Social effects in simple computer model of aging.

A simple evolutionary model for biological aging is modified such that it requires a minimum population for survival, like in human society. This social effect leads to a transition between extinction and survival of the species.

Genomic style of proteins: concepts, methods and analyses of ribosomal proteins from 16 microbial species.

We have introduced the concept of genomic 'style' of proteins. By style we understand those properties of a large set of proteins which are specific to the genome of one species (species primary-self) and different from the genome of another species (species contrasted-self). To characterise the style, we took advantage of the frequencies of amino acids and dipeptides present in non-identical segments of the complete set of orthologous ribosomal proteins encoded by 16 microbial species. We confirm the dependence of the overall amino acid composition on the genomic (G+C) content, and introduce a rectification procedure making it possible to extricate appropriate species-specific characteristics, which are no longer related to this content. The rectified frequencies are used to calculate inter-species distance matrices, and to build genomic evolutionary trees. Remarkably, the phylograms derived from the frequencies of non-identical residues in proteins closely resemble the classical phylograms based upon the conservation of identical residues in ribosomal RNAs. We believe that the concept of genomic style of proteins can be a useful tool for the study of evolution.

Cancerous tumor: the high frequency of a rare event.

A simple model for cancer growth is presented using cellular automata. Cells diffuse randomly on a two-dimensional square lattice. Individual cells can turn cancerous at a very low rate. During each diffusive step, local fights may occur between healthy and cancerous cells. Associated outcomes depend on some biased local rules, which are independent of the overall cancerous cell density. The models unique ingredients are the frequency of local fights and the bias amplitude. While each isolated cancerous cell is eventually destroyed, an initial two-cell tumor cluster is found to have a nonzero probabilty to spread over the whole system. The associated phase diagram for survival or death is obtained as a function of both the rate of fight and the bias distribution. Within the model, although the occurrence of a killing cluster is a very rare event, it turns out to happen almost systematically over long periods of time, e.g., on the order of an adults life span. Thus, after some age, survival from tumorous cancer becomes random.

Report from the national transplantation pregnancy registry (NTPR): outcomes of pregnancy after transplantation.

The NTPR continues to analyze the safety of pregnancy in female transplant recipients as well as outcomes of pregnancies fathered by male transplant recipients. With regard to female recipients, pregnancy does not appear to adversely affect graft function, when the function of the transplanted graft is stable prior to pregnancy. A small percentage of recipients with each transplanted organ develops rejection, graft dysfunction or graft loss. These events may occur in recipients with pre-pregnancy graft dysfunction or on occasion, occur unpredictably. Female cyclosporine-treated kidney recipients with both shorter and longer intervals from transplant to conception have been analyzed, with favorable outcomes noted. It appears sensible to continue to advise recipients to wait one to 2 years after transplant to allow for stable graft function as well as stabilization of immunosuppressive medications. However, given that favorable outcomes can occur with either shorter or longer intervals, these recipients need to be counseled and followed on a case-by-case basis. Newer agents and more potent regimens are under continued surveillance. Two cases with structural malformations have been noted in female recipient offspring with exposure to MMF during pregnancy. Data remain limited and are insufficient to determine a specific malformation incidence. The risk of graft rejection as well as graft dysfunction must be weighed against the risk of potential teratogenicity when maintaining female recipients on MMF during pregnancy. For male recipients maintained on MMF, there have been no patterns of problems noted in their offspring. The structural malformation incidence in newborn of cyclosporine-treated recipients is in the range expected for the general population without any specific predominance of malformations. It remains to be seen whether or not any specific pattern of problems will become apparent in the newborn with newer regimens. Controversy surrounding breastfeeding continues, although it has become an option that some recipients choose to consider. Data have accrued in liver, heart, pancreas-kidney and lung recipients. Among lung recipients, there appears to be poorer maternal survival postpartum, which may be related to pregnancy or may be inherent in this population. Continued entries to the registry, especially in light of newer combinations of immunosuppressive agents, should help to provide the guidelines for management. All centers are encouraged to participate.

Results of liver transplantation for nodular regenerative hyperplasia.

