OPTN/SRTR 2019 Annual Data Report: Kidney.

Despite the ongoing severe shortage of available kidney grafts relative to candidates in need, data from 2019 reveal some promising trends. After remaining relatively stagnant for many years, the number of kidney transplants has increased each year since 2015, reaching the highest annual count to date of 24,273 in 2019. The number of patients waiting for a kidney transplant in the United States was relatively stable, despite an increase in the number of new candidates added in 2019 and a decrease in patients removed from the waiting list owing to death or deteriorating medical condition. However, these encouraging trends are tempered by ongoing challenges. Nationwide, only a quarter of waitlisted patients receive a deceased-donor kidney transplant within 5 years, and this proportion varies dramatically by donation service area, from 15.5% to 67.8%. The non-utilization (discard) rate of recovered organs remains at 20.1%, despite adramatic decline in the discard of organs from hepatitis C-positive donors. Non-utilization rates remain particularly high for Kidney Donor Profile Index ≥85% kidneys and kidneys from which a biopsy specimen was obtained. While the number of living-donor transplants increased again in 2019, only a small proportion of the waiting list receives living-donor transplants each year, and racial disparities in living-donor transplant access persist. As both graft and patient survival continue to improve incrementally, the total number of living kidney transplant recipients with a functioning graft is anticipated to exceed 250,000 in the next 1-2 years. Over the past decade, the total number of pediatric kidney transplants performed has remained stable. Despite numerous efforts, living donor kidney transplant remains low among pediatric recipients with continued racial disparities among recipients. Congenital anomalies of the kidney and urinary tract remain the leading cause of kidney disease. While most deceased donor recipients receive a kidney from a donor with KDPI less than 35%, the majority of pediatric recipients had four or more HLA mismatches. Graft survival continues to improve with superior outcomes for living donor recipients.

The Presentation and Diagnosis of the First Known Community-Transmitted Case of SARS-CoV-2 in the Republic of Ireland.

Introduction This case series describes the diagnosis of the first case of community transmission of SARS-CoV-2 in the Republic of Ireland. Cases Case 1: A 25 year old male presented with dyspnoea, cough and high fevers for 4 days. He was commenced on broad-spectrum antimicrobials and oxygen therapy. His respiratory function deteriorated in spite of these measures and he required mechanical ventilation. CT showed left upper lobe consolidation as well as multifocal ground-glass opacification. Case 2: A 43 year-old male presented with headache and was found incidentally to have pneumonia. He was recently diagnosed with pituitary apoplexy secondary to an adenoma with resultant pituitary insufficiency but MRI brain was stable. His respiratory function deteriorated in spite of antibiotics and he required mechanical ventilation. CT showed likely atypical infection with resultant ARDS. Outcome Both underwent nasopharyngeal RT-PCR testing for SARS-CoV-2. Patient 2 was positive. Patient 1 was extubated and made a good recovery. Patient 2 was transferred to another centre for ECMO therapy. He died 27 days after transfer. Conclusion Given the atypical presentations in generally otherwise young and healthy individuals, the decision was made outside of national guidance to perform testing for SARS-CoV-2. This diagnosis had far-reaching implications for the SARS-CoV-2 pandemic within Ireland.

Updated recommendations of the International Society of Geriatric Oncology on prostate cancer management in older patients.

