SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. PATIENTS AND METHODS: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. RESULTS: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. CONCLUSIONS: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.

Eosinophilic granulomatosis with polyangiitis: sequential use of mepolizumab following rituximab for inadequate asthma control despite vasculitis remission.

We report the case of a 54-year-old woman with antineutrophilic cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis presenting with mononeuritis multiplex, intestinal hemorrhage, cardiomyopathy, fever, and worsening asthma symptoms. She was initially treated with steroids and cyclophosphamide but eventually required rituximab to control a vasculitis flare. However, her asthmatic symptoms did not improve, despite attaining vasculitis remission. Symptoms abated only after the treatment transition to mepolizumab. After a 1-year interval, there were no further episodes of asthma exacerbation and no requirement for systemic steroid therapy. This report reinforces the use of rituximab for induction and maintenance of remission in patients with eosinophilic granulomatosis with polyangiitis and predominant vasculitic manifestations, whereas mepolizumab demonstrated better control of the persistent eosinophilic manifestations, ensuing sustained remission and improved quality of life.

Spatial clustering, social vulnerability and risk of leprosy in an endemic area in Northeast Brazil: an ecological study.

BACKGROUND: Despite the global decline in the detection of leprosy cases, its incidence has remained unchanged in certain settings and requires the determination of the factors linked to its persistence. We examined the spatial and space-time distribution of leprosy and the influence of social vulnerability on the occurrence of the disease in an endemic area of Northeast Brazil. METHODS: We performed an ecological study of all leprosy cases reported by Sergipe state, Northeast Brazil from 2001 to 2015, to examine the association of the Social Vulnerability Index and the prevalence and persistence of leprosy among the State's municipalities. Socio-economic and leprosy surveillance information was collected from the Brazilian information systems, and a Bayesian empirical local model was used to identify fluctuations of the indicators. Spatial and space-time clusters were identified using scan spatial statistic tests and to measure the municipalities' relative risk of leprosy. RESULTS: Leprosy clusters and burden of disease had a strong statistical association with the municipalities' Social Vulnerability Index. Municipalities with a high social vulnerability had higher leprosy incidence, multibacillary leprosy and newly diagnosed cases with grade 2 disability than areas with low social vulnerability. CONCLUSION: Social vulnerability is strongly associated with leprosy transmission and maintenance of disease incidence. Leprosy control programmes should be targeted to the populations with high social vulnerability.

CFTR biomarkers: time for promotion to surrogate end-point.

In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

Inhaled phosphodiesterase type 5 inhibitors restore chloride transport in cystic fibrosis mice.

Sildenafil and vardenafil, two selective inhibitors of phosphodiesterase type 5 (PDE5) are able, when applied by intraperitoneal injection, to activate chloride transport in cystic fibrosis (CF) mice homozygous for the F508del mutation. Oral treatment with the drugs may be associated with adverse haemodynamic effects. We hypothesised that inhaled PDE5 inhibitors are able to restore ion transport in F508del CF airway epithelium. We developed a restraint-free mouse chamber for inhalation studies. PDE5 inhibitors were nebulised for 15 min at concentrations adjusted from recommended therapeutic oral doses for male erectile dysfunction. We measured in vivo nasal transepithelial potential difference 1 h after a single inhalation of sildenafil, vardenafil or tadalafil in F508del CF and normal homozygous mice. After nebulisation with the drugs in F508del mice, chloride transport, evaluated by perfusing the nasal mucosa with chloride-free buffer containing amiloride followed by forskolin, was normalised; the forskolin response was increased, with the largest values being observed with tadalafil and intermediate values with vardenafil. No detectable effect was observed on sodium conductance. Our results confirm the role of PDE5 inhibitors in restoring chloride transport function of F508del CF transmembrane conductance regulator protein and highlight the potential of inhaled sildenafil, vardenafil and tadalafil as a therapy for CF.

Physiologic and behavioural signs during a dental appointment in children and teenagers with Cerebral Palsy: a comparative cross-sectional study.

