Anatomic greater tuberosity healing does not influence the functional outcomes of reverse shoulder arthroplasty for acute proximal humerus fractures.

Background: To investigate the functional outcomes of reverse shoulder arthroplasty (RSA) in acute complex proximal humerus fractures (PHF) in patients with an anatomic greater tuberosity union in comparison to patients with a displaced or resorbed tuberosity. Method: It is a retrospective study with prospective data collection including 32 consecutive PHF with a minimum two-year follow-up treated with RSA. A radiological study and a CT scan were performed specifically for the study. Two shoulder surgeons and a musculoskeletal radiologist assessed the position and union of the greater tuberosity. The functional outcomes were assessed with the Constant-Murley, DASH, ASES and ADLER scores. Results: The mean overall CS was 59.55. In 17 cases, the greater tuberosity healed in an anatomical position. In 15 cases, it was non-anatomical. In 53% of patients, greater tuberosity union was obtained. The CS was 62.76 in the anatomic union group and 55.9 in the non-anatomic union group. No significant differences were observed. No differences were observed in the ASES, DASH and ADLER scores. Conclusion: After RSA for PHF, anatomic greater tuberosity healing was obtained in 53% of patients. The influence of the position and union of the greater tuberosity on the functional results could not be evidenced.

Construction of land-use change matrix and estimation of greenhouse gas inventory focusing on settlements in South Korea.

BACKGROUND: Five ministries are involved in estimating the greenhouse gas (GHG) inventory in the South Korean land use, land-use change, and forestry (LULUCF) sectors. However, these ministries have not established a consistent land classification standard between land-use categories. Therefore, the GHG inventory is estimated at the approach 1 level with no spatial clarity between land-use categories. Moreover, the settlements category is not estimated because activity data and the spatial scope are lacking. This study proposed a methodology for constructing a land-use change (LUC) matrix in the LULUCF sector for improving approach level and estimating the GHG inventory in the settlements. RESULT: We examined 10 sets of spatiotemporal data in South Korea to construct a LUC matrix. To maintain consistency in the spatial land classification, we constructed a LUC matrix using cadastral maps, which provide useful data for consistent land-use classification in South Korea. The LUC matrix was divided into remaining and land-converted settlements between 2005 and 2019 with estimated areas of 878,393.17 and 203,260.42 ha, respectively. CO2 emissions, according to Intergovernmental Panel Climate Change's Guideline Tier 1, were estimated at 18.94 MtCO2 for 15 years, with an annual CO2 emission of 1.26 MtCO2 yr-1. CO2 emission by land conversion type was found to be the largest at 16.93 MtCO2 in the case of forest converted to settlements. In addition, the area with the largest CO2 emission density was Sejong-si at 7.59 tCO2/ha. CONCLUSION: Based on reviewing available spatial data in South Korea, it is possible to improve Approach 3, which is more advanced than previous Approach 1 in the settlement category. In addition, the national GHG inventory also can be estimated by our constructed LUC matrix and activity data in this study. Under the many discussions about developing the Approach system, this study can provide in-detail information on developing LUC in South Korea in the settlement category as well as suggesting a methodology for constructing the LUC matrix for countries with similar problems to South Korea.

Is the Position and Union of the Tuberosities Assessable by Means of the Simple Radiograph After Reverse Shoulder Arthroplasty for Complex Proximal Humerus Fractures?

Background: The assessment of tuberosity position and union in reverse shoulder arthroplasty (RSA) for complex proximal humerus fractures (PHF) has been carried out by means of routine simple radiographs. To evaluate the interobserver agreement and intraobserver reproducibility of the simple radiograph in comparison to the CT scan. Methods: The position and consolidation of the tuberosities in 2 radiographic projections and in a CT scan of 32 consecutive patients operated on a RSA for PHF was assessed by 5 observers. Interobserver agreement and intraobserver reproducibility in both imaging tests were also assessed. Results: The interobserver agreement for the greater tuberosity position was 0.52 in the simple radiograph and 0.45 in the CT scan. For the greater tuberosity union, agreement was moderate in the simple radiograph (0.52), but fair in the CT scan (0.35). For the lesser tuberosity position and union, the agreement was fair in the radiograph and poor in the CT scan. Conclusion: Only moderate agreement was observed in the assessment of the position and union of the tuberosities in the RSA for PHF in the simple radiograph and no improvement in it was seen for the 2D CT scan.