BACKGROUND: The median age of prostate cancer diagnosis is 66 years, and the median age of men who die of the disease is eighty years. The public health impact of prostate cancer is already substantial and, given the rapidly ageing world population, can only increase. In this context, the International Society of Geriatric Oncology (SIOG) Task Forces have, since 2010, been developing guidelines for the management of senior adults with prostate cancer. MATERIAL AND METHODS: Since prostate cancer and geriatric oncology are both rapidly evolving fields, a new multidisciplinary Task Force was formed in 2018 to update SIOG recommendations, principally on health status screening tools and treatment. The task force reviewed pertinent articles published between June 2016 and June 2018 and abstracts from European Association of Urology (EAU), European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and American Society of Clinical Oncology Genito-urinary (ASCO GU) meetings over the same period, using search terms relevant to prostate cancer, the elderly, geriatric evaluation, local treatments and advanced disease. Each member of the group proposed modifications to the previous guidelines. These were collated and circulated. The final manuscript reflects the expert consensus. RESULTS: The 2019 consensus is that men aged 75 years and older with prostate cancer should be managed according to their individual health status, and not according to age. Based on available rapid health screening tools, geriatric evaluation and geriatric interventions, the Task Force recommends that patients are classified according to health status into three groups: (1) 'healthy' or 'fit' patients should have the same treatment options as younger patients; (2) 'vulnerable' patients are candidates for geriatric interventions which-if successful-may make it appropriate for them to receive standard treatment and (3) 'frail' patients with major impairments who should receive adapted or palliative treatment. The 2019 SIOG Task Force recommendations also discuss prospects and unmet needs for health status evaluation in everyday practice in older patients with prostate cancer.

Feasibility, acceptability, and tolerability of RGN107 in the palliative wound care management of chronic wound symptoms.

OBJECTIVE: To assess the feasibility, acceptability and tolerability of RGN107 use, a natural powder blend of Arnica Montana, Calendula Officinalis, Mentha Arvensis and Santalum Album, among hospice patients and their wound caregivers in the palliative wound care management of chronic wound symptoms at end-of-life. METHOD: Data were collected between May 2013 and November 2015. A pilot trial conducted among 50 hospice patients with symptomatic (pain, odour, or exudate) chronic wounds. Caregivers received initial RGN107 protocol training, actively applied the powder to patient wounds for 4-weeks, and completed an 8-week retrospective survey. Feasibility was assessed by measuring process outcomes, including the number and proportion of participants referred, screened eligible, enrolled, withdrawn and successfully completed. Acceptability measures included: a protocol training evaluation, caregiver pre and post self-efficacy ratings, retrospective usability, symptom control management and comparative technique caregiver ratings, and recorded open-ended comments. Tolerability was assessed through a 12-week cumulative review of the study adverse event profile. RESULTS: Feasibility, tolerability and acceptability of use of the RGN107 powder for chronic wounds were established. Recruitment goals were achieved and 92 % of the patients successfully completed the study. 95 % of wound caregivers would recommend the powder for use in this population. CONCLUSION: This study supports the feasibility, acceptability and tolerability of a wound care powder that espouses a multi-symptom palliative comfort care approach for hospice patients with chronic wounds at end-of-life. Further research is needed to establish the efficacy of the powder.

Molecular epidemiology of Mycobacterium abscessus complex isolates in Ireland.

BACKGROUND: The Mycobacterium abscessus complex are the rapidly growing mycobacteria (RGM) most commonly causing lung disease, especially in cystic fibrosis (CF) patients. Ireland has the world's highest CF incidence. The molecular epidemiology of M. abscessus complex in Ireland is unreported. METHODS: We performed rpoB gene sequencing and multi-locus sequence typing (MLST) on M. abscessus complex strains isolated from thirty-six patients in 2006-2012 (eighteen known CF patients). RESULTS: Twenty-eight strains (78%) were M. abscessus subsp. abscessus, eight M. abscessus subsp. massiliense, none were M. abscessus subsp. bolletii. Sequence type 1 (ST1) and ST26 (M. abscessus subsp. abscessus) were commonest. Seven M. abscessus subsp. abscessus STs (25%) were novel (two with novel alleles). Seven M. abscessus subsp. massiliense STs were previously reported (88%), including two ST23, the globally successful clone. In 2012, of 552 CF patients screened, eleven were infected with M. abscessus complex strains (2%). CONCLUSIONS: The most prevalent M. abscessus subsp. abscessus and M. abscessus subsp. massiliense strains in Ireland belong to widely-distributed STs, but there is evidence of high M. abscessus subsp. abscessus diversity.

Patellar height measurement in trochlear dysplasia.