AIM: To evaluate the heart rate (HR) and behaviour of children and teenagers with Cerebral Palsy (CP) when having a dental appointment. METHODS: A comparative cross-sectional study was carried out with 60 participants with CP, between 2 and 14 years old (study group-SG), and 60 normotypical individuals (CG). The sample was paired according to age, gender and socioeconomic status. Behaviour was evaluated during dental prophylaxis using the Frankl Scale, and HR was measured at five moments: before the appointment, when sitting in the dental chair, during the clinical examination, during prophylaxis and immediately after prophylaxis. Mann-Whitney, Friedman and Chi-square tests were applied at a significance level of 5%. RESULTS: SG presented significantly higher HR (p < 0.001) and more participants with uncooperative behaviour (p < 0.001) than CG in all observational periods. Furthermore, SG participants with uncooperative behaviour presented higher HR values than those in SG who were cooperative in all observational periods (p ≤ 0.002). CONCLUSIONS: Individuals with CP have a higher HR before and during the clinical session, and are frequently more uncooperative with the procedure than normotypical individuals.

Plasma lipoproteins in visceral leishmaniasis and their effect on Leishmania-infected macrophages.

This work aimed at investigating the lipid profile of zoonotic visceral leishmaniasis (VL) patients' sera and the effect of lipoproteins on the in vitro production of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-10 and IL-12 by Leishmania infantum-infected and uninfected macrophages. Lipids were quantified in 26 VL patients' sera and 26 healthy controls from a VL endemic area. The patients' sera had higher triglyceride and very low density lipoprotein (VLDL) levels, and much lower apolipoprotein A1, total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) levels than the control sera. Lipoprotein fractions were obtained by ultracentrifugation of sera. The addition of LDL and HDL to Leishmania-infected and uninfected macrophages, in physiological concentrations, enhanced the production of IL-6 and IL-10, but not of IL-12. LDL stimulated the production of TNF-alpha only in infected macrophages, whereas HDL stimulated the production of lower amounts of TNF-alpha in both infected and uninfected macrophages. VLDL stimulated only the production of IL-10. It is proposed herein that LDL may influence the development of VL by promoting the production of TNF-alpha by infected macrophages. A decrease in plasma LDL in some VL patients (to 20 mg/mL or less); however, would tend to reduce the production of TNF-alpha and therefore to limit the development of immune-mediated pathology, not withstanding the fact that it would perhaps increase the permissiveness of macrophages to Leishmania growth.

The Iberian legacy into a young genetic xeroderma pigmentosum cluster in central Brazil.

In central Brazil, in the municipality of Faina (state of Goiás), the small and isolated village of Araras comprises a genetic cluster of xeroderma pigmentosum (XP) patients. The high level of consanguinity and the geographical isolation gave rise to a high frequency of XP patients. Recently, two founder events were identified affecting that community, with two independent mutations at the POLH gene, c.764 + 1 G > A (intron 6) and c.907 C > T; p.Arg303* (exon 8). These deleterious mutations lead to the xeroderma pigmentosum variant syndrome (XP-V). Previous reports identified both mutations in other countries: the intron 6 mutation in six patients (four families) from Northern Spain (Basque Country and Cantabria) and the exon 8 mutation in two patients from different families in Europe, one of them from Kosovo. In order to investigate the ancestry of the XP patients and the age for these mutations at Araras, we generated genotyping information for 22 XP-V patients from Brazil (16), Spain (6) and Kosovo (1). The local genomic ancestry and the shared haplotype segments among the patients showed that the intron 6 mutation at Araras is associated with an Iberian genetic legacy. All patients from Goiás, homozygotes for intron 6 mutation, share with the Spanish patients identical-by-descent (IBD) genomic segments comprising the mutation. The entrance date for the Iberian haplotype at the village was calculated to be approximately 200 years old. This result is in agreement with the historical arrival of Iberian individuals at the Goiás state (BR). Patients from Goiás and the three families from Spain share 1.8 cM (family 14), 1.7 cM (family 15), and a more significant segment of 4.7 cM within family 13. On the other hand, the patients carrying the exon 8 mutation do not share any specific genetic segment, indicating an old genetic distance between them or even no common ancestry.

Early referral to cystic fibrosis specialist centre impacts on respiratory outcome.

