex with NADPH and methotrexate-gamma-tetrazole. The crystal structure of the methotrexate-gamma-tetrazole (MTXT)-NADPH ternary complex with recombinant human dihydrofolate reductase (DHFR) has been determined and refined to R = 15.9% for 7003 data from 10.0 to 2.3 A resolution for the R3 lattice. Interpretation of difference Fourier electron density maps revealed that the cofactor NADPH is bound in an extended conformation, and the closest contact between cofactor and inhibitor is 3.1 A, between N(5) of the MTXT pteridine ring and the nicotinamide C(4) which transfers a hydride during the enzyme-catalyzed reaction. As in other DHFR complexes, MTXT is interpreted as protonated at N(1) by Glu-30, and the 2-amino group is hydrogen bonded to a structurally conserved water which also interacts with Glu-30 and Thr-136. The 4-amino group of MTXT hydrogen bonds to the carbonyl of Ile-7 and the phenolic hydroxyl of Tyr-121, and the alpha-carboxylate forms a salt bridge with the conserved Arg-70. In this structure, the amide carbonyl forms two hydrogen bonds with Asn-64 and a water molecule, whereas the gamma-tetrazole ring does not interact directly with the enzyme. The largest changes in the secondary structure on formation of the ternary complex involve the fold of a flexible loop near residues 40-46, and to a lesser extent the helical region near residues 102-109 and the beta-sheet regions near residues 71-75 and 157-159.


[Allergic asthma to latex, proven by a bronchial provocation test]. The authors report the case of a female cook who develops contact urticaria associated with rhinitis and asthma-type dyspnea when using rubber gloves in the course of her work. Allergy to latex was confirmed by a PRICK-test with latex, the presence of specific IgE in the serum, and the onset of contact urticaria after putting on gloves. A latex glove was rinsed with 10 cc of distilled water and the resulting solution, used as a spray, brought on a bronchospasm in the first two minutes. This bronchial provocation test proves that latex can cause asthma-type dyspnea when work involves contact with the substance. The speed of onset and intensity of the respiratory symptoms observed show that such a provocation test must be carried out with extreme care in patients with a marked sensitivity to latex. The future lies in the possibility of easily standardizing the latex protein concentration in order to be able to administer progressive doses without any systemic risk. This case draws attention to the probably underestimated possibility of latex-induced asthma in all subjects who are brought into repeated contact with latex, whatever their profession.


[Anaphylaxis caused by carboxymethylcellulose: report of 2 cases of shock from injectable corticoids]. Two cases of anaphylactic shock are reported, occurring after intra-articular injections of corticosteroids, containing carboxymethylcellulose (CMC), benzylic acid, polysorbate 80, and merthiolate. Skin tests and leukocyte histamine release are positive to CMC and negative to the other substances including the corticosteroids: prednisolone acetate and cortivazol . No cross-reactivity with hydroxypropylcellulose was demonstrated. These tests lead to incriminate CMC in these patients. Anaphylaxis to CMC seems exceptional, though CMC is widely used in agro-alimentary and pharmaceutical industries, as well as hydroxypropylcellulose. In one case, the possibility of a sensitization by CMC as a food additive is discussed, insofar as the patient has a fixed eruption which has been suspected to be owed to intolerance to food additives.


Autoimmune features in atherosclerotic ischemic cardiomyopathy. An high frequency of antimitochondrial autoantibodies has been reported in subjects affected with primary cardiomyopathies and it has been hypothesized that they could be involved in the pathogenesis of these diseases. In order to find out whether such autoantibodies could on the contrary represent an epiphenomenon of myocardial cell damage, we searched for antimitochondrial (AMA), antinuclear (ANA) and antismooth-muscle (SMA) non-organ specific autoantibodies in a group of 50 subjects (47 females and 3 males), over 65 years of age, affected with ischemic cardiomyopathy (ICM) due to atherosclerosis, a condition resembling other cardiomyopathies as it concerns ultrastructural aspects of myocardial tissue. The frequency of the autoantibodies tested in our patients resulted quite similar to that occurring in our healthy elderly control subjects (AMA: 14% vs 5.7%; ANA: 28% vs 23%; SMA: 12% vs 11.4%) and in normal aged population. On the basis of our data, the myocardial cell damage "per se" does not seem to influence significatively the production of non-organ specific autoantibodies.


[Poor tolerance of exertion during sports and bronchial hyperreactivity]. 135 sportsmen and women, 55 girls, 80 boys, aged from 7 to 30 years, from various sports, who complained of bad tolerance of exertion were examined with an exercise test and isocapnic spontaneous hyperventilation. 61, about 45%, during a hyperventilation test had a fall of V.E.M.S. greater than or equal to 20%, showing bronchial hyperreactivity. After three tests, this fall index was greater than or equal to 50%. 68% of the positive responses were seen in boys and 2/3 of the subjects with a positive response were atopics. No other argument could be maintained from the questioning or clinical history to predict the positive or negative character of the hyperventilation (age, sporting level, symptoms, previous asthma or asthmatic, allergy). H.S.V.I. of the chests of a sporting population that complains of exertion intolerance, therefore allows verification of an H.R.B. assessment of its severity and to follow evolution after treatment.


Calorimetric study of thermal denaturation of type I human placenta collagen. The thermal denaturations of type I human placenta collagen were studied in different aqueous solutions in the temperature range from 274 to 345 K by differential scanning calorimetry. The thermodynamic parameters of denaturational process were accurately. The average temperature of denaturation of the collagen Td is 47.1 degrees C, and the denaturational enthalpy delta Hd is 8.43 kJ per mole of residue in salt-free aqueous solution at pH 3.7. The linear relationship of delta Hd with Td has been obtained for the various collagens studied. The various factors concerning the stabilization of collagen structure of the Sigma collagen have been demonstrated. The dominant factors are hydrogen bonding and the participation of water molecules in the collagen structure. It is concluded from the thermodynamic evidence obtained that the water-carbonyl model is preferable to other models. By means of calculating the van't Hoff enthalpy of the collagen denaturation, the number and the size of cooperative blocks of the Sigma collagen have been evaluated. Its molecule contains five cooperative blocks, each having 600 residues or so. The type I human placenta collagen is a multi-domain protein.