A number of measurements of patellar height are in clinical use all of which reference from the tibia. The patellotrochlear index (PTI) has been proposed recently as a more accurate reflection of the functional height of the patella and described in normal knees. We compared patellar height measurements in patients with patellofemoral dysplasia. In a retrospective analysis of the MRI scans of 33 knees in 29 patients with patellofemoral dysplasia we assessed the inter- and intraobserver reliability of four patellar height measurements: the recently described PTI, Insall-Salvati (IS), Blackburne-Peel (BP) and Caton-Deschamps (CD) ratios. We also assessed the correlation between the different measurements in predicting patella alta. Three blinded observers on two separate occasions performed the measurements. There were 21 females and 8 males with a median age of 21 years (range 13-33). Statistical analysis revealed good inter-observer reliability for all measurements (0.78 for PTI, 0.78 for IS, 0.73 for BP and 0.77 for CD). Intra-observer reliability was also good (0.80, 0.83, 0.75 and 0.78, respectively). There was weak correlation between the PTI and the other ratios for patella alta. There was a strong correlation between the CD and BP ratios (0.96) and a moderate correlation between IS and CD and IS and BP ratios (0.594 and 0.539, respectively). We propose the PTI as a more clinically relevant measure than the IS, CD and BP ratios.

Conservative treatment as an option in the management of pancreatic pseudocyst.

BACKGROUND: Management of pancreatic pseudocysts is associated with considerable morbidity (15-25%). Traditionally, pancreatic pseudocysts have been drained because of the perceived risks of complications including infection, rupture or haemorrhage. We have adopted a more conservative approach with drainage only for uncontrolled pain or gastric outlet obstruction. This study reports our experience. PATIENTS AND METHODS: A consecutive series of 36 patients with pancreatic pseudocysts were treated over an 11-year period in one district general hospital serving a population of 310,000. This study group comprised of 19 men and 17 women with a median age of 55 years (range, 10-88 years). Twenty-two patients had a preceding attack of acute pancreatitis whilst 12 patients had clinical and radiological evidence of chronic pancreatitis. The aetiology comprised of gallstones (16), alcohol (5), trauma (2), tumour (2), hyperlipidaemia (1) and idiopathic (10). RESULTS: All patients were initially managed conservatively and intervention, either by radiological-assisted external drainage or cyst-enteric drainage (by surgery or endoscopy), was only performed for persisting symptoms or complications. Patients treated conservatively had 6 monthly follow-up abdominal ultrasound scans (USS) for 1 year. Fourteen of the 36 patients (39%) were successfully managed conservatively, whilst 22 patients required intervention either by percutaneous radiological drainage (12), by endoscopic cystogastrostomy (1) or by open surgical cyst-enteric anastomosis (9). Median size of the pancreatic pseudocysts in the 14 patients managed conservatively (7 cm) was nearly similar to that of the 22 patients requiring intervention (8 cm). The most common indications for invasive intervention in the 22 patients were persistent pain (16), gastric outlet obstruction (4), jaundice (1) and dyspepsia with weight loss (1). Although one patient required surgery for persistent pain, no other patients required urgent or scheduled surgery for complications of untreated pancreatic pseudocysts. Two of the 12 patients treated by percutaneous radiological drainage had recurrence of pancreatic pseudocysts requiring surgery. Two patients developed an intra-abdominal abscess following cyst-enteric drainage of pancreatic pseudocysts and one patient had a pulmonary embolism. On the mean follow-up of 37.3 months, one patient with alcoholic pancreatitis died 5 months after surgical cyst-enteric bypass. CONCLUSIONS: These results suggest that many patients with pancreatic pseudocysts can be managed conservatively if presenting symptoms can be controlled.

Portopulmonary hypertension in decompensated cirrhosis with refractory ascites.