Psicología y dolor crónico infantil / No disponible

Los conocimientos derivados de la Psicología y las contribuciones de los psicólogos han sido fundamentales en el progreso del estudio, evaluación y tratamiento del dolor infantil, particularmente del dolor crónico. El objetivo de este artículo es realizar una aproximación a algunas de las parcelas en las cuales los conocimientos de la Psicología y el trabajo de los psicólogos revisten especial interés en relación con el dolor crónico infantil. Y, así, en estas páginas se resumen los hallazgos más relevantes relacionados con el estudio de los factores de riesgo de la cronificación del dolor, el tratamiento psicológico y, en especial, las intervenciones cognitivo-conductuales cuando se utilizan en población infantil y la incorporación de las tecnologías de la información y la comunicación, particularmente la tecnología móvil inteligente para la evaluación y tratamiento de los jóvenes con dolor crónico

Psychology-based knowledge, along with the contributions of psychologists, has been instrumental for the progress of the study, assessment, and treatment of pediatric pain, particularly pediatric chronic pain. The objective of this article is to provide a brief analysis of some of the areas in which psychological-related knowledge and the work of psychologists are of special interest in relation to pediatric chronic pain. Here, we summarize the most relevant findings related to the study of risk factors for the development of pediatric chronic pain, psychological treatment, and especially cognitive-behavioral interventions when used with youths with chronic pain, and the incorporation of information and communication technologies, particularly mobile technology for the evaluation and treatment of young people with chronic pain

What are the needs of adolescents and young adults after a cancer treatment? A Delphi study.

Advances in the early detection of cancer and the development of more effective treatments have resulted in a larger number of adolescents and young adults (AYAs), becoming cancer survivors. However, knowledge regarding their needs and if those needs are adequately addressed remains limited. The aims of this study were to: (1) better understand the needs of AYAs after cancer treatment; (2) analyse the importance of those needs; (3) determine which needs are not adequately addressed; and (4) test the hypothesis that AYA cancer survivors have different needs than adult survivors. Twenty-nine health oncology professionals, 17 AYA survivors and 12 relatives of AYA survivors participated in the Delphi study. The needs identified could be classified into six categories, and all were rated as highly important by all participants. The category perceived as least adequately addressed across the three groups was 'Counselling and psychological support.' The findings provide important new information regarding the needs of AYA cancer survivors that can inform the development of interventions to improve the quality of life of these individuals.

Validity of three rating scales for measuring pain intensity in youths with physical disabilities.

BACKGROUND: There is growing evidence confirming that youths with physical disabilities are at risk for chronic pain. Although many scales for assessing pain intensity exist, it is unclear whether they are all equally suitable for youths. The aim of this study was to address this knowledge gap by comparing the validity of the Numerical Rating Scale (NRS-11), the Wong Baker FACES Pain Rating Scale (FACES), and a 6-point categorical Verbal Rating Scale (VRS-6) for assessing pain intensity among youths (aged 8-20) with physical disabilities. METHODS: One hundred and thirteen youths (mean age = 14.19 years; SD = 2.9) were interviewed and asked to rate their current pain intensity and recalled (in the past week) worst, least, and average pain with the NRS-11 and the FACES. Participants were also asked to rate their average pain intensity during the past 4 weeks using a VRS-6, and were administered measures assessing pain interference, disability and psychological functioning. RESULTS: Analyses showed that all of the pain intensity measures were associated positively with each other. Nevertheless, the NRS-11 appeared to out-perform both the VRS-6 and in particular the FACES scale with respect to: (1) the associations with the validity criterion (i.e. pain interference, disability and psychological functioning) and (2) a lack of any moderating effect of age on the association between the measure and the criterion variables. CONCLUSIONS: The findings support the validity of the NRS-11 for assessing pain intensity in youths with physical disabilities between the ages of 8 and 20 years.

Effects of supplemental progesterone after artificial insemination on expression of interferon-stimulated genes and fertility in dairy cows.