Crystallographic refinement of trichosanthin at 2.6A resolution. The molecule model of trichosanthin has been rebuilt by using the electron density map improved by the solvent flatten and in accordance with the primary structure put forward by Collins. The crystallographic refinement of two trichosanthin molecules (3828 nonhydrogen atoms) in an asymmetric unit has been carried out by means of the restrain least-square procedure and diffraction data to a resolution of 2.6 A. The results are: an R factor 0.223 and the r.m.s. deviation of the bond length = 0.023 A. The new molecular model is in good agreement with the electron density map calculated with the coefficient 2Fo-Fc.


Disulfide containing proteins denatured in 6 mol/L guanidinium chloride are not completely unfolded. The unfolded states of serum albumin, lysozyme and ribonuclease denatured in GuHCl with their disulfide bridges intact or reduced and carboxyamidomethylated have been compared by their circular dichroism, second-derivative and difference spectra in the ultraviolet region. Results obtained indicate that although the secondary structures of denatured proteins with intact disulfides are largely destroyed, they still have considerable ordered conformation even in 6 mol/L guanidinium chloride as indicated by the differences in the extents of exposure of the aromatic residues compared to the denatured proteins without the native disulfide bonds.


Study of the RNA splicing defect in the common Chinese beta-thalassemia gene, IVS-II nt. 654 C-->T by using mRNA/PCR. With direct sequencing of the amplified cDNA, we analysed the transcript and mRNA splicing defect in a common Chinese beta-thalassemia mutant (IVS-II nt. 654 C-->T). The result shows that this mutant gene would not only produce abnormally processed beta-globin mRNA, but also transcribes a small amount of normally spliced mRNA, hence leading to beta+ thalassemia. The method described herein provides a simple and sensitive approach to the studies of gene expression and molecular defects in genetic diseases at transcriptional level.


Etiological implication of autoantibodies to zona pellucida in human female infertility. Autoantibodies to zona pellucida (ZP) have been implicated as a cause of infertility in woman by three lines of clinical and laboratory evidence. First, positive anti-zona activities, as assessed by the passive hemagglutination reaction (PHAR) using bovine red blood cells sensitized with porcine zona antigen, were detected in 45 of 1,872 serum samples collected from infertile women, but in only three (two nonpregnant and one pregnant) of 592 serum samples from control subjects. Their incidence in 320 women with unexplained infertility (5.6%) was much higher than that in 1,552 women with infertility of known cause (1.7%, P < 0.01), which was comparable to the incidence observed in 193 age-matched fertile nonpregnant and pregnant women (1.5%, P < 0.05). None of the serum samples from 292 age-matched adult men and 100 children of between 5 and 10 years old gave a positive PHAR. Second, follow-up study for a minimum of 2 years with treatment revealed that no pregnancy occurred in 11 infertile women with a consistently positive PHAR, and only three pregnancies in 19 infertile women with a fluctuating positive PHAR. Third, three of seven serum samples from women who gave a consistently positive PHAR produced strong immunofluorescence reactions on human ZP even after adsorption with porcine and human AB blood cells. Pre-exposure of human ZP to the sera showing positive immunofluorescence, including that of one patient undergoing an in vitro fertilization program, greatly diminished the number of spermatozoa of normal quality that bound to and penetrated across human ZP. The observed high incidence of anti-zona activities and long-term resistancy to treatment in women with unexplained infertility may be closely correlated with inhibition of sperm-egg interaction by anti-zona autoantibodies produced in these women.


Analysis of T-lymphocyte subsets after phytohemagglutinin stimulation in normal and type 1 diabetic mothers and their infants. Our aim was to investigate the immunological status of diabetic pregnancy, which is an overlap of diabetic immunity abnormalities and the immunological modifications normally occurring during pregnancy. We studied lymphocyte subpopulations and lymphokine production, after 96 h of phytohemagglutinin (PHA) stimulation, from normal and Type I diabetic pregnant women at delivery time and from the respective cord blood. Peripheral blood mononuclear cells (PBMC) from both normal and Type I diabetic mothers showed an increase in CD8+ and a decrease in CD4+ cells compared to the respective cord blood mononuclear cells (CBMC). Moreover, Type I PBMC showed a lower number of "activated" CD3+ DR+ cells and a higher number of CD8+ CD25+ cells with respect to normal women, which may reflect the dysregulatory pattern due to the autoimmune condition. Type I CBMC showed a big increase in the number of CD4+ Leu8+ cells, a cell subpopulation characterized by inhibitory activity. Finally, as regards lymphokine release in culture supernatants, type I diabetes seemed to be associated with an over-production of IL1 and IL6, although the latter increase is less evident in CBMC cultures. The present study shows that diabetic pregnancy is associated with major alterations of cell-mediated immunity leading to a state of immunodepression. Moreover, our study suggests that the maternal immunological status influences fetal immunity, as demonstrated by the increase in the number of regulatory cells and by the altered pattern of lymphokine production (IL1 and IL6) by lymphocytes derived from diabetic CBMC. The latter phenomenon perfectly mirrors maternal PBMC characteristics.


Effect of labor on lymphocyte subsets in full-term neonates. To determine the effect of labor on lymphocyte subsets in full-term neonates. Cord blood obtained at delivery from full-term neonates, six born vaginally and six born by elective Cesarean section, was analyzed for lymphocyte subsets. Monoclonal antibodies, immunofluorescence, and flow cytometry were utilized to determine the lymphocyte phenotype frequencies in these neonates. These frequencies were compared by mode of delivery and to adult peripheral blood reference ranges using a two-tailed Student's t-test, P < 0.05. A profile of significantly elevated T (CD2, CD3) and helper cells (CD4) and depressed Natural Killer cells (CD16, CD56) is characteristic of term Cesarean section neonates. Significantly depressed frequency of T cells (CD2, CD3) and helper T cells (CD4) and elevated Natural Killer cells (CD16, CD56) is characteristic of vaginally delivered neonates. The mode of delivery affects the lymphocyte subset frequencies in full-term neonates.