Liver transplantation has been performed in individuals with a pretransplant clinical diagnosis of cirrhosis but with nodular regenerative hyperplasia histologically. The purpose of this report is to investigate the results of liver transplantation in patients proven to have nodular regenerative hyperplasia post-transplant. A retrospective review was undertaken of four patients who underwent liver transplantation with a histologic diagnosis of nodular regenerative hyperplasia. All were felt to be cirrhotic on clinical grounds. Final histology of the explanted liver was confirmed by a single pathologist. Their ages ranged from 39 to 54 years, and three of the four were male. Three had pretransplant needle liver biopsies, two percutaneous and one transjugular. All revealed nonspecific reactive changes. Ultrasound and MRI were interpreted as consistent with cirrhosis in four of four and three of four cases, respectively. Portal vein flow was hepatopedal in three and absent in one. Pretransplant clinical characteristics and frequency were as follows: bleeding varices two, clinical ascites three, encephalopathy three, and impaired hepatic synthetic function two. All four patients underwent successful liver transplantation. There were no episodes of acute rejection. All are alive and well with normal graft function 2 to 4 years post-transplant. We conclude the following. 1) Patients with clinical end-stage liver disease due to underlying nodular regenerative hyperplasia can successfully undergo transplantation. 2) Nodular regenerative hyperplasia can present with signs and symptoms of liver failure, is difficult to diagnose by needle biopsy, and can be difficult to discriminate clinically from cirrhosis. 3) Although each case must be individually evaluated transplantation may be the optimal therapy in patients presenting with complications of liver failure.

Pregnancy after liver transplantation.

The first known posttransplantation pregnancy was in 1958 in a renal transplant recipient who had received a kidney from her identical twin sister. The first known posttransplantation pregnancy in a liver transplant recipient was in 1978. Information available from female kidney transplant recipients helped in the decision making involved in the management of this case, as well as those that followed. Over the last 20 years, issues specific to liver transplantation and pregnancy have been identified. Similar to the kidney transplant recipient population, when prepregnancy recipient graft function is stable and adequate, pregnancy appears to be well tolerated. Also similar to kidney transplant recipients, there has been no evidence of a specific malformation pattern among the children, and although prematurity and low birth weight occur, overall newborn outcomes have been favorable. Pregnancy in the setting of recurrent liver disease, such as recurrent hepatitis C, poses a potential problem among liver transplant recipients, as well as the possible adverse effects of immunosuppression on maternal kidney function. Also of significance, peripartum graft deterioration has more severe consequences in this transplant recipient population. Therefore, pregnancy must be considered carefully in this transplant recipient group. Since 1991, the National Transplantation Pregnancy Registry (NTPR) has studied the safety of pregnancy outcomes in solid-organ transplant recipients. The purpose of this review is to catalog studies in the literature, as well as to present current data from the registry with management guidelines.

An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria.

Serotonin-related adverse side-effects of psychotropic drugs were first recorded in humans in 1960. However, since 1991, these related cases have been diagnosed as 'serotonin syndrome (SS)' according to the criteria reported by Sternbach. In this article, we have reviewed and further explored the validity of these criteria. The clinical profile of 24 cases of the SS published between 1991 and 1995 has been analysed in detail and compared with the symptomatology of 38 previous cases which were also further analysed. Mainly Medline and references from other reports were used to review these cases. The general concept put forward by Sternbach has been approved. On the basis of the severity of overall clinical presentation, it appeared that there is a need to further classify SS into three main groups as: (1) mild state of serotonin-related symptoms; (2) serotonin syndrome (full-blown form); (3) toxic states. Furthermore, the detailed analysis of the SS cases published so far suggests that 'the diagnostic criteria for SS' also require further revision, and these are presented here. We also review, present and discuss the guidelines for the management and treatment of SS.

Molecular dynamics in solid pregnenolone studied by 1H spin-lattice relaxation.

