Assessment of body fat mass, anthropometric measurement and cardiometabolic risk in children and adolescents with achondroplasia and hypochondroplasia.

Achondroplasia is a rare skeletal dysplasia characterized by rhizomelic short stature, whose prevalence is about 1 per 25,000 births. For some patients with achondroplasia, excess body weight is one of the major concerns due to an impaired linear growth. Epidemiological studies revealed a premature onset of cardiovascular or cerebrovascular events in achondroplasia. An association between obesity and cardiometabolic risk factors related to cardiovascular events remains unknown in patients with achondroplasia/hypochondroplasia. This cross-sectional study investigated anthropometric measurements, body compositions and cardiometabolic risk factors in pediatric patients with achondroplasia/hypochondroplasia. Thirty-two patients with achondroplasia and ten with hypochondroplasia aged between 1.9 and 18.7 years were enrolled in this study. Half of the participants presented at least one cardiometabolic abnormality. Elevated systolic blood pressure was the most common abnormality. None of the participants developed metabolic syndrome or type 2 diabetes mellitus. Body mass index-standard deviation score and hip/height ratio were strongly correlated with percent body fat assessed by dual energy X-ray absorptiometry although no significant association was found between anthropometric measurements or body fat mass and any cardiometabolic risk factors. No significant difference in body fat mass, as well as body mass index-standard deviation score and hip/height, was found between cardiometabolically normal group and cardiometabolically abnormal groups. These results suggest that not only weight gain and hip/height changes should be monitored but also individual cardiometabolic risk factors should be evaluated to avoid cardiometabolic events in the healthcare management of pediatric patients with achondroplasia/hypochondroplasia.

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 1.

In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2.

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

Clinical practice guidelines for the management of children with mother-to-child transmitted hepatitis C virus infection.

BACKGROUND: The first guidelines for care of pregnant women carrying the hepatitis C virus (HCV) and their infants were published in 2005 in Japan. Since then, evidence has gradually accumulated worldwide regarding the natural course and treatment of this condition and, especially in recent years, treatment for chronic hepatitis C in adult patients has made great progress. However, the clinical practice policy for children has not been standardized, and new clinical practice guidelines for children with mother-to-child (MTC) transmitted HCV infection have become necessary. METHODS: In the development of the current guideline, we requested cooperation from The Japanese Society for Pediatric Infectious Diseases, The Japan Society of Hepatology, and the Japan Society of Obstetrics and Gynecology. The committee members were recommended and approved by each society to participate in developing the guidelines. The guideline was also created in accordance with the Minds Guide for Practice Guideline Development. The statements were prepared by consensus-building using the Delphi method, based on the comprehensively searched academic papers and guidelines. These articles were retrieved through searching the PubMed, Cochrane Library, and the Igaku Chuo Zasshi databases. RESULTS: Eight clinical questions (CQs) with clinical statements were developed regarding etiology (CQs 1-3), diagnosis (CQs 4 and 5), and treatment (two CQs 6 and 7). In each statement, the consensus rate, evidence level, and recommendation level were determined. CONCLUSION: The guidelines will be helpful in the management of children with hepatitis C MTC transmission.

CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia.

AIM: Bile acid biosynthesis is strictly regulated under physiological conditions. The expression of fibroblast growth factor (FGF) 19 is induced when bile acids bind to the farnesoid X receptor in the intestinal epithelium. Fibroblast growth factor 19 is then transported by the portal flow, causing transcriptional inhibition of cytochrome P450, family 7, subfamily A, polypeptide 1 (CYP7A1), a key enzyme in bile acid biosynthesis, through the extracellular signal-regulated kinase (ERK) pathway. However, the regulatory mechanisms of these signaling pathways in hepatocytes under chronic cholestasis remain unclear. We investigated the regulation of these signaling pathways in patients with biliary atresia (BA). METHODS: We analyzed the regulation of molecules in these signaling pathways using liver and serum samples from eight BA children and four non-cholestatic disease controls. RESULTS: CYP7A1 mRNA expression was not inhibited in BA microdissected hepatocyte-enriched tissue (HET) despite high serum bile acid concentrations. The FGF19 protein was synthesized in BA HET, and its serum concentration was elevated. Fibroblast growth factor receptor 4 was phosphorylated in BA livers. However, ERK phosphorylation was significantly reduced. We examined SPRY2 expression to determine how the ERK pathway was inactivated downstream of the FGF receptor; the expression was significantly increased in BA HET. CONCLUSIONS: This is the first study to measure the CYP7A1 mRNA levels in human BA HET. Fibroblast growth factor 19 was increased in BA hepatocytes. By focusing on its regulation in hepatocytes, we showed that the FGF19 pathway did not suppress bile acid synthesis, probably due to an altered mechanism involving upregulated SPRY2 in BA patients.