The objectives of the current study were to evaluate the effects of supplemental progesterone after artificial insemination (AI) on expression of IFN-stimulated genes (ISG) in blood leukocytes and fertility in lactating dairy cows. Weekly cohorts of Holstein cows were blocked by parity (575 primiparous and 923 multiparous) and method of insemination (timed AI or AI on estrus) and allocated randomly within each block to untreated controls, a controlled internal drug release (CIDR) containing 1.38g of progesterone from d 4 to 18 after AI (CIDR4), or a CIDR on d 4 and another on d 7 after AI and both removed on d 18 (CIDR4+7). Blood was sampled to quantify progesterone concentrations in plasma and mRNA expression in leukocytes for the ubiquitin-like IFN-stimulated gene 15-kDa protein (ISG15) and receptor transporter protein-4 (RTP4) genes. Pregnancy was diagnosed on d 34±3 and 62±3 after AI. Treatment increased progesterone concentrations between d 5 and 18 after AI in a dose-dependent manner (control=3.42, CIDR4=4.97, and CIDR4+7=5.46ng/mL). Cows supplemented with progesterone tended to have increased luteolysis by d 19 after AI (control=17.2; CIDR4=29.1; CIDR4+7=30.2%), which resulted in a shorter AI interval for those reinseminated after study d 18. Pregnancy upregulated expression of ISG in leukocytes on d 19 of gestation, but supplementing progesterone did not increase mRNA abundance for ISG15 and RTP4 on d 16 after insemination and tended to reduce mRNA expression on d 19 after AI. For RTP4 on d 19, the negative effect of supplemental progesterone was observed only in the nonpregnant cows. No overall effect of treatment was observed on pregnancy per AI on d 62 after insemination and averaged 28.6, 32.7, and 29.5% for control, CIDR4, and CIDR4+7, respectively. Interestingly, an interaction between level of supplemental progesterone and method of AI was observed for pregnancy per AI. For cows receiving exogenous progesterone, the lower supplementation with CIDR4 increased pregnancy per AI on d 62 in cows inseminated following timed AI (CIDR4=39.2; CIDR4+7=27.5%); in those inseminated following detection of estrus, however, the use of a second insert on d 7 resulted in greater pregnancy per AI (CIDR4=26.9; CIDR4+7=31.5%). Pregnancy loss did not differ among treatments. Supplemental progesterone post-AI using a single intravaginal insert on d 4 was beneficial to pregnancy in cows inseminated following timed AI, but incremental progesterone with a second insert on d 7 did not improve fertility of dairy cows.

Efficacy of ampicillin trihydrate or ceftiofur hydrochloride for treatment of metritis and subsequent fertility in dairy cows.

Our objectives were to evaluate the efficacy of ampicillin trihydrate for the treatment of metritis in dairy cows compared with ceftiofur hydrochloride and the subsequent effects on pregnancy at first insemination (P/AI). Cows in the first 12 d in milk (DIM) with a uterine discharge score of 5 (watery, reddish or brownish discharge of foul smell) and rectal temperature <39.5°C were diagnosed with metritis based on the fetid discharge, and cows with metritis and rectal temperature ≥39.5°C were diagnosed as having puerperal metritis. Cows with metritis (n=528) were blocked by parity and type of metritis as fetid discharge or puerperal metritis and, within each block, assigned randomly to receive 11mg/kg of ampicillin (n=259) or 2.2mg/kg of ceftiofur (n=269) once daily for 5 d. Day of diagnosis of metritis was considered study d 1. A cohort of 268 cows without metritis was selected randomly at 12 DIM. Rectal temperature was measured in cows with metritis on study d 1 to 7, and 12, and vaginal discharge was scored on study d 5, 7, and 12. Metritis cure was characterized by vaginal discharge score of <5 or by vaginal discharge score of <5 and no fever. At 32±3 DIM, vaginal discharge was scored for diagnosis of purulent vaginal discharge. At 39±3 DIM, endometrial cytology was performed. At 53±3 and 67±3 DIM, ovaries were scanned to determine estrous cyclicity. Pregnancy was evaluated after the first AI. Cure of metritis based on vaginal discharge <5 was greater for ampicillin than ceftiofur on d 5 (37.1 vs. 25.2%) and 7 (57.2 vs. 46.3%), but not on d 12 (82.0 vs. 85.0%). Cure of metritis based on vaginal discharge <5 and no fever was greater for ampicillin than for ceftiofur only on d 7 (50.4 vs. 37.9%), but not on d 5 (23.1 vs. 17.6%) and 12 (66.1 vs. 67.4%). Cows with puerperal metritis had reduced cure compared with cows with fetid discharge on d 5 (30.5 vs. 12.8%), 7 (55.2 vs. 33.6%), and 12 (72.0 vs. 61.1%). The proportion of cows with fever on any day after therapy started did not differ between treatments. Fifty-three percent of cows with metritis based on fetid discharge developed fever after initiating antimicrobial therapy. Cows receiving ampicillin had less prevalence of purulent vaginal discharge than those treated with ceftiofur (57.7 vs. 67.8%), but they were both greater than cows without metritis (21.9%). Prevalence of cytological endometritis did not differ between ampicillin and ceftiofur (30.0 vs. 25.4%), but they were both greater than cows without metritis (14.5%). The proportion of estrous cyclic cows (75.0%) and P/AI did not differ among treatments (ampicillin=28.0% vs. ceftiofur=28.3% vs. without metritis=30.5%). Clinical cure was faster for ampicillin than for ceftiofur, but on study d 12 both treatments resulted in similar cure. Clinical cure was less for cows with puerperal metritis than for cows with fetid uterine discharge. Despite differences in uterine health, P/AI at the first insemination did not differ among treatments.