Development and distribution of the white blood cells within various structures of the human menstrual corpus luteum examined using an image analysis system. Emerging evidences suggest that immunoendocrine interactions play definitive roles during development and regression of the human menstrual corpus luteum (hmCL). We have studied the distribution of immune cells within individual structures of hmCL during various stages of its development. Immunoperoxidase-stained ultra-thin frozen sections were evaluated using light microscopy fitted with an image analysis system. The results suggest that monocytes/macrophages and MHC class II positive cells are the most prominent immune cells within the hmCL throughout its whole lifespan. Both cell types are concentrated within the trabeculae. In addition, MHC class II positive cells are abundant also within the granulosa-luteal layer. T helper/inductor (Th/i) and T cytotoxic/suppressor (Tc/s) cells were detected only in minor amounts within the thecal trabeculae of mature tissue. Possible links between the occurrence and functional roles of the immune cells studied are discussed.


Identification of lymphocyte subsets in the human fallopian tube. Immunohistochemical investigations for the detection of lymphocyte subsets in the human oviduct have been performed. Knowledge about local immunity especially cell-mediated immunity, in the fallopian tube has been, up to now, limited. As an essential structure for the human reproduction process, the tubal mucous membrane is exposed to a variety of antigens. A total number of 20 tubal biopsies obtained from fertile women during gynecological operations like tubal ligations or hysterectomy were examined by the immunoperoxidase technique. Seven specimens were obtained during the proliferative phase, ten during the secretory phase and three during a caesarean section with tubal ligations. It could be established that the presence of lymphocytes in the oviductal mucous membrane is physiological. These cells can be identified by their typical immunohistochemical patterns. There were no significant differences of the type and number of lymphocytes in the mucosa within the phases of menstrual cycle. The dominant cell types in the tubal mucosa were the CD3+ and CD8+ lymphocytes. It can be suggested that the lymphocytes in the tubal mucosa may involved in the process of immune tolerance, which could realize the transport of sperms and blastocysts through the oviduct under normal conditions without activation of local immune mechanisms. The lymphoid tissue of the oviduct is a specialized form of mucosal-associated lymphoid tissue (MALT).


The leukocytic reaction of the human uterine cervix. Sperm interaction with the immune system of the human cervix is poorly understood. The leukocytic response of the human cervix to sperm was examined in a closely monitored patient population (N = 10), using monoclonal antibody cell identification techniques. Baseline data were collected from both cervical mucus and smears sampled before treatment by donor insemination. Donor insemination was timed to coincide with ovulation by monitoring plasma LH concentrations twice daily. Following insemination the numbers of leukocytes were recorded in cervical mucus and smear samples taken over a 24-h period relative to the time of treatment. Controls treated with "pure sperm," seminal plasma, cryopreservative, and cervical smearing alone were also included in the study. Only those women treated with sperm cells exhibited substantial elevations in leukocyte numbers following inseminations. Additionally, serial cervical smearing induced an inflammatory response of the cervix. In all the women, the neutrophil was the predominant leukocyte of the cervix both during the baseline and treatment periods (median values ranged from 77 to 86%). Macrophages, T-helper lymphocytes, and T-suppressor lymphocytes were also detected, but only in low numbers (2-10.6%). Two patients and one control ("pure sperm") became pregnant during their study cycle. We conclude that the leukocytic reaction is a physiological response of the cervix to sperm, the function of which remains to be established.


Quantitative and qualitative changes in the intraepithelial lymphocyte population in the uterus of nonpregnant and pregnant sheep. Previous studies have revealed the presence of a unique population of CD45R+ granulated cells in the sheep uterine epithelium. In the present study, dramatic changes in this cell population and in the nongranulated lymphocytes in the uterine and endometrial glandular epithelium of non-cycling, cycling, pregnant, and postparturient sheep are described. In noncycling and cycling sheep, the granules in the granulated intraepithelial cells were small. From days 55 to 134 of pregnancy, the granules in these cells were large, and there was a significant increase (P < 0.01) in the proportion of this cell population in the uterine epithelium but not in the endometrial glandular epithelium located in the deeper region of the stroma. The number of these cells declined dramatically (P < 0.01) from 2 to 15 days after parturition. Both the tissue distribution and the time of activation of these cells suggests they are different from the granulated lymphocytes described in placentae of mice and man. It is concluded that this unique population of granulated cells is derived from lymphocytes, and that these cells become metabolically active from mid- to late-pregnancy and may play a physiological role during pregnancy or birth. In contrast, the number of nongranulated intraepithelial lymphocytes were suppressed throughout pregnancy and they probably do not play a role in pregnancy.


Physiologic adaptations of pregnancy.

Physiologic adaptations of pregnancy. Normal pregnancy changes include physiologic anemia, leukocytosis, and thrombocytopenia. Cardiac rate and stroke volume increase, vascular resistance falls, and creatinine clearance markedly rises. Thyroid binding globulin and cortisol binding globulin both increase, as do complement proteins and fibrinogen, the latter resulting in a normally high erythrocyte sedimentation rate. Estrogen and progesterone rise dramatically. Low back pain, hip and sacroiliac complaints are common. The cytolytic activity of natural killer (NK) cells is decreased, as are adhesion and chemotaxis of phagocytic cells. Antibody responses are normal. CD4 cells proportionately decrease. A large number of circulating proteins suppression lymphocyte proliferation, and T-cell interleukin-2 (IL-2) production may be suppressed. In studies of pregnant patients, controls must include normal pregnant women.


Cytokines considered critical in pregnancy. Cytokines considered critical in pregnancy include interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma, granulocyte-macrophage colony stimulating factor (GM-CSF), and colony stimulating factor (CSF-1). They affect blastocyst attachment, trophoblast outgrowth, implantation, proliferation of cells isolated from placentas, proliferation of trophoblast cell lines, and percent fetal resorption in spontaneously aborting mice. Cytokines also affect chorionic gonadotrophin and progesterone production by trophoblast. Cytokine effects vary with concentration, route of administration, and timing of secretion.