Total Bile Acid Concentration in Duodenal Fluid Is a Useful Preoperative Screening Marker to Rule Out Biliary Atresia.

OBJECTIVES: Duodenal tube test (DTT) is used as a preoperative screening to rule out biliary atresia (BA). In previous reports, DTT was assessed by the color of the duodenal fluid, but there were no quantitative criteria. The aim of this study was to examine the efficacy of DTT based on the total bile acid (TBA) concentration in duodenal fluid. METHODS: This is a single-center retrospective study of infants with cholestasis who underwent DTT from 2008 to 2016 at the Osaka University Hospital. The cut-off values of maximum TBA in duodenal fluid (dTBA), dTBA/serum TBA ratio (sTBA), and dTBA/serum gamma-glutamyl transpeptidase (sGGT) ratio were assessed for the accuracy in excluding BA. RESULTS: A total of 37 infants were included in this study; 16 infants with BA and 21 infants with other causes of intrahepatic cholestasis. dTBA demonstrated sensitivity of 100% and specificity of 90.5% with the cut-off value of 16.8 µmol/L. Specificity was further improved to 95.2% with dTBA/sTBA ratio (cut-off value: 0.088) and 100% with dTBA/sGGT ratio (cut-off value: 0.076 µmol/U). DTT could be performed 0.8 ±â€Š1.4 days after admission. Hypoglycemia was developed in 1 infant. CONCLUSIONS: DTT evaluated by dTBA, dTBA/sTBA ratio, and dTBA/sGGT ratio had high accuracy to rule out BA and could avoid unnecessary surgery in some infants.

The effects of an educational program for non-physician health care providers regarding fertility preservation.

PURPOSE: The American Society of Clinical Oncology (ASCO) Clinical Practice guidelines recommend that physicians, nurses, social workers, and other health care providers should be prepared to discuss the risk of infertility with patients. We conducted an educational program for non-physician health care providers regarding fertility preservation and evaluated the effects of the educational program. METHODS: The 4-h educational program consisted of lectures about infertility as a potential risk of cancer treatment, fertility preservation, and psychosocial support. Knowledge, confidence, institutional change, and self-practice were assessed pre-program, immediately post-program, and 6 months post-program. RESULTS: Of 124 participants who joined the program, 74 completed and returned the follow-up survey 6 months after the program. Sixty-one percent of the participants were nurses, 27% were social workers, and 4% were psychologists. The scores for confidence and knowledge increased between pre- and immediate post-program periods (p < 0.01), and between pre- and 6-month post-program periods (p < 0.01). The knowledge score was 52, 76, and 71% at the 3 points respectively. The participants became more likely to disseminate fertility preservation counseling at their institutions (p < 0.01) and use informational resources (p < 0.01). Overall, self-practice and institutional support did not change. CONCLUSIONS: The study revealed that this educational program is applicable for non-physicians to learn about fertility preservation. The participants improved significantly in confidence and knowledge, but not in counseling skills.

Pregnancy outcomes in female childhood cancer survivors: Nationwide survey in Japan.

BACKGROUND: The aim of this study was to investigate the outcomes of pregnancy in female childhood cancer survivors (CCS) in Japan, to encourage greater attention to the reproductive health of CCS. METHODS: This was a retrospective nationwide questionnaire survey of delivery at ≥22 weeks of gestation in CCS at perinatal centers registered with the Japanese Perinatologists Association between 2010 and 2014. We evaluated the maternal characteristics, pregnancy and neonatal outcomes and the relationship between cancer treatment and these outcomes. RESULTS: The total number of CCS was 61, and the total number of deliveries was 71, corresponding to 0.019% of total deliveries. Regarding cancer, 46% of the patients had had leukemia. Epilepsy was seen in seven (11%). Mean gestational age at delivery was 37.9 weeks. The rate of preterm delivery was 24%. Mean birthweight was 2,718 g. There were three congenital anomalies (4.2%). The rate of preterm delivery was higher and mean birthweight lower in the women treated with radiotherapy than in those without radiotherapy (42% vs 16%, P = 0.025; 2,436 ± 737 g vs 2,827 ± 483 g, P = 0.010). The adjusted OR of radiotherapy for preterm deliveries was 3.53 (P = 0.049). CONCLUSIONS: Although the number of deliveries by CCS was low in Japan, the pregnancy outcomes were favorable. The important points for managing pregnancy in CCS were preterm delivery as an obstetric complication, especially in CCS who had been treated with radiotherapy, and epilepsy as a maternal complication, which may be related to previously received treatment.