Correlation of immunological markers with graft vasculopathy development in heart transplantation.

This study examined the imbalance between T effector cells (Th1 defined as CD3+ interferonγ+) and T regulatory cells (Treg defined as CD4+CD25(high)FoxP3+) as a valuable albeit limited marker of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). CAV remains, with neoplasms, the most important cause of death in patients surviving the first year after HTx. It is an immune-mediated pathology, although nonimmune factors may also play a role. The process included concentric fibrous intima hyperplasia that narrows the entire length of the affected arteries. Coronary angiography is the usual method of diagnosis. Because a transplanted heart is a denervated organ, CAV is not diagnosed until the disease reaches an advanced stage, in which case transplantation is the only option for treatment. Although the host's immune response against an allogeneic graft is the major cause of endothelial dysfunction, the objective of this study was to detect anti-allogeneic responses on peripheral blood, seeking to identify signs of CAV before classical methods to predict outcomes in HTx recipients. CD3, CD4, CD8, CD19, CD56, Th1, and the Treg mononuclear cell populations were studied in 37 de novo and 20 long-term (more than 3 years) HTx patients as well as 20 healthy volunteers using flow cytometry. A progressive increase in CD8 and Th1 percentages and decrease in the CD4 population were detected during follow-up. Although Th1 changes also reflect processes not related to CAV receiver operating characteristics analysis of Th1/Treg ratio showed an area under the curve of 0.976, with an estimated sensitivity of 100% and specificity of 90%. The positive prediction value was 58.8% and the negative prediction value, 100%. These results prove that the Th1/Treg ratio was an important marker to following host immune response after HTx. The results confirm the need to test other T lymphocyte subsets.

Use of non-nucleoside analogues together with rifampin in HIV patients with tuberculosis.

OBJECTIVE: The concomitant use of rifampin (RFP) with efavirenz (EFV) or nevirapine (NVP) is frequent in HIV patients with tuberculosis (TB). The necessity of increasing the dose of EFV remains controversial. The aim of the study was to evaluate the outcome of HIV infection in patients treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and RFR. METHODS: Retrospective analysis of HIV patients who were simultaneously treated with RFP and NVP or EFV. The dose of EFV was considered to be adjusted in those patients receiving 600 mg when weighing <60 kg and 800 mg if >60 kg and was considered nonadjusted when the dose given was 600 mg in patients >60 kg. RESULTS: 63 patients were included: 13 received NVP and 50 received EFV-based ART (30 adjusted and 20 nonadjusted). Treatment failure was observed in 7 (53.8%) of the NVP group; 11 (55%) of the nonadjusted EFV group, and 8 (26.7%) of the adjusted EFV group (P = .04). The relative risk (RR) of treatment failure comparing nonadjusted and adjusted EFV was 3.36 (95% Cl, 1.02-11.11). The proportion of treatment failure was 9/18 (50%) in the nonadjusted and 5/27(18.5%) in the adjusted EFV group. CONCLUSIONS: The effectiveness of NVP and nonadjusted EFV was lower than adjusted EFV-based ART. It may be advisable to increase the dose of EFV to 800 mg once daily when administered with rifampin in patients weighing >60 kg.