BACKGROUND: The prevalence of portopulmonary hypertension (PPHTN) in patients with cirrhosis and refractory ascites is unknown. Its presence may preclude patients from receiving a transjugular intrahepatic portosystemic shunt or liver transplantation as a definitive treatment for their end stage cirrhosis. PURPOSE: To determine the prevalence, possible aetiological factors, and predictive factors for the development of PPHTN in these patients. METHODS: Sixty two patients (53 males, nine females; mean age 54.5 (1.4) years) with biopsy proven cirrhosis and refractory ascites underwent angiographic measurements of pulmonary and splanchnic haemodynamics. Endothelin 1 levels were measured from the pulmonary artery. Forty nine patients underwent radionuclide angiography for measurements of central blood volume, pulmonary vascular, and cardiac chamber volumes. Forty seven patients also underwent two dimensional echocardiography for measurements of cardiac structural and functional parameters. Cardiac output, and systemic and pulmonary vascular resistance were calculated. RESULTS: Ten patients (16.1%) fulfilled the criteria for PPHTN (mean pulmonary artery pressure >/= 25 mm Hg and pulmonary vascular resistance >/= 120 dynxs/cm(5)), with significantly higher mean right atrial (15.4 (1.2) v 7.9 (0.5) mm Hg; p<0.001), and right ventricular pressures (24.7 (1.5) v 14.7 (0.6) mm Hg; p<0.001), and endothelin 1 levels (3.04 (0.40) v 1.98 (0.12) pg/ml; p=0.02). No significant differences in any of the other parameters measured were detected between the two groups. A right atrial pressure of >/= 14 mm Hg had a 83% positive predictive value for the presence of PPHTN. CONCLUSIONS: Portopulmonary hypertension is common in cirrhosis with refractory ascites, possibly due to excess endothelin 1 in the pulmonary circulation. An elevated right atrial pressure >/= 14 mm Hg predicts the presence of PPHTN, which may be helpful in deciding management options in these patients.

Building a gateway to promote cardiovascular health research in African-American communities: lessons and findings from the field.

African American communities traditionally mistrust academic research. This forms a significant barrier to understanding cardiovascular risk factors in this population, which bears an excess risk of cardiovascular disease and stroke. A clergy/academic partnership was established to build a gateway for salient research and for improving resources for reducing cardiovascular disease risk in the community. From this partnership emanated the African American Family Heart Study. People with a family history of premature coronary heart disease (CHD) have an increased risk for the disease--as high as 12 times that of the general population, if among siblings. Considerably less is known about the actual remediable risk factors in African American families with premature CHD. We initiated the Family Heart Study with a full characterization of 161 apparently healthy, unaffected 30- to 59-year-old African Americans whose siblings were 85 African American index cases with documented premature CHD prior to 60 years of age. We compared their risk factor values to population reference norms obtained in the Third National Health and Nutrition Examination Survey (NHANES III) and the National Health Interview Survey (NHIS) for cigarette smoking. Only 13% of African American male siblings and 14% of female siblings from these families were without any major remediable risk factors. The fact that so many siblings were at extremely high risk calls into question the current applications by provider systems of national guidelines in high-risk African American families. This is an easily identifiable population that would be likely to benefit greatly from targeted screening and culturally sensitive and appropriate treatment.

Building a gateway to promote cardiovascular health research in African American communities: lessons and findings from the field.

African American communities traditionally mistrust academic research. This forms a significant barrier to understanding cardiovascular risk factors in this population, which bears an excess risk of cardiovascular disease and stroke. A clergy/academic partnership was established to build a gateway for salient research and for improving resources for reducing cardiovascular disease risk in the community. From this partnership emanated the African American Family Heart Study. People with a family history of premature coronary heart disease (CHD) have an increased risk for the disease--as high as 12 times that of the general population, if among siblings. Considerably less is known about the actual remediable risk factors in African American families with premature CHD. We initiated the Family Heart Study with a full characterization of 161 apparently healthy, unaffected 30- to 59-year-old African Americans whose siblings were 85 African American index cases with documented premature CHD prior to 60 years of age. We compared their risk factor values to population reference norms obtained in the Third National Health and Nutrition Examination Survey (NHANES III) and the National Health Interview Survey (NHIS) for cigarette smoking. Only 13% of African American male siblings and 14% of female siblings from these families were without any major remediable risk factors. The fact that so many siblings were at extremely high risk calls into question the current applications by provider systems of national guidelines in high-risk African American families. This is an easily identifiable population that would be likely to benefit greatly from targeted screening and culturally sensitive and appropriate treatment.