Physicians' practice of discussing fertility preservation with cancer patients and the associated attitudes and barriers.

PURPOSE: The aim of this study is to describe physicians' clinical practice of discussing fertility issues with cancer patients and determine the factors associated with such discussion. METHODS: In this cross-sectional study, a nationwide Internet survey was conducted among physicians who provided daily medical care to cancer patients at hospitals or clinics. Participants answered a questionnaire assessing characteristics, discussion practices, attitudes, and barriers regarding fertility preservation. RESULTS: Among the 180 participants, 42% discussed fertility issues with patients daily, and 30% had experience in referring patients to fertility preservation specialists. A multivariate logistic regression analysis showed that those who agreed or strongly agreed with the statements "physicians are responsible for discussing fertility preservation" (OR = 2.04, 95% CI 1.14-3.63, p < 0.05) and "patients who have an exceedingly aggressive disease and need immediate cancer treatment should not be told about fertility issues" (OR =1.84, 95% CI 1.09-3.10, p < 0.05) were nearly twice as likely to discuss fertility issues with patients. CONCLUSIONS: Compared to Western countries, fertility issues are less likely to be discussed in Japan. To increase opportunities for patients to discuss fertility issues, the ASCO guidelines should be widely understood. Additionally, these results suggest that physicians who are more likely to discuss fertility issues might feel more conflicted about whether they in fact should discuss such issues with patients with poor prognosis or insufficient time for cancer treatment.

Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

OBJECTIVE: Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature. DESIGN: This was a longitudinal cohort study. PATIENTS: Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year. MEASUREMENTS: Serum NT-proCNP levels and height were measured. RESULTS: NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72). CONCLUSION: Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients.

Peginterferon Therapy in Children With Chronic Hepatitis C: A Nationwide, Multicenter Study in Japan, 2004-2013.

OBJECTIVES: The aim of the present study was to review the medical treatment of Japanese children and adolescents with chronic hepatitis C in the past 10 years. METHODS: This nationwide, multicenter study evaluated patients who were younger than 18 years of age when diagnosed with chronic hepatitis C virus (HCV) infection and were treated with pegylated interferon (PEG-IFN) monotherapy or PEG-IFN/ribavirin (RBV) combination therapy between 2004 and 2013. The subjects' median age was 10 (3-18) years, with a male to female ratio of 52:50 and a genotype-1 to genotype-2 ratio of 45:57. Among the 102 patients, 18 received PEG-IFN monotherapy and 84 received PEG-IFN/RBV combination therapy. The IL28B genotype polymorphism was analyzed in patients infected with genotype-1. RESULTS: In patients with HCV genotype-1 infections, sustained virological response (SVR) rates obtained by PEG-IFN monotherapy and by PEG-IFN/RBV combination therapy were 100% (2/2) and 72% (31/43), respectively. In patients with HCV genotype-2 infections, SVRs were 75% (12/16) and 100% (41/41), respectively. In 32 genotype-1 patients available for the IL28B genotype (rs8099917), SVR was achieved in more patients in the IL28B major allele group than in the minor allele group (15/17 vs 7/15, P = 0.021) after PEG-IFN/RBV combination therapy. The frequencies of adverse events were similar between the treatment regimens. CONCLUSIONS: Overall, both therapies showed encouraging results, and were reasonably safe in children and adolescents with chronic hepatitis C. The IL28B genotype was useful for predicting the treatment response to PEG-IFN/RBV combination therapy in this cohort.

Placental examination: prognosis after delivery of the growth-restricted fetus.