Immune recognition at the maternal-fetal interface: overview. Trophoblast antigens at the maternal-fetal interface that are capable of stimulating maternal immune responses have been studied. Candidates are blood group I and P, HLA, Fc gamma-receptors, TLX, and phospholipids. Antigens I and P on trophoblast have been implicated in pregnancy loss but incompatible i,p mothers are rare. HLA-G is expressed on cytotrophoblast; however, no evidence for HLA-G allotypy or maternal responses to these molecules exists, although HLA-G has been implicated in recruitment of suppressor T cells. Receptors for IgG (Fc gamma-RI, Fc gamma-RII and Fc gamma-III) are present on trophoblast but allotypy is limited to the NA1-NA2 antigen system associated with Fc gamma-RIII on neutrophils. Maternal Fc-gamma R blocking antibodies have been linked to pregnancy success. The TLX alloantigen system was described by using xenogeneic antisera. Idiotype-antiidiotype regulated maternal responses to TLX are proposed as necessary for successful pregnancy. Several putative TLX monoclonal antibodies (Mab) recognize a regulator of complement activation called MCP (membrane cofactor protein, or CD46). Mab to MCP do not exhibit allotypy. Syncytial and cytotrophoblastic membranes are rich sources of MCP. Preliminary data suggest that a conformational site induced by C3b (iC3) binding to MCP may be responsible for TLX allotypy. Certain pregnancy loss patients produce antiphospholipid antibodies (aPA). Some investigators believe that aPA recognize a plasma protein cofactor, beta 2 GPI and not phospholipid per se. We produced three Mab specific for beta 2 GPI, one of which fails to recognize beta 2 GPI bound to phospholipid [corrected].(ABSTRACT TRUNCATED AT 250 WORDS)


Ontogeny of T lymphocyte function in the neonate. T cell precursors are first detected in the thymus at eight weeks of gestation. By 15 to 20 weeks of gestation, T-cell precursors expressing alpha beta and gamma delta T-cell receptors are present in the thymus in numbers relatively similar to those found in postnatal life. However, recent data suggest that T-cell receptor diversity is more limited during fetal and neonatal life than in adults. Additionally, the functional capacity of T cells in the fetus and neonate is immature, in that neonatal T cells express a limited repertoire of lymphokines in response to activation. Specifically, the production of the lymphokines, interferon-gamma and interleukin-4, which participate in the maturation of cytotoxic cells, activation of macrophages, and the maturation and modulation of B cell function and isotype expression, is reduced more than tenfold compared to cells from adults. This appears to result primarily from the lack of memory T cells in the fetus and neonate, reflecting their antigenic naivete. The difference in lymphokine expression is due to diminished transcription of these genes in neonatal T cells in response to activation. Preliminary data indicate that differences in essential promoter elements regulating transcription of these lymphokine genes plays a role in their differential expression in T cells.


The effects of sex hormones on the immune system in pregnancy. The immune system is affected by sex steroids. Immunoglobulin synthesis, T-cell subsets, and a variety of cytokines are targets for sex steroids. Hormonal variations are found in patients with rheumatic diseases. These variations include the hydroxylation of estrone and the oxidation of testosterone, both of which are altered in rheumatic disease. These changes are magnified in the pregnant state. More estrogen metabolites of the C-16 variety can bind to cells (lymphocytes and erythrocytes) and his reaction is accelerated in pregnancy. The role of the catechol estrogens is discussed. These compounds may be important to some of the vasospastic symptoms seen during pregnancy in patients; moreover, oxidation of testosterone to weak androgens is found in women with systemic lupus erythematosus (SLE). Overall, interesting observations and conclusions will evolve from a better understanding of sex hormone metabolism and its effects on the immune system in pregnancy.


Glucocorticoid therapy for rheumatic diseases: maternal, fetal, and breast-feeding considerations. Glucocorticoids form the mainstay of therapy for many rheumatic diseases, especially systemic lupus erythematosus (SLE). Prednisone is the drug of choice, because it has been well described during the pregnancy and is the primary drug for maintenance therapy or to induce a remission. Principles for prescribing glucocorticoids would apply during pregnancy, recognizing that many effects of rheumatic disease and long-term therapy are similar to physiologic changes of pregnancy. Particular attention should be placed on screening for pregnancy-induced glucose intolerance, hypertension, and delayed fetal growth. Although animal studies suggest an increased risk of oral clefts associated with glucocorticoids, several human studies have failed to demonstrate teratogenic or toxic effects. Nevertheless, rare cases of transient fetal adrenal suppression have been reported, so all infants should be monitored in the nursery. Breast-feeding is safe, with clinically insignificant amounts of the drug being concentrated in breast milk.


NSAIDs: maternal and fetal considerations. Nonsteroidal anti-inflammatory drugs (NSAIDs) gained popularity in the late 1970s. Inhibition of prostaglandin synthesis with indomethacin has been reported to be effective for prevention of labor and for treatment for symptomatic polyhydramnios. Concern about its possible constrictive effect on the fetal ductus arteriosus has limited its use in pregnancy. Maternal indomethacin therapy has also been associated with reduction in urine production in the fetus and with oligohydramnios. Obstetricians have discouraged pregnant women from taking analgesic doses of aspirin, mainly because of the availability of paracetamol (acetaminophen), which causes less gastric irritation, but also because of fear of maternal and fetal hemorrhage and of possible premature closure of the ductus. These fears largely derive from studies on patients taking large doses and from extrapolation from other NSAIDs. The likelihood that treatment with 60-75 mg/day of aspirin markedly reduces the incidence of preeclampsia and fetal intrauterine growth retardation makes it important to reexamine its use. This review describes the pharmacology and pharmacokinetics of aspirin with particular reference to pregnancy and considers teratogenesis, prolongation of pregnancy and labor, maternal bleeding, fetal and neonatal bleeding, possible effects on the ductus arteriosus and pulmonary circulation, and possible nonspecific effects on intelligence and breast feeding and acute toxicity in the neonate.


Treatment with immunosuppressive and disease modifying drugs during pregnancy and lactation. Active rheumatic disease may necessitate the treatment of pregnant and lactating patients with disease modifying (DMARD) or immunosuppressive drugs. This review summarizes data from the literature, and attempts to give some recommendations. Possible teratogenic effects of gold, penicillamine, and chloroquine are still disputed. As long as the issue is not settled, it seems prudent to stop using these agents as soon as pregnancy is diagnosed. Hydroxychloroquine has been used by some rheumatologists for treating pregnant patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) without malformations detected in the neonates. Sulphasalazine does not increase the rate of congenital abnormalities. Selected case reports have not shown any teratogenicity of cyclosporine A so far. However, the drug may cause fetal retardation. The use of standard doses of azathioprine does not increase the risk of congenital anomalies. By contrast, the antitumor agents cyclophosphamide, chlorambucil, and methotrexate are possibly teratogenic when given during early pregnancy, but may be less harmful in late pregnancy. Data on the excretion of DMARD and the cytostatic drugs are sparse. Because of insufficient data, breast feeding is not recommended in patients on antimalarials, penicillamine, cyclosporine A, and cytostatic drugs. Intramuscular gold and sulphasalazine seem to impose no major risk on the nursing infant.