[Reliability of ultrasound examination confirmed at autopsy in foetuses suffering from Dandy-Walker Syndrome]. / Attendibilità dell'esame ecografico confermata all'esame autoptico in feti affetti da Sindrome di Dandy-Walker.

BACKGROUND: The Dandy-Walker Syndrome (DWS) is a congenital malformation of the structures of the posterior cranial fossa with failure of the Luschka and Magendie foramina, which connect the ventricular system to the subarachnoid space, to open. In this syndrome, the cerebellar vermis may be absent or hypoplastic, the hemispheres small, the encephalic trunk and cervical spinal bone marrow flattened, complete or partial absence of cerebellar vermis, cystic dilatation of IV ventricle and frequently hydrocephalus. METHODS: We evaluated 56 cases of fetal malformations of the central nervous system from January 1998 to May 2001. Of these 56, 11 regarded the Dandy-Walker Syndrome. Ultrasound examinations were carried out at the 9(th) and 10(th) weeks, at the 21(st)-23(rd) weeks and at the 31(st) to 34(th) weeks of gestation so as to assess foetal anatomy and morphology. RESULTS: The results of the 11 pregnancies with Dandy-Walker Syndrome were as follows: 3 spontaneous miscarriages (at the 15(th), 18(th) and 20(th) weeks of gestation), 5 therapeutic abortions, 3 term pregnancies. Of the 3 newborns we were only able to follow the clinical course of two of them; both newborns underwent an intervention for ventriculo-peritoneal fluid derivation. At the moment both babies, aged respectively 30 and 25 months, are in good physical, intellectual and behavioural condition. CONCLUSIONS: Bearing in mind the notable clinical and socioeconomic importance of this malformation, we consider foetal morphological ultrasound to be a valid instrument for the correct management of pregnancy. Identification of lesions makes use of the comparison of ultrasound data with the results of histopathological examinations.

Linkage disequilibria between mtDNA haplotypes and chromosomal arrangements in a natural population of Drosophila subobscura.

The association between mtDNA haplotypes and chromosomal arrangements in a natural population of Drosophila subobscura from Calvia (Balearic Islands, Spain) was studied in order to search for linkage disequilibria, in an attempt to explain the populational dynamics of the mtDNA haplotypes of this species in nature. The presence of Wolbachia was not detected. Two main haplotypes (I and II) were found, as well as a series of less common ones. The Tajima D-test seemed to indicate some kind of seasonal population bottleneck. An analysis of linkage disequilibrium and factorial analysis of correspondences detected an association between haplotype I and the J(ST) inversion and haplotype II and the J(1) inversion.

Colonization of America by Drosophila subobscura: heterotic effect of chromosomal arrangements revealed by the persistence of lethal genes.

About 20 years ago Drosophila subobscura, a native Palearctic species, colonized both North and South America. In Palearctic populations lethal genes are not associated in general with particular chromosomal arrangements. In colonizing populations they are not randomly distributed and usually are associated to a different degree with chromosomal arrangements caused by the founder event. The persistence of two lethal genes in the colonizing populations, one completely associated with the O(5) inversion and the other partially associated with the O(3+4+7) arrangement, has been analyzed. In all populations studied (five North American and six South American) the observed frequency of the lethal gene completely associated with the O(5) inversion is higher than expected, the difference being statistically significant in all South American and one North American populations. The observed frequency of the lethal gene partially associated with the O(3+4+7) arrangement is also significantly higher than expected. Taking into account that the O(5) inversion exhibits significant latitudinal clines both in North and South America, an overdominant model favoring the heterokaryotypes seems to be in operation. From this model, a polynomial expression has been developed that allows us to estimate the relative fitness and the coefficient of selection against all karyotypes not carrying the O(5) inversion. The relative fitness of the O(5) heterokaryotypes is higher in South American than in North American populations. Furthermore, the observed frequencies of the lethal genes studied are in general very close to those of the equilibrium. This case is an outstanding demonstration in nature of an heterotic effect of chromosomal segments associated with lethal genes on a large geographic scale.

Colonization of America by Drosophila subobscura: spatial and temporal lethal-gene allelism.