PURPOSE OF REVIEW: This article describes the role of placental examination in the prognostic evaluation of fetal growth restriction (FGR) infants. RECENT FINDINGS: A new comprehensive placental classification system was reported. Maternal underperfusion, fetal thrombotic vasculopathy (FTV), villitis (including villitis of unknown etiology and infectious villitis), inflammation, and immature/dysmature villi are important factors affecting FGR prognosis, whereas genomic imprinting is a key factor affecting growth and diseases, as well as placental abnormality. SUMMARY: We discuss the role of placental examination in determining FGR prognosis. Maternal underperfusion, fetal thrombotic vasculopathy, and villitis (including villitis of unknown etiology and infectious villitis) are the most important findings affecting FGR prognosis. Although limited, data have suggested an association of inflammation and immature/dysmature villi with postnatal growth in FGR infants. Placental size also contributes postnatally through fetal programming. In addition, placental imprinting can be a key of pre and postnatal growth and diseases, including imprinting disorders, as well as placental abnormalities such as placental mesenchymal dysplasia.

Natural history of chronic hepatitis B virus infection in childhood and efficacy of interferon therapy.

OBJECTIVES: In short-term observations, interferon (IFN) therapy has been shown to be effective in producing both biochemical and virological responses in children with chronic hepatitis B virus (HBV) infection. However, in long-term follow up, no studies have shown a clear advantage of IFN therapy during childhood. We conducted a retrospective study on the sustained effect of IFN therapy among a Japanese pediatric population. METHODS AND SUBJECTS: A retrospective study was performed on 155 children with chronic HBV infection who were followed in two affiliated hospitals during the period from 1986 to 2013. RESULTS: The 155 patients comprised 97 males and 58 female. Infection route was maternal transmission in 96/155 patients. HBV genotype was A in 17, B in 6, and C in 51 patients. IFN therapy was performed in 48 patients. One year after the completion of IFN therapy, normalization of alanine aminotransferase (ALT) and lower viral levels (<10(4) copies/ml) was observed in 43 and 29 patients, respectively. The sustained effects of IFN therapy were evaluated by comparison between 43 hepatitis B e-antigen (HBeAg)-positive patients treated with IFN and 67 patients with chronic hepatitis B observed without IFN therapy. A Cox's proportional hazard analysis showed a higher seroconversion rate in the IFN group than in the untreated group (p = 0.003). Similarly, there were higher rates of ALT normalization and lower viral levels in the IFN group than in the untreated group (p = 0.001 for both). CONCLUSION: IFN therapy showed sustained effects for achieving ALT normalization and HBeAg seroconversion and for reducing the viral load in children with chronic hepatitis B.

Association of IL28B polymorphisms with virological response to peginterferon and ribavirin therapy in children and adolescents with chronic hepatitis C.

AIM: The objective of the current study was to find baseline predictive factors of response to therapy with pegylated interferon and ribavirin (PEG-IFN/RBV therapy) in children and adolescents with chronic hepatitis C. METHODS: IL28B genotype and mutations in the core of hepatitis C virus (HCV) were analyzed in 30 patients treated with PEG-IFN/RBV for HCV infection. The initial rate of decrease in the viral load was assessed during the first 2 weeks of treatment. RESULTS: IL28B major allele was seen more frequently in patients with sustained virologic response (SVR) than in non-SVR patients (P < 0.001). There was no difference between these two groups in frequency of Core 70 mutation. Among patients with genotype-1, SVR was achieved in more patients (P = 0.007) in the IL28B major allele group than in those in the minor allele group. The early decrements in the viral load (log/2 weeks) were 3.80 ± 0.86 in the genotype-2 major allele group, 1.82 ± 0.84 in the genotype-1 major allele group, and 0.41 ± 0.33 in the genotype-1 minor allele group. CONCLUSIONS: Among pediatric patients with HCV infection the effectiveness of PEG-IFN/RBV therapy may be lower in the group with genotype-1 IL28B minor alleles than in other groups with IL28B major allele. Treatment strategy should be carefully implemented in patients with IL28B unfavorable type.

Two Japanese familial cases of Caffey disease with and without the common COL1A1 mutation and normal bone density, and review of the literature.