The use of low dose aspirin in pregnancy. Pregnancy-induced hypertension (PIH) in general and preeclampsia in particular are major causes of maternal and perinatal morbidity. Data from our studies and from a number of prospective controlled trials have suggested that aspirin in doses of 60-150 md/day during the second and third trimester reduces the risk of PIH and improves maternal and neonatal outcomes. The number of patients enrolled in these studies is relatively small. However, meta-analysis of existing trials suggests that low dose aspirin reduces the risk of PIH and severe low birth weight. Although no maternal or neonatal adverse effects associated with aspirin were observed, the use of aspirin in the third trimester has been reported to cause hemostatic abnormalities in both mother and neonate. Other complications associated with prostaglandin synthetase inhibitors include premature closure of the ductus and neonatal primary pulmonary hypertension. The use of aspirin in the first trimester is not associated with increased risk of structural malformations. On the basis of these findings and pending the results of ongoing large-scale randomized multicenter trials, we suggest that daily low dose aspirin (1 to 2 mg/kg/day) be recommended only for select women at high risk for developing PIH and its associated complications.


The effect of cyclophosphamide pulses on fertility in patients with lupus nephritis. The effect of cyclophosphamide pulse therapy given in relatively small doses (10 mg/kg per pulse) in 17 females with lupus nephritis has been studied. Four females developed menopause; in one transient amenorrhea occurred. No changes in menstrual cycle were noted in the other 11 females, four of whom subsequently delivered five normal babies. These data suggest the relative safety of small doses of cyclophosphamide pulse therapy on gonadal function in females under age 40 years.


Condition specific antepartum testing: systemic lupus erythematosus and associated serologic abnormalities. Antepartum fetal surveillance is well established in the optimal management of any pregnancy complicated by maternal systemic lupus erythematosus and/or its associated serologic abnormalities. Our experience in antepartum surveillance of the "lupus pregnancy" from 1980 to 1988 is reviewed. An overall perinatal mortality rate of 6.06% compares favorably to the total intrauterine death rate range usually reported for this disease.


Fetal echocardiography in the assessment of lupus pregnancies. Fetal echocardiography is the most sensitive tool in detecting the earliest possible changes of the cardiovascular system related to maternal lupus. The institution of aggressive therapy at that time may still be able to reverse the process before permanent fetal cardiac injury occurs. Experience with this technique is described.


Umbilical and uterine artery flow velocity waveforms in pregnant women with systemic lupus erythematosus treated with aspirin and glucocorticosteroids. Pregnancy in systemic lupus erythematosus (SLE) is at high risk to the mother and fetus. Impaired utero-placental perfusion may increase fetal loss and intrauterine growth retardation. We assessed the changes in impedance to blood flow in the umbilical and uterine arteries in five patients with SLE treated with low dose aspirin and corticosteroids, using Doppler ultrasound longitudinally throughout pregnancy. Blood flow velocity waveforms of the umbilical and uterine arteries were studied by transabdominal and transvaginal Doppler ultrasound, respectively. Resistance index (RI) was measured every two to four weeks from week 10 to term, and the values obtained were compared to those of normal pregnancies. All five patients delivered uneventfully. One neonate was delivered at 36 weeks (2550 g) and one neonate was growth retarded (1900 g at 38 weeks). Three women delivered at 39 weeks (3585 g, 2850 g, and 2800 g). Most umbilical artery RI values obtained throughout pregnancy were above the 95th percentile of normal pregnancies. The highest values of RI of the umbilical artery were assessed in the case of fetal growth retardation. However, most measurements of RI of the uterine artery were under the 95th percentile of normal. The improved pregnancy outcome in patients with SLE treated with aspirin and corticosteroids seems to correlate with their normal uterine artery flow velocity wave forms.


Early Doppler studies in lupus pregnancy. The management of 56 pregnancies in 54 patients is presented, 52 with systemic lupus erythematosus and two patients with primary antiphospholipid syndrome. All underwent serial Doppler blood flow studies of the umbilical and uterine arteries from 14 weeks of gestation. Drug therapy was directed at disease activity and the fetus and mother monitored intensively to identify optimum time for delivery. End diastolic blood flow (EDF) studies were compared with anticardiolipin antibodies (aCL) and the lupus anticoagulant (LAC) to predict outcome of pregnancy in terms of mortality, Caesarian delivery, hypertension, and gestation. The absence of end-diastolic blood flow predicted Caesarian delivery more accurately. The presence of EDF and the absence of aCL was consistent with a normotensive pregnancy. The presence of LAC was the best of the three in predicting fetal demise.


Activation of the complement pathway: comparison of normal pregnancy, preeclampsia, and systemic lupus erythematosus during pregnancy. To evaluate a flare of systemic lupus erythematosus (SLE) during pregnancy and to differentiate it from diseases of pregnancy, serological parameters are often utilized. However, there are conflicting reports regarding the merit of conventional measurements of complement and activation products. While in normal pregnancy the levels of serum C3, C4, and CH50 gradually rise, a decline in these levels occurs during the course of pregnancy in selected SLE patients. There is controversy regarding whether such falls represent decreases in the overall synthesis of complement or activation, the former theory being supported by a report of normal levels of the C1s-C1 inhibitor complex. During normal pregnancies, increases of complement split products, such as plasma C3a, may occur, and these correlate positively with elevations of C3. In pregnancies complicated by lupus, increases of C3a are often accompanied by a decline in total C3 and CH50. In a minority of non-SLE patients, preeclampsia has been associated with elevations of a variety of complement split products. Ba, C3a, C4d, SC5b-9, indicating activation of both the classical and alternative pathways. The CH50 levels tend to remain normal in these patients. In contrast, elevations of complement split products frequently accompany disease flares in patients with SLE. A high ratio of CH50/Ba may differentiate patients with preeclampsia from those with active SLE. A decline in conventional measures of C3, C4, or CH50 which is accompanied by elevations of complement split products appears to differentiate a lupus flare from non-SLE diseases of pregnancy.