Spin-lattice relaxation times T1 in solid pregnenolone have been studied over a wide range of temperatures, from 77 up to 417 K. The dynamic processes arising from C3 motion of the three methyl substituents are separated, and their activation parameters are determined.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Safety of pregnancy in the female transplant recipient population must include consideration of 3 outcomes--mother, baby and transplanted graft. In the majority of female recipients studied, pregnancy does not appear to cause excessive or irreversible problems with graft function, if the function of the transplant organ is stable prior to pregnancy. However, a small percentage of recipients identified within each organ system may develop rejection, graft dysfunction and/or graft loss that may be related to the pregnancy and may occur unpredictably. Outcomes are not entirely similar among all organ systems, and one must consider risks on an individual organ basis. It appears reasonable to advise female recipients to wait one or 2 years after transplantation before attempting pregnancy to insure that function of the transplanted organ is adequate and stable and also to allow for stabilization of immunosuppressive medications. Favorable outcomes, however, have occurred when recipients have become pregnant less than one year from transplant, so cases must be analyzed individually. Immunosuppressive medications may have to be adjusted during pregnancy, and in some cases, rejections occur requiring additional immunosuppressive regimens (steroids and in several cases OKT3). Whether increasing immunosuppressive doses during pregnancy to adjust for falling levels lessens the rejection risk has never been studied prospectively. There is concern based on animal reproductive studies that the risk of birth defects and/or spontaneous miscarriage is increased in women exposed to MMF during pregnancy. Of the 9 pregnancies reported to the registry to date, there have been no birth defects noted among 5 liveborn of female recipients exposed to MMF. Data remain limited. For female recipients, a high incidence of low birth-weight and prematurity compared to the general population has been a consistent outcome, however, there has been no specific pattern of malformation in their newborn or any apparent increase in the incidence of small-for-gestational-age newborn. Long-term follow-up of children to date by the NTPR has been encouraging. A recent report in the literature has suggested impairment of immune function in newborn of CsA-treated mothers. Further study is needed. Some mothers have chosen to breastfeed. The potential risk to the newborn of ingested immunosuppressives compared with the potential benefits of breastfeeding is unknown and options must be discussed with the recipient. From earlier registry reports, recipients with deteriorating graft function, such as liver recipients with recurrent hepatitis C and/or other recipients with deteriorating graft function, appear to be at risk for worsened graft function with pregnancy. Outcomes of male recipient fathered pregnancies have been favorable and appear to be similar to the general population, but this group has not been as well studied as female recipients. No structural problems have been noted in the 38 offspring of males on MMF at the time of conception. Within each organ group, some female recipients have reported more than one pregnancy, sometimes on differing immunosuppressive regimens. If there is stable graft function, additional successful pregnancies are possible. Continued entries to the registry, especially in light of newer immunosuppressives and combinations of agents, are needed to continue to provide guidelines for management. The NTPR acknowledges the cooperation of transplant recipients and over 200 centers nationwide who have contributed their time and information to the registry. The NTPR is supported by grants from Novartis Pharmaceuticals Corp., Fujisawa Healthcare, Inc., Roche Laboratories Inc. and Wyeth-Ayerst Pharmaceuticals, Inc.

Molecular dynamics in solid anhydrous beta-estradiol studied by 1H NMR.

Proton second moment and spin-lattice relaxation times T1 and T1p in solid anhydrous beta-estradiol are measured as a function of temperature. The results show that the C3 reorientation of the single methyl group provides the mechanism dominating relaxation at low temperatures and reveal the existence of a conformational motion of the carbon skeleton dominating relaxation at high temperatures. The activation energies of the respective motions are found to be 9.3 and 37.3 kJ/mol.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Specific data on pregnancies following transplantation continue to accrue in the National Transplantation Pregnancy Registry (NTPR) in each type of organ recipient, with the following conclusions: 1. While the majority of kidney recipients appear to tolerate pregnancy well, a small percentage develops rejection, graft dysfunction and/or graft deterioration. Overall, there is a slight increase in the mean postpartum creatinine level when compared with the prepregnancy level, which has been noted in previous investigations by the NTPR. One neonatal death attributed to thrombotic cardiomyopathy was noted in a set of twins of a tacrolimus-based kidney recipient, but no other death has been noted in any of the additional reports among the recipients given newer immunosuppression regimens. Follow-up of offspring of these recipients is ongoing. 2. No structural malformations have been noted among offspring exposed to mycophenolate mofetil, but exposures are limited. (5 mothers, 29 fathers). 3. Female liver recipients with biopsy-proven acute rejection during pregnancy appear to be at greater risk for both poorer newborn outcomes and recurrent rejection episodes. In the setting of acute rejection diagnosed during pregnancy, close attention is warranted, anticipating that birthweight may be lower and that a substantial percentage of these female recipients may have recurrent rejection episodes. 4. Pancreas-kidney grafts can maintain normoglycemia throughout pregnancy. A high incidence of maternal hypertension, prematurity and low birthweight have been noted, so, as in other recipient groups, these are high-risk pregnancies. Maternal pancreas and kidney function must be closely monitored. 5. No specific prepregnancy predictors of adverse outcomes have yet been identified among heart or lung recipients although none of the deaths among heart recipients in the NTPR database occurred within 2 years of delivery. When compared with other solid organ recipients, female lung recipients may face higher risks, particularly related to rejection. Whether prepregnancy factors can help to predict either heart or lung recipients at risk requires continued study. 6. No structural malformations or significant learning disabilities have been noted in follow-up of the offspring of CsA-treated females, the largest group of offspring followed to date with a mean age of 4-5 years. Continued surveillance of children will be essential to determine if effects become apparent as age-related developmental delays or other problems in immune function or fertility later in life. 7. Newer regimens as well as new combinations of agents will continue to be studied. It is essential that non-viable as well as viable pregnancy outcomes be reported to the registry (i.e., recipients with pregnancies that result in spontaneous abortion or termination should be included for study). True estimates of non-viable outcomes have been difficult to assess. Additionally, inclusion of reports of pathologic evaluations at delivery hospitals will be helpful to determine whether spontaneous abortions are a result of lethal malformations related to immunosuppressive or other medication exposure. Safety of pregnancy for parent and child remain the primary goals of the NTPR.