BACKGROUND: Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered. METHODS: In this retrospective multicentric study, data from all CF children fulfilling the following criteria were collected: 1) Age 6-<18 at the end of 2003; 2) diagnosis before 8 y; 3) follow-up in an accredited CF Belgian centre; 4) at least 1 spirometry and respiratory culture available for 2003. Group A included children referred > or =2 years after the diagnosis. Patients from Group A were then matched with a single early referred patient on the basis of 2 criteria: same centre, as closest age as possible (Group B). RESULTS: Data from 217 children were collected (Group A: 67/217). Late referred patients had a lower FEV(1) (77.2%+/-22.4 vs 86.7% pred.+/-19.4, p=0.01) and a higher prevalence of Pseudomonas aeruginosa (38.6 vs 17.5%, p<0.05). CONCLUSION: In this population of CF children, a delay of 6.1 y (vs 0.1 y) between diagnosis and referral to a specialist clinic resulted in poorer respiratory outcome at age 13.

Injuries to the Stomatognathic System in Brazilian Jiu-Jitsu Athletes.

As a contact sport, Brazilian jiu-jitsu requires the fighter to expose his/her stomatognathic system to the adversary, making him/her more susceptible to oral and maxillofacial injuries and disorders. The aim of the present study was to determine the prevalence of injuries and disorders of the stomatognathic system and associated factors among practitioners of Brazilian jiu-jitsu. A total of 179 athletes were interviewed and submitted to a physical examination. The majority was male, in the beginner category and had participated in competitions. Athletes with more experience had a higher frequency of orofacial injuries (PR = 1.77; 95% CI: 1.01-1.38), such as oral mucous lacerations and skin abrasions in the facial region, which mainly occurred during training sessions. A mouthguard is not mandatory for the sport and many athletes (both beginners and more experienced athletes) do not use one due to difficulty breathing with the device. A prefabricated (type II) mouthguard was the most common among the athletes who used this equipment, although it does not offer adequate protection. Athletes on more advanced levels wore mouthguards significantly more often (PR = 1.96; 95% CI: 1.11-2.45). In conclusion, more experienced jiu-jitsu athletes had a higher frequency of orofacial injuries, such as lacerations and abrasions, and are more likely to wear a mouthguard. However, longitudinal studies are needed in order to assess the possible causes and risks.

A specific database for providing local and national level of integration of clinical data in cystic fibrosis.

It has recently been stated that a database is an essential tool in the management of CF. The purpose of this work is to create a specific database allowing optimal performance of storage, search and retrieval functions on patients with CF. A specific database was developed using a Windev licence, for application via Microsoft supported platforms or Intranet system. The database allows real-time point of care data management of medical, investigational and administrative data. It is currently being used in the 6 Belgian reference centres. It represents a useful tool for gathering information on routine clinical and lab data, bacteriology, treatments, complications and specific outcomes for clinical and research purposes. The ongoing evolution of the database includes enhancements toward research data orientation including comparison of patient data between different centres and completeness of the National CF registry questionnaire. A complimentary copy of the software can be provided to multidisciplinary accredited CF centres worldwide upon request.

[Cystic fibrosis and pseudomonas aeruginosa current and future strategies]. / Mucoviscidose et Pseudomonas aeruginosa: stratégies actuelles et à venir.

Cystic fibrosis and Pseudomonas aeruginosa current and future strategies Pseudomonas aeruginosa is long recognized as the main pathogen in cystic fibrosis and avoiding or postponing chronic colonization of the lungs by this germ is considered as the most important challenge for the clinicians dedicated to the care of CF patient. The need for early intervention is widely accepted but its optimal modalities are still debated and the failure rate of this approach is estimated around 20%. This underlines the potential of other strategies including attempts to develop an effective vaccine against PA and anti-PA prophylaxis. Surprisingly enough, the latter approach which could involve early use of inhaled antibiotics has never been studied prospectively. In chronically colonized patients, inhaled antibiotics and oral azythromycin are of value, slowing the FEV1 decline and reducing the number of exacerbations. Whether intravenous antibiotics are to be used electively (during exacerbations) or more systematically (every 3 months for example) remains controversial.

Biological variability of the sweat chloride in diagnostic sweat tests: A retrospective analysis.