Overview of lupus pregnancies.

Overview of lupus pregnancies. Pregnancy in patients with systemic lupus erythematosus (SLE) requires consideration of 5 major issues: (1) What is the risk to the mother? (2) What is the risk to the fetus? (3) What is the effect and treatment of antiphospholipid antibody? (4) What is the risk of neonatal lupus? (5) Stability of the family unit, particularly in the events of maternal disability or death, should be discussed by all parties when a pregnancy is planned. Consistency of measurement criteria, standardized treatment protocols, and long-term follow-ups are needed in the future.


Vascular events in placentae and organ allografts. This investigation explores the transplantation analogy of placentae with allografted human organs. Biopsies of cardiac and renal allografts and placentae were studied immunocytochemically with antibodies to components of the immunological, coagulational, anticoagulational, and fibrinolytic systems. Cellular rejection of cardiac and renal allografts was identified by infiltrating lymphocytes and macrophages. This was accompanied by vascular damage characterized by loss of endothelial anticoagulant pathways, vascular deposits of fibrin, and depletion of arterial tissue plasminogen activator (tPA). Failing allografts, including placentae from abnormal pregnancies, demonstrated coagulation/fibrinolytic changes consistent with vascular rejection, regardless of the presence of cellular infiltrates. An IgM autoantibody to allogeneic endothelium was associated with vascular protection. Its presence in cardiac and renal transplant biopsies was associated with an absence of fibrin deposits, and its absence was associated with vascular damage. Atherosclerosis commonly was identified in allograft biopsies (including placentae from abnormal pregnancies). These changes were shown in serial biopsies of transplanted hearts to be preceded by or associated with diminished IgM autoantibody, impaired endothelial anticoagulant pathways, vascular fibrin deposits, and depleted arterial reactivity for tPA. These results indicate the transplantation analogy of pregnancy should be viewed more specifically as vascular smooth muscle cell and endothelial responses to as yet unidentified microenvironmental stimuli.


A study of 100 high risk lupus pregnancies. Certain subgroups of lupus patients and those with circulating antiphospholipid antibodies (aPL) in particular, suffer a high rate of fetal loss. Over the past 4 years, we have prospectively studied 100 pregnancies in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome. In addition to conventional methods of monitoring SLE and fetal development, we have also used Doppler flow assessment of placental perfusion from the 14th wk of pregnancy onward. Patients with the antiphospholipid syndrome and previous history of thrombotic events were treated with daily heparin (10,000 IU) and low-dose aspirin (75 mg). Those without a history of thrombosis were treated with low-dose prednisolone, azathioprine, or hydroxychloroquine. Pregnancy loss was reduced from 81.3% in 101 previous pregnancies to 36.8% in 100 pregnancies managed by us. None of the patients who received hydroxychloroquine throughout the pregnancy presented fetal malformations. Careful management and close monitoring of the lupus pregnancy has substantially improved fetal outcome.


Previous pregnancy outcome is an important determinant of subsequent pregnancy outcome in women with systemic lupus erythematosus. Women with systemic lupus erythematosus (SLE) have increased adverse pregnancy outcomes. The reasons for these problems include maternal disease, clinical or serologic activity, medication use, and residual organ impairment from prior disease flares. In retrospective studies, pregnancy data are often treated cross-sectionally, with births rather than mothers as the unit of analysis. Multiple pregnancies from the same mother may be highly correlated with each other. In an unmatched retrospective study, the first two pregnancy outcomes in lupus patients with anticardiolipin antibody (anti-CL IgG or IgM isotype) (cases N = 47) and without anticardiolipin antibody (controls, N = 125) were assessed according to birth order. A good outcome was defined as a full-term (> 38 weeks) live birth without neonatal complications. All other pregnancy outcomes were considered adverse outcomes. Therapeutic abortions and ectopic or molar pregnancies were excluded. Both cases and controls with an adverse outcome in their first pregnancy had at least a 50% chance of another adverse outcome in their second pregnancy. Cases with a late miscarriage (fetal loss at 14 to 20 weeks' gestation) in their first pregnancy had the highest risk, 80%, of an adverse outcome in their second pregnancy. Both previous pregnancy loss and anti-CL antibody status should be considered in the analysis of pregnancy outcomes in women with SLE.


The effect of systemic lupus erythematosus on pregnancy and pregnancy outcome. This review provides an analysis of reports published since 1980 on the effect of systemic lupus erythematosus (SLE) on pregnancy and pregnancy outcome. The question whether pregnancy increases clinical flares and the severity of flares in patients with SLE during pregnancy has not been resolved because of difficulty in defining exacerbations of SLE and of preeclampsia. An analysis of major detailed reports indicates that maternal complications are reduced in patients who are in clinical remission prior to the onset of pregnancy compared with women with persistent disease activity. Complications are observed in 30%-50% of patients with inactive disease at onset of gestation. After exclusion of spontaneous abortions during the first trimester, fetal survival was 85%-90% in most reported case series. The best outcomes were reported in patients with inactive disease at onset of pregnancy. It seems likely that some maternal complications and fetal wastage in this population are related to anticardiolipin antibodies.


Pregnancy course and complications in patients with systemic lupus erythematosus. Among 165 patients with systemic lupus erythematosus (SLE), we observed 21 pregnancies in 19 patients since 1987. The mean duration of disease at the time of pregnancy was 4.5 +/- 3 years. All but three patients required immunosuppressive treatment before and during pregnancy. The effect of pregnancy on the course of SLE was studied. Severe disease exacerbations were rare and largely confined to patients with renal involvement. Most patients showed elevated titers of dsDNA antibodies during pregnancy but clinical activity of disease was usually mild. Complement C3 decrease appeared to be the most sensitive marker for pregnancy-related complications. The detection of antibodies to phospholipids was frequent during pregnancy in contrast to a low prevalence before and after pregnancy. Their presence could be associated with intrauterine growth retardation. Preterm delivery before the 37th week of pregnancy had to be performed in the majority of patients. None of the patients experienced abortion although three patients had to delivered in the 29th week of pregnancy because of increasing symptoms of pre-eclampsia. Two of these children died and the third child suffered from intracranial hemorrhage in the early postpartum period. Our data demonstrate that successful pregnancy outcome was related to a gestational age of more than 32 weeks, making careful monitoring and appropriate therapeutic management necessary.