About twenty years ago Drosophila subobscura, a western Palearctic species, colonized both North and South America. Lethal genes in the O chromosome has been subject to much research. Lethal gene allelisms between American populations far away have been studied. These allelisms were not negligible, but all cases were due to the lethal gene completely associated to the O5 chromosomal inversion. Here we analyze the lethal genes in a new American population of D. subobscura (Centralia, Washington), located fairly close to a previously studied population (Bellingham, Washington) and separated in space and time with other American populations (Gilroy I and II in California and Santiago de Chile). The frequencies of lethal and semilethal genes of Centralia were 16.9+/-4.6 and 6.2+/-3.0, respectively. The intrapopulational allelism of Centralia was 0.122+/-0.036. Interpopulational allelisms were studied using the lethal genes from the populations separated in space and time from Centralia. The interpopulational allelisms between Centralia and Gilroy I (California) and between Centralia and Bellingham (Washington) were higher than the intrapopulational allelism (0.155+/-0.032 and 0.153+/-0.024, respectively). In all these cases allelism was due to a complete association between a lethal gene and the O5 chromosomal inversion. Accordingly, no other lethal genes are shared in these populations.

Lead exposure in children: levels in blood, prevalence of intoxication and related factors.

Lead is a highly toxic metal, the main source of which is contamination from combustion of unleaded petrol. The aims of this work were to detect the degree of lead exposure in a large sample of children; determine the relationship between blood lead levels (BPb) and age, sex, habitat and season of the year; and correlate BPb with zinc protoporphyrin (ZPP) values. A cross-sectional study was carried out. Blood from routine extractions drawn at our centre was used. BPb and ZPP were measured by atomic absorption spectrophotometry and haematofluorimetry, respectively. We analysed 1158 blood samples from children. BPb (mean +/- SEM): 0.22 +/- 0.04 mumol l-1. Correlation BPb-age: BPb = 0.19 + 0.086 x age (months), r = 0.129, P < 0.0001. BPb was greater in boys (0.23 +/- 0.007 versus 0.20 +/- 0.006 mumol l-1, P < 0.0002). No differences were observed between habitats (urban versus rural). BPb were higher in the warm months (0.24 +/- 0.013 versus 0.21 +/- 0.007 mumol l-1, P < 0.0001). Prevalence of lead intoxication (BPb > 0.48 mumol l-1) was 4.2%. No differences in prevalence were found among the different groups. The correlation between BPb and ZPP showed r = 0.0969, P = 0.0024. Utility for screening: sensitivity of 53.7% and specificity of 59.3% (cut-off point of 60 mumol ZPP mol-1 haem). We can conclude that lead exposure in children in our sample was in the range reported in similar studies in other areas and countries, and below the toxic limit. None of the factors analysed significantly influenced lead intoxication prevalence. There was no good correlation between ZPP and BPb in our samples and the ZPP cut-off point used did not present good specificity and sensitivity values.

Pleiotropic effects of dihydrotestosterone in immortalized mouse proximal tubule cells. Technical note.

Dihydrotestosterone (DHT) binding studies and the effects of DHT on the expression of beta-glucuronidase (Gus) and kidney androgen-regulated protein (KAP) genes and cell growth were investigated in immortalized early PKSV-PCT and late PKSV-PR proximal tubule cells, derived from transgenic mice carrying the L-pyruvate kinase/SV40 hybrid gene. [3H]DHT binding studies indicated that both cell lines have conserved substantial amounts of androgen receptors. The levels of KAP and Gus transcripts in PKSV-PCT cells, and those of KAP transcripts in PKSV-PR cells, decreased when cells were shifted from a serum-supplemented to a steroid-free medium. The addition of 30 nM DHT to the steroid-free medium resulted in a slight increase in Gus and in a more marked increase in KAP transcripts in both cell lines. Dihydrotestosterone also affected the growth of PKSV-PCT and PKSV-PR cells, since this hormone added to the steroid-free medium stimulated the incorporation of [3H]thymidine in a dose-dependent manner and induced the formation of domes, which represent indicators of ionic transport processes. Thus, because these early and late mouse proximal tubule cells have conserved androgen receptors, they represent attractive cell systems to analyze the action of androgens on specific functions of the mouse proximal tubule.