UNLABELLED: Caffey disease, also known as infantile cortical hyperostosis, is a rare bone disease characterized by acute inflammation with swelling of soft tissues and hyperostosis of the outer cortical surface in early infancy. The common heterozygous mutation of the COL1A1 gene, p.Arg1014Cys, has been reported in patients with Caffey disease. However, its pathogenesis remains to be elucidated, and the reason for the incomplete penetrance and transient course of the disease is still unclear. In the present study, we performed mutation analysis of the COL1A1 and COL1A2 genes and measured bone mineral density in two Japanese familial cases of Caffey disease. The index case and two clinically healthy members of one family carry the common heterozygous mutation; in contrast, no mutation in COL1A1 or COL1A2 was identified in the affected members of the second family. In addition, we found normal bone mineral density in adult patients of both families who have had an episode of cortical hyperostosis regardless of the presence or absence of the common p.Arg1014Cys mutation. CONCLUSION: The results reveal that Caffey disease is genetically heterogeneous and that affected and unaffected adult patients with or without the common COL1A1 mutation have normal bone mineral density.

Transferability of Effective Consultation Skills for Decision-Making Support in the Voluntary Surrender of Older Adult Drivers' Licences in Super-Aged Japan.

INTRODUCTION: Previously, we identified eight effective consultation skills to support decision-making in the voluntary surrender of older adult drivers' licences in super-aged Japan. This study aimed to clarify the transferability of these skills. METHODS: We collected text data by interviewing 11 safe-driving counsellors (four police officers, four clerical staff and three nurses) in the License Division of the National Police Agency from February to March 2022. Interviews were semi-structured and conducted by telephone or email. During the interview, participants were asked to recall their experiences as counsellors providing decision-making support to older drivers and to compare their experiences with the eight consultation skills. We analysed the content of the responses by quantitative text analysis with KH Coder 3 software. RESULTS: As a characteristic of the words and phrases used by counsellors in their narratives about consultation skills, the most frequently extracted words from among 3147 words were think, parties and family, and promote had the highest mediation centrality. The eight subgraphs were 'Respecting the will of relevant parties from their standpoint is natural', 'Listening attentively and empathetically to relevant parties is effective', 'Presenting objective data to guide decisions is successful', 'Showing cognitive functioning test results is often effective', 'Counselors with medical expertise can elicit positive counseling outcomes', 'Intervention by medical or police counselors facilitates the decision to surrender voluntarily', 'Counseling skills need to be improved' and 'A diagram of the 8 skills is helpful for inexperienced counselors'. CONCLUSION: The results suggest that the eight consultation skills have similarities and are transferable. This transferability might contribute to practical application or cohort follow-up study research. These skills can be incorporated into counsellor training, and counsellors can be expected to use these skills in the future. Regardless of the safe-driving counsellor's years of experience, the skills can help them provide uniform and accurate support in decision-making regarding the voluntary surrender of older adult drivers' licences. These skills are a promising approach to help older adults lead safe and secure lives as they age.

Generalized lichen nitidus in Russell-Silver syndrome.

Generalized lichen nitidus is a rare disease, and there are only a few reports associating it with a genetic disorder. Here we report a case of generalized lichen nitidus in Russell-Silver syndrome.

A patient with pachydermoperiostosis harboring SLCO2A1 variants with a history of differentiating from acromegaly.

Pachydermoperiostosis (PDP) is a rare hereditary disease characterized by digital clubbing, pachydermia, and periostosis. We describe a Japanese male patient with PDP who was differentially diagnosed with acromegaly by identification of compound heterozygous variants in SLCO2A1. Recent studies have reported various clinical manifestations, as well as skeletal and dermal features, in patients with PDP. Genetic testing provided not only PDP diagnosis and differentiation from acromegaly, but also information about possible complications and comorbidities throughout life.

Humoral immunity is involved in the development of pericentral fibrosis after pediatric live donor liver transplantation.

Although LT can be successful for treating end-stage liver disease in children, some patients develop fibrosis around the central vein area (PCF). This raises the possibility that PCF could lead to later cirrhosis and graft failure. Here, we report a retrospective immunohistochemical study of 28 patients who received a live donor liver transplant. We assessed the incidence and etiology of PCF using CD3, CD20, HLA-DR, and C4d-specific antibodies. Histological evidence of PCF was found in 13 cases (46.4%), of which 11 (84.6%) had experienced ACR and/or CP events post-transplant. Immunohistochemical evaluation revealed significantly stronger staining with these antibodies in the central vein area in PCF, especially for CD20 and C4d. This implies humoral immunopathology and suggests involvement of humoral immunity in the development of PCF. These results further imply that suppression of cellular immunity alone is insufficient to prevent PCF. We therefore suggest that suppression of both humoral and cellular immunity in combination would be required for prevention of PCF.