Antiphospholipid antibodies: method of detection. Antiphospholipid antibody, measured by enzyme-linked immunosorbent assay (ELISA) or by radioimmunoassay, and the lupus anticoagulant represent similar but different tests. The ELISA is now well standardized. It is at least partly, and possibly primarily, dependent on the presence of a cofactor, beta 2-glycoprotein I. Tests for both antiphospholipid antibody by ELISA and lupus anticoagulant should be performed in patients suspected of having this syndrome.


Antiphospholipid antibodies: proposed mechanisms of action. Antiphospholipid antibodies (APA) are a family of immunoglobulins that react with anionic phospholipids, or anionic phospholipids-protein complexes. Recent evidence would support the latter definition. Lupus anticoagulants (LA) inhibit in vitro phospholipid dependent coagulation tests [e.g., activated partial thromboplastin time (APTT), prothrombin time (PT), and dilute Russell viper venom time (dRVVT)]. This inhibition appears to be specific for reagent phospholipids. The addition of freeze-thawed platelets or activated platelets will result in correction of the LA-induced abnormality. Anticardiolipin antibodies (ACA) are related to LA but appear to be distinct. ACA are detected by solid phase assays (ELISA, RIA) and require a plasma cofactor: beta 2 Glycoprotein-I (beta 2 GPI). ACA and LA activities can be separated in individual patient plasmas by affinity chromatography. In some instances they are of differing isotypes. Preliminary evaluation of beta 2 GPI in coagulation assays suggests it may function as a cofactor for LA activity. Recent work also suggests human prothrombin may represent a necessary cofactor for in vitro LA activity. Paradoxically, patients with LA/ACA may sustain thromboembolic events involving both venous and arterial sites. The prothrombotic properties of LA/ACA have not been satisfactorily characterized. A number of proposals have been reported, including inhibition of prostacyclin (PGI2) generation by endothelial cells, decreased activity of the protein C system, impaired fibrinolysis, and inhibition of beta 2GPI. Among these various hypotheses, down regulation of the protein C system appears most plausible. Also, LA/ACA may interfere with the phospholipase A2-phospholipid substrate complex involved in the generation of arachidonic acid from membrane phospholipids.


Treatment of patients with antiphospholipid antibodies during pregnancy. Most authors agree upon the causal association between antiphospholipid antibodies [lupus anticoagulant (LAC) and/or anticardiolipin antibodies] and adverse pregnancy outcome. Placental insufficiency, caused by thrombosis, infarction and maldevelopment, is thought to be the main cause of fetal loss in patients with LAC. Therapy given thus far to prevent fetal loss can be divided into (1) immunosuppression by corticosteroids, azathioprine, or intravenous gamma globulin (IVGG), (2) anti-aggregants to overcome imbalance of thromboxane/prostacycline production in patients with LAC, and (3) anticoagulants to neutralize the possible impairment of clotting inhibitor systems. Different therapeutic success rates have been reported by various authors who used the same combination of therapy. We report the results of different therapy regimens in 154 pregnancies in 31 women with LAC. These patients suffered from SLE with LAC or from APLA syndrome and experienced either recurrent miscarriages or thromboembolic phenomena in the past. With no therapy there were seven (6.8%) live births and 95 (93.2%) failures. Various combinations of corticosteroids, anti-aggregants and anticoagulants were used for treatment. Of 52 treated pregnancies, 27 (51.9%) were successful. Sixteen (69.1%) of 23 pregnancies treated by all three modalities ended in live births. Four of these successful pregnancies occurred after failure of treatment by prednisone and anti-aggregants only. In order to minimize osteoporosis caused by the combination of steroids and heparin, we have used warfarin in the second trimester and have lately substituted low molecular weight heparin for heparin. In the absence of a therapeutic schedule predicated on a large prospective study, therapy during pregnancy in patients having LAC should be individualized according to their obstetric and medical history.(ABSTRACT TRUNCATED AT 250 WORDS)


Induction of experimental primary and secondary antiphospholipid syndromes in naive mice. In the current series of experimental studies we show that anticardiolipin antibodies (ACA) are pathogenic: Infusion of serum ACA to the tail vein of naive mice induces experimental antiphospholipid syndrome (APLS) characterized by thrombocytopenia, prolonged aPTT, and recurrent fetal resorptions. Similar experimental APLS is induced by active immunization with serum as well as with natural human monoclonal ACA. APLS is also associated with low fecundity rate. The experimental APLS models were employed to demonstrate the efficacy of aspirin, low molecular heparin, and interleukin-3 preventing recurrent fetal loss. In another experiment, immunization with human monoclonal anti-DNA antibody was followed by the induction of APLS secondary to experimental systemic lupus erythematosus (SLE). In all studies, IgGs were found to be more pathogenic than IgMs ACA. These studies confirm the autoimmune nature of APLS.


Pregnancy and rheumatoid arthritis: an overview. The literature concerning the relationship of rheumatoid arthritis (RA) to pregnancy is reviewed. The amelioration of RA during pregnancy is a complex process. No specific factor that causes amelioration and is amenable to therapeutic intervention has been identified. Either RA is associated with lower fertility/fecundity, or pregnancy induces a protective effect against the development of the disease. The biological mechanism of these findings is not established.


Remission of rheumatoid arthritis during pregnancy and maternal-fetal class II alloantigen disparity. Rheumatoid arthritis (RA) is an autoimmune disorder known to be associated with specific class II genes. Although it has been known since 1938 that the majority of women with RA experience disease improvement or remission during pregnancy, the reasons remain unknown. Pregnancy represents an immunologic challenge and maternal immune recognition of the semi-allogeneic fetus occurs as part of normal pregnancy. We hypothesized that maternal immune response to fetal HLA antigens might be associated with the effect of pregnancy on arthritis activity. To test this hypothesis, we studied HLA antigens in mother-child pairs comparing maternal-fetal HLA antigen sharing for pregnancies where arthritis improved with those where disease was active. No significant difference was observed in the two groups for class I HLA antigens. Fetal-maternal disparity for HLA-DR and HLA-DQ antigens was observed significantly more frequently in pregnancies with remission or improvement compared with those in which disease was active. These observations suggest that maternal immune response to fetal paternally-inherited class II HLA antigens may be important in RA remission observed during pregnancy.