Endocervical cancer is associated with an increase in the ligands and receptors for transforming growth factor-beta and a contrasting decrease in p27(Kip1).

OBJECTIVE: The aim of this study was to investigate the relationship between the expression of the TGF-beta ligands and TGF-beta receptors to the expression of p27(Kip1), a TGF-beta-regulated gene, in endocervical cancer. METHODS: To examine the expression of TGF-beta and p27(Kip1) in malignant transformation of the uterine endocervix, a panel of 23 formalin-fixed and paraffin-embedded human cervical specimens, including 8 with benign endocervical glands, 8 with cervical adenocarcinoma in situ, and 7 with cervical adenocarcinomas, was used. Tissues were immunostained with polyclonal antibodies that react specifically with TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta RI, TGF-beta RII, and p27(Kip1). RESULTS: Immunostaining for TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta RI, TGF-beta RII, and p27(Kip1) was detected in normal endocervix, with the TGF-betas showing weak cytoplasmic staining, while p27(Kip1) showed strong nuclear staining. Expression of TGF-beta increased significantly upon neoplastic transformation with the TGF-beta ligands and receptors showing strong cytoplasmic staining in adenocarcinoma in situ compared to normal endocervix. Interestingly, expression of TGF-beta was lower in adenocarcinoma than in adenocarcinoma in situ, but still significantly higher than in normal endocervix. TGF-beta 2 and TGF-beta 3 showed higher levels of immunostaining than TGF-beta 1 in adenocarcinomas. In contrast, p27(Kip1) protein expression decreased with progressive malignancy, with lower p27(Kip1) protein levels detected in adenocarcinoma than in adenocarcinoma in situ, while normal endocervix showed the highest level of p27(Kip1) protein expression. CONCLUSION: Elevated expression of the TGF-beta ligands and receptors is found in both cervical adenocarcinoma in situ and adenocarcinoma compared to normal endocervix. In contrast, a progressive decrease in p27(Kip1) occurs upon neoplastic transformation of the normal endocervix to cervical adenocarcinoma. These results suggest that neoplastic transformation of the endocervix may be related to dysregulation of TGF-beta and p27(Kip1) seen as an elevation of TGF-beta and a reduction of p27(Kip1) expression that may lead to loss of cell cycle control.

Transforming growth factor-beta 1 and its receptors in human lung cancer and mouse lung carcinogenesis.

The transforming growth factor-betas (TGF-beta s) are multifunctional proteins that inhibit the proliferation of many epithelial cells through a set of cell protein receptors that includes the TGF-beta type I (RI) and type II (RII) receptors. Loss of growth inhibition by TGF-beta is thought to contribute to the development of many types of tumors. In the present study, we have examined expression of the proteins and mRNAs for TGF-beta 1, TGF-beta RI, and TGF-beta RII in normal human lung, well-characterized non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens. Immunohistochemical staining for TGF-beta 1, TGF-beta RI, and TGF-beta RII using specific antibodies in normal human lung showed expression of the 3 proteins in the epithelium of bronchi and bronchioles as well as in alveoli. Differential expression of TGF-beta RI and TGF-beta RII proteins was detected in 5 NSCLC cell lines using Western blot analysis, with reduced levels in 3 cell lines. A panel of 45 formalin-fixed and paraffin-embedded NSCLC specimens showed positive immunostaining for TGF-beta 1, TGF-beta RI, and TGF-beta RII, with reduced TGF-beta RII in poorly differentiated adenocarcinomas and squamous cell carcinomas and some moderately differentiated adenocarcinomas. In situ hybridization studies conducted with specific riboprobes for TGF-beta 1, TGF-beta RI, and TGF-beta RII showed corresponding localization of expression of the mRNAs in the specimens that showed positive immunostaining for the proteins. To investigate the roles of TGF-beta 1, TGF-beta RI, and TGF-beta RII in chemically induced mouse lung tumorigenesis, we examined the expression of their proteins and mRNAs in 2 mouse model systems. Whereas expression of the proteins and mRNAs for TGF-beta 1 and TGF-beta RI was comparable in lung adenomas and bronchioles of A/J mice treated with benzo(alpha)pyrene, decreased immunostaining and hybridization for TGF-beta RII protein and mRNA was detected in 50% of lung adenomas in these mice. Interestingly, expression of TGF-beta 1 and the TGF-beta receptor proteins was similar to that of bronchioles in C57B1/6 mice and their littermates heterozygous for deletion of the TGF-beta 1 gene treated with diethylnitrosamine. These data show that reduced levels of expression of TGF-beta RII occur in some, but not all, human and mouse lung tumors. This suggests that different mechanisms of action, some of which may involve the TGF-beta signaling pathway, may contribute to the progression of lung tumorigenesis.