Pregnancy outcomes in 10 female pancreas-kidney recipients.

Female recipients of pancreas-kidney transplants may have an increased chance for pregnancy, because transplantation often restores fertility. Data on pregnancy after pancreas-kidney transplantation were analyzed by the National Transplantation Pregnancy Registry at US transplant centers. Ten recipients who were on cyclosporine-based immunosuppression were studied. A total of 15 pregnancies had resulted, of which 12 were live births. Among the 12 newborns, prematurity and low birth weight occurred in 75% and 83% of the cases, respectively. Three had complications associated with prematurity. Two thirds of the infants were delivered by cesarean section. All children are developing well with no apparent residual problems. During pregnancy, hypertension and urinary tract infections occurred frequently among recipients. Two recipients had three subsequent graft losses within 2 years of giving birth; however, both were successfully retransplanted. Successful pregnancy is possible for female pancreas-kidney recipients.

Risks of subsequent pregnancies on mother and newborn in female heart transplant recipients.

BACKGROUND: Female heart transplant recipients are able to carry pregnancies successfully. This study evaluates the effect of subsequent pregnancies on newborn and maternal outcomes and graft survival. METHODS: Subjects were identified through a previously reported multicenter study, case reports from literature review, and recipients entered in the National Transplantation Pregnancy Registry. A retrospective analysis was completed of 35 heart transplant recipients with first pregnancies (FP) and 12 who had one or two additional pregnancies (P>1). Newborns were assessed for gestational age, neonatal birth weight, and complications. Maternal data included pregnancy outcome, peripartum complications, including infection and rejection, current graft function, and recipient survival. RESULTS: Forty-seven pregnancies (35 FP and 12 P>1) from 35 heart transplant recipients were studied. FP outcomes included 26 live births (one set of twins), four miscarriages, and six therapeutic abortions, whereas P>1 outcomes included 11 live births (one set of twins), and two miscarriages. There was no significant difference between mean birth weights (2353+/-986 gm vs 2588+/-521 g, P>1 vs FP; mean+/-SD; p=NS) or prematurity incidence (<37 weeks; 50% vs 40%; p=NS) for the live-born infants. Compared with the FP group, there was a trend toward increased neonatal complications in P>1 (40% vs 12%; p=NS). Complications were significantly more common in premature newborns compared with full-term newborns (33% vs 5%; p < 0.05). No structural malformations were identified in the live-born infants. Maternal complication rates were the same in both groups (40%). Of 28 recipients available for follow-up, the maternal survival rate was 75% for the FP group and 89% for the P> group. Mean rejection rate per year was slightly increased after pregnancy in the P>1 group. Surviving recipients had similar graft function by echocardiographic left ventricular ejection fraction. CONCLUSIONS: Post-heart transplantation pregnancies often have successful outcomes, but there is a high incidence of prematurity and low birth weight. Subsequent pregnancies do not seem to significantly increase the incidence of complications in either the newborn or mother or increase graft rejection or failure. Larger studies of posttransplantation pregnancies may provide more definitive information.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Female solid organ recipients with good graft function generally tolerate pregnancy well. However, the combination of mother, fetus, transplanted organ, and immunosuppressive and other medications increases the complexity of management and raises the specter of adverse outcomes. For the mother, considerations include the nature of the original disease (i.e. genetic risk of transmission), co-morbid conditions which increase pregnancy risk (i.e. hypertension, diabetes, renal insufficiency), and long-term maternal prognosis. For the fetus, questions include the adequacy of maternal physiology (cardiac, renal, glycernic control, etc.), exposure to medications, and exposure to infectious agents. The transplanted organ must accommodate the increased workload of pregnancy and the needs of the fetus. The delicate balance between immunosuppression and rejection may be altered by