Parity status and the development of rheumatoid arthritis. Rheumatoid arthritis (RA) is one of a number of autoimmune diseases with a marked female excess in incidence, particularly during the reproductive years. It is of interest to investigate whether reproductive factors are important in determining susceptibility to RA. However, difficulties in dating the pathological onset of the disease can make it difficult to distinguish between the reproductive influence history on disease and the influence of (subclinical) disease on reproduction. In women with RA compared to controls, there is no excess of being unmarried. Most but not all studies, show an increase in nulliparity, whereas parity rates in fertile RA women are unchanged. There is an increased rate of onset postpartum, particularly in the first three months after delivery. There is no unifying biological explanation for these epidemiological findings, and it is likely that the apparently obvious link between reproductive experience and pregnancy is complex.


Estrogens and rheumatoid arthritis.

Estrogens and rheumatoid arthritis. Epidemiological and immunological evidence has suggested that female sex hormones may play a role in the etiology and course of autoimmune diseases such as rheumatoid arthritis (RA). In this review the present clinical data with regard to estrogens and RA are discussed, with emphasis on the possible preventive effect of oral contraceptives on the incidence of RA and on the possibility of using estrogens as adjuvant therapy in RA. It is concluded that oral contraceptives may mitigate or postpone the onset of RA slightly, but that estrogens are not able to alleviate the symptoms of RA. Presently there is no evidence to promote the use of estrogens in preventing or treating RA in females.


The effect of pregnancy on ankylosing spondylitis, psoriatic arthritis, and juvenile rheumatoid arthritis. It has long been established that rheumatoid arthritis improves during pregnancy. The gestational course of other inflammatory arthritides like ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile rheumatoid arthritis (JRA) has been less well studied. The present review summarizes the results of our retrospective and prospective studies on the interaction between these diseases and pregnancy. The results showed clear differences for their gestational course. Patients with PsA improved or even remitted in 80% of the pregnancies, whereas 80% of the AS patients had unaltered or aggravated disease symptoms. The 20% of AS patients who markedly improved while pregnant all had AS with accompanying diseases like psoriasis, ulcerative arthritis, or small joint arthritis. Quiescent JRA was not reactivated by pregnancy, and active disease at conception ameliorated in about 60%. Fetal outcome was not adversely affected by AS, PsA, or JRA nor did there occur serious intercurrent diseases during pregnancy. In AS and PsA patients delivery was mainly uncomplicated. Sequelae of JRA were a frequent cause for cesarean section in JRA patients. A postpartum flare during the first 3 months after delivery occurred in about 90% of the AS pregnancies, 70% of the PsA pregnancies, and about 50% of the JRA pregnancies.


Pregnancy and scleroderma.

Pregnancy and scleroderma. Scleroderma is a rare disease with a marked female excess in incidence. The pattern of age of onset, together with the effects of the disease, are such that the majority of women with scleroderma experience pregnancy prior to diagnosis. There are three questions of interest: (1) Does pregnancy adversely affect the prognosis of scleroderma? Isolated case reports suggest that renal disease, and in particular hypertensive crises, are associated with pregnancy in the absence of any renal abnormality before pregnancy. However, such events are rare. (2) Does scleroderma adversely affect either fertility or the outcome of pregnancy? Women with established scleroderma, again in case series, have a high rate of spontaneous miscarriage which is not found consistently in epidemiological studies. Prematurity and low birth rates are more frequent problems. (3) Does reproductive history influence disease and particularly Raynaud's phenomenon may antedate diagnosis by many years and might influence reproductive outcome, in general reproductive outcome is similar to that seen after diagnosis, although fertility appears to be reduced.


Mapping of the familial Mediterranean fever gene to chromosome 16. Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever, synovitis, peritonitis, or pleurisy. Some patients eventually develop systemic amyloidosis. The biochemical cause of the disease is unknown. We have conducted a genome-wide search for the FMF locus using 125 different DNA markers and mapped the FMF gene to the short arm of chromosome 16. The study was performed on 35 Israeli families primarily of North African and Iraqi origin. For the five markers D16S82 (p41-1 Sacl), D16S80 (24-1 Taq1), D16S84 (pCMM65 Taq1), D16S83 (pEKMDA2-1 Rsal), and HBA (5'HVR Rsal) we obtained maximum lod scores of 2.72 (theta = 0.08), 10.34 (theta = 0.04), 9.66 (theta = 0.050, 9.35 (theta = 0.03), and 14.31 (theta = 0.08), respectively. Multipoint analysis with HBA and D16S84 defined as a fixed loci gave a maximum lod score of 19.86 centromeric to D16S84. Crossovers defined by these markers place the FMF gene in an area of approximately 5 cM between D16S80 and D16S84. Other genes mapped to this area (16p13.3) include phosphodiesterase IB (PDE1B), hydroxyacyl-glutathione hydrolase (HAGH), phosphoglycolate phosphatase (PGP), and the gene that causes adult polycystic kidney disease (PKD1). None of these genes bear an obvious pathophysiological relationship to FMF. Using additional markers from this region we hope to localize more precisely the FMF gene and to offer the possibility of prenatal diagnosis in selected cases. Our ultimate goal is to isolate and characterize the FMF gene.


The effect of pregnancy on renal function in amyloidosis of familial Mediterranean fever. The effect of pregnancy on kidney function was studied in 29 pregnancies of 17 patients with familial Mediterranean fever (FMF) and amyloidosis. Pregnancy associated deterioration of renal function occurred in seven patients who had advanced renal disease at conception, marked by serum creatinine > or = 1.5 mg/dl or urine protein > or = 2 g/24 h. This finding suggests that the severity of renal disease at conception may predict the fate of kidney function during pregnancy and puerperium.


Colchicine treatment in conception and pregnancy: two hundred thirty-one pregnancies in patients with familial Mediterranean fever. The effect of maternal use of colchicine on fetuses is unknown. The children of 116 women with Familial Mediterranean Fever (225 completed pregnancies) were studied. There was no unusual frequency of fetal abnormality among women taking colchicine before or during pregnancy. Colchicine treatment does not apparently harm mother or child.