Human pulmonary acinar aplasia: reduction of transforming growth factor-beta ligands and receptors.

Pulmonary hypoplasia has been found in the human neonatal autopsy population and has been attributed to an alteration in epithelial-mesenchymal interactions during development of the lung. Pulmonary acinar aplasia is a very rare and severe form of pulmonary hypoplasia. The transforming growth factor-betas (TGF-beta) are multifunctional regulatory peptides that are secreted by a variety of normal and malignant cells and are expressed in developing organs including the lung; their tissue distribution patterns have possible significance for signaling roles in many epithelial-mesenchymal interactions. Here, we report our examination of TGF-beta in the lungs of a term female infant diagnosed with pulmonary acinar aplasia whose autopsy revealed extremely hypoplastic lungs with complete absence of alveolar ducts and alveoli. Immunohistochemical and in situ hybridization analyses were used to localize and measure the proteins and mRNA, respectively, for TGF-beta1, TGF-beta2, TGF-beta3, and TGF-beta type I and type II receptors (TGF-beta RI and RII) in formalin-fixed and paraffin-embedded sections of these hypoplastic lungs and normal lungs. Immunostaining for TGF-beta1, TGF-beta2, and TGF-beta RI and RII was significantly lower in the bronchial epithelium and muscle of the hypoplastic lungs than in normal lungs, whereas no difference was detected in staining for other proteins including Clara cell 10-kD protein, adrenomedullin, hepatocyte growth factor/scatter factor, and hepatocyte growth factor receptor/Met in the hypoplastic and normal lungs or in the liver and kidneys of this infant compared with normal liver and kidney. In addition, in situ hybridization showed that TGF-beta1 and TGF-beta RI transcripts were considerably reduced in the bronchial epithelium of the hypoplastic lung compared with normal lung. These results show that there is a selective reduction of TGF-beta in pulmonary acinar aplasia and suggest that the signaling action of TGF-beta in epithelial-mesenchymal interactions in the lungs of this developmental condition may be compromised.

Coordinate expression of transforming growth factor-beta1 and adrenomedullin in rodent embryogenesis.