the pregnancy. The impact of pregnancy on recurrent disease can also be an issue. Medication issues include changes in drug pharmacokinetics and the potential for adverse effects on the fetus. These effects could include chromosomal aberrations, structural malformations, organ-specific toxicity, intrauterine growth retardation, and immune system development. For female kidney recipients there are sufficient data to demonstrate a direct relationship between creatinine levels before and during pregnancy and risk of graft loss in the postpartum period. Pregnancy itself does not appear to adversely affect stable graft function. Among liver recipients, those with recurrent viral hepatitis may have deterioration of graft function with subsequent pregnancies. These recipients should be apprised accordingly, as maternal deaths have occurred in this setting. Postpartum depression and potential for medication noncompliance require vigilance. The safety of pregnancy from the NTPR analysis to date has been largely derived from the experience with CsA-based regimens. For recipients on CsA there have been good maternal outcomes without any specific or predominant malformation patterns in the offspring. For the general population, malformations occur in approximately 3% of live births. To date, there is no indication that this incidence has increased despite the complex medical regimens of transplant recipients. Data are accruing with tacrolimus and Neoral. Continuing data entry and continued follow-up of off-spring will allow for further recommendations, especially in light of the new medications and combinations. Recipients should be advised to wait one to 2 years after transplant before considering pregnancy. Those with stable graft function, and with no rejection, graft dysfunction, or deterioration should still be apprised of the high risk of prematurity and low birthweight, although maternal risks appear low. These are high-risk pregnancies, requiring close communication and cooperation between the high-risk obstetrician and the transplant team. The use of the FDA pregnancy categories should not be the sole reason for choosing a particular immunosuppressive drug. Agents such as Neoral and tacrolimus would appear to offer some advantage as blood levels can be measured. At present, no safety guidelines can be given for mycophenolate mofetil, OKT3, or ATG. Identification of prepregnancy factors predictive of higher risks and appropriate counseling and management guidelines are major NTPR goals, and depend on the continued assistance and cooperation of the transplant community.

National Transplantation Pregnancy Registry: report on outcomes in cyclosporine-treated female kidney transplant recipients with an interval from transplant to pregnancy of greater than five years.

Successful renal transplantation enables previously infertile females to conceive and carry a pregnancy. Much of the reported data on posttransplantation pregnancy accrued before the advent of cyclosporine, when steroids and azathioprine were the mainstays of maintenance immunosuppression. One factor affecting pregnancy outcome in kidney recipients is the length of time from transplantation to conception or transplant interval. It has been recommended that patients wait at least 2 years posttransplantation to conceive, as transplant intervals of shorter duration have had less favorable outcomes. Some have suggested that extended transplant intervals (> 5 years) paradoxically result in adverse outcomes. We have extracted data on cyclosporine-treated recipients with transplant intervals longer than 5 years from the National Transplantation Pregnancy Registry, and report 17 pregnancies from 15 recipients (transplant interval, 5.9 +/- 0.9 years). There were 13 live births (76.5%) and four spontaneous abortions (23.5%). The mean gestational age was 37.7 +/- 2.04 weeks and mean birth weight was 2,753 +/- 679 g. Prematurity occurred in 30.8%, low birth weight in 15.4%, very low birth weight in 7.7%, and neonatal complications in 15.4%. There were no maternal or neonatal deaths. The mean serum creatinine before pregnancy was 1.31 mg/dL, and there was no significant change during or after pregnancy. There were no rejections during or up to 3 months postpartum. Graft survival at 2 years was 100%. We conclude that most pregnancy outcomes in cyclosporine-treated recipients with transplant intervals greater than 5 years are favorable for the newborn, recipient, and graft.