Transforming growth factor-beta (TGFbeta) and adrenomedullin (AM) are multifunctional regulatory peptides that are secreted by a variety of normal and malignant cells. The TGFbetas are expressed in developing organs and adults, and their tissue distribution pattern has possible significance for signaling roles in many epithelial-mesenchymal interactions. AM is also expressed in a variety of embryonic and adult tissues. The present study reports a comparison of the patterns of expression of the proteins and messenger RNAs (mRNAs) for TGFbeta1 and AM in the developing mouse embryo. Immunohistochemical and in situ hybridization analyses were performed on formalin-fixed paraffin-embedded sections of developing embryonic mouse tissues using specific antibodies and complementary RNA probes for TGFbeta1 and AM. The early placenta, including the giant trophoblastic cells, showed high levels of staining and hybridization for TGFbeta1 and AM proteins and mRNAs. The heart was the first organ that showed expression of TGFbeta1 and AM during embryogenesis. The spatio-temporal patterns of expression of TGFbeta1 and AM in cardiovascular, neural, and skeletal-forming tissues as well as in the main embryonic internal organs showed striking similarities. The lung, kidney, and intestine, in which epithelial-mesenchymal interactions occur, showed similar patterns of TGFbeta1 and AM expression. These data show colocalization of TGFbeta1 and AM in specific cell types associated with several tissues in the developing mouse embryo. Additionally, RT-PCR amplification and Northern blot hybridization showed expression of TGFbeta1 and AM mRNAs in all embryonic and adult mouse and rat tissues examined. Our data show that the expression of TGFbeta1 and AM is regulated in a spatial and temporal manner such that overlapping patterns of expression of TGFbeta1 and AM occur in several tissues at the same stage of development and in the same cellular location in rodent embryogenesis.

Concurrent and distinct transcription and translation of transforming growth factor-beta type I and type II receptors in rodent embryogenesis.

The transforming growth factor-betas (TGF-betas) are multifunctional regulatory polypeptides that play a crucial role in many cell processes and function through a set of cell surface protein receptors that includes TGF-beta type I (RI) and type II (RII). The present study reports a comprehensive comparison of the patterns of expression of TGF-beta RI and RII proteins and mRNAs in the developing mouse embryo using immunohistochemical and in situ hybridization analyses. Although widespread expression of both TGF-beta receptors was detected throughout the embryonic development period so that many similarities occur in localization of the TGF-beta receptors, TGF-beta RI was expressed in a well-defined, non-uniform pattern that was different in many respects from that of TGF-beta RII. Whereas higher levels of TGF-beta RI compared to TGF-beta RII were detected in some tissues of the embryo at the beginning of organogenesis, the level of TGF-beta RII increased more dramatically than that of TGF-beta RI during late organogenesis; this was especially true in many neural structures where TGF-beta RI and RII were comparable by day 16. The lung, kidney and intestine, in which epithelial-mesenchymal interactions occur, showed a complex pattern of TGF-beta RI and Rll expression. Additionally, northern blot hybridization and reverse transcription-polymerase chain reaction (RT-PCR) amplification showed non-uniform expression of the transcripts for TGF-beta RI and RII in embryonic and adult mouse and rat tissues. These data show that regulation of TGF-beta1 RI and RII occurs concurrently, but distinctly, in a spatial and temporal manner in rodent embryogenesis which may allow control of signal transduction of TGF-beta during development.

Osteopenia as a feature of the androgen insensitivity syndrome.

OBJECTIVE: The syndrome of androgen insensitivity, a paradigm of a hormone resistance syndrome, manifests as failure of masculinization despite normal or high concentrations of serum testosterone. The defect in these 46 XY patients resides in the androgen receptor gene, with consequent defective androgen action and abnormal sexual differentiation. We sought to evaluate whether the adverse sequelae of androgen resistance may extend to skeletal tissue by measuring bone mineral density in six patients with androgen insensitivity. DESIGN: A cross-sectional retrospective study. MEASUREMENTS: Bone mineral density was measured by means of a Dexa (Hologic QDR 1000 scanner). The diagnosis of androgen insensitivity was confirmed in each patient by karyotype and assay of sex hormones. RESULTS: The five adult patients with androgen insensitivity had been exposed to both defective androgen action and variable periods of oestrogen deficiency. The latter resulted from the low circulating oestrogen concentrations (for premenopausal females) before gonadectomy and inadequate oestrogen replacement after gonadectomy. All five adults with androgen insensitivity had osteopenia in both the lumbar spine (T-score -1.52 to -3.85) and femoral neck (T-score -1.34 to -4.91). CONCLUSIONS: Osteopenia in patients with androgen insensitivity may relate to defective androgen action, oestrogen deficiency or a combination of the two. These observations have implications for the management of patients with androgen insensitivity and may provide insight into the effects of androgens on the female as well as the male skeleton.