BACKGROUND: The sweat test is the current gold standard for the diagnosis of cystic fibrosis (CF). CF is unlikely when sweat chloride (Clsw) is lower than 30mmol/L, Clsw>60 is suggestive of CF, with intermediate values between 30 and 60mmol/L. To correctly interpret a sweat chloride value, the biological variability of the sweat chloride has to be known. METHODS: Sweat tests performed in two centers using the classic Gibson and Cooke method were retrospectively reviewed (n=5904). Within test variability of Clsw was measured by comparing results from right and left arm collected on the same day. Between test variability was calculated from subjects with sweat tests performed on more than one occasion. RESULTS: Within test variability of Clsw calculated in 1022 subjects was low with differences between -3.2 (p5) and +3.6mmol/L (p95). Results from left and right arm were classified differently in only 3 subjects. Between test variability of Clsw in 197 subjects was larger, with differences between -18.2mmol/L (p5) and +14.1mmol/L (p95) between repeat tests. Changes in diagnostic conclusion were seen in 55/197 subjects, the most frequent being changing from indeterminate to 'CF unlikely' range (48/102). CONCLUSION: Variability of sweat chloride is substantial, with frequent changes in diagnostic conclusion, especially in the intermediate range.

Comparison of lung deposition of amikacin by intrapulmonary percussive ventilation and jet nebulization by urinary monitoring.

The intrapulmonary percussive ventilation (IPV), frequently coupled with a nebulizer, is increasingly used as a physiotherapy technique; however, its physiologic and clinical values have been poorly studied. The aim of this study was to compare lung deposition of amikacin by the nebulizer of the IPV device (Percussionaire; Percussionaire Corporation; Sandpoint, ID) and that of standard jet nebulization (SST; SideStream; Medic-Aid; West Sussex, UK). Amikacin was nebulized with both devices in a group of five healthy subjects during spontaneous breathing. The deposition of amikacin was measured by urinary monitoring. Drug output of both devices was measured. Respiratory frequency (RF) was significantly lower when comparing the IPV device with SST (8.2 +/- 1.6 breaths/min vs. 12.6 +/- 2.5 breaths/min, p < 0.05). The total daily amount of amikacin excreted in the urine was significantly lower with IPV than with SST (0.8% initial dose vs. 5.6% initial dose, p < 0.001). Elimination halflife was identical with both devices. Drug output was lower with IPV than with SST. The amount of amikacin delivered to the lung is sixfold lower with IPV than with SST, although a lower respiratory frequency was adopted by the subjects with the IPV. Therefore, the IPV seems unfavorable for the nebulization of antibiotics.

Successful protocol of anaesthesia for measuring transepithelial nasal potential difference in spontaneously breathing mice.

Numerous difficulties arise during in vivo measurements of transepithelial nasal potential difference (PD) in mice, such as inadequate duration and depth of anaesthesia, bronchoaspiration of solutions perfused in the nose, and respiratory and/or cardiovascular depression. Anaesthesia was induced in adult C57 mice with intraperitoneal injection of a combination of fentanyl, droperidol and medetomidine, each of these at either a small dose (0.20, 10 and 0.33 mg/kg, respectively) or at a large dose (0.40, 20 and 0.40 mg/kg, respectively), combined with a fixed dose of 0.375 microg clonidine. In order to establish a pharmacokinetic-pharmacodynamic relationship, blood concentrations of the first three drugs were measured in 24 animals by liquid-chromatography tandem mass spectrometry. At the end of the experiment, naloxone, a competitive morphinic antagonist, and atipamezole, an alpha-2 adrenergic antagonist, were administered. Bronchoaspiration was prevented by tilting the animal head downwards and by absorbing the excess fluid from the opposite nostril and from the oral cavity. Optimal assessment of anaesthesia associated with regular respiration, loss of blink, pupillary and pedal withdrawal reflexes was obtained with doses of fentanyl, droperidol and medetomidine corresponding to 0.20, 20 and 0.40 mg/kg, respectively. Blood concentrations of fentanyl around 17 ng/mL induced loss of respiratory efforts and were followed by death during the experiment. Integrity of ion transport was demonstrated under continuous perfusion by successive depolarization after amiloride and repolarization after chloride-free solution. The combination investigated in this study lead to adequate surgical anaesthesia (stage III, plane 2) for prolonged nasal PD measurements in spontaneously breathing mice.

In vitro evaluation of efficacy of 5 methods of disinfection on mouthpieces and facemasks contaminated by strains of cystic fibrosis patients.

INTRODUCTION: Home-nebulizers are a potential source of bacterial infection of the respiratory tract in patients suffering from cystic fibrosis. Recommendations for disinfecting this equipment are often arbitrary and sometimes contradictory. OBJECTIVE: To assess in vitro the effectiveness of 5 methods of disinfecting this equipment. METHODS: 160 mouthpieces and 160 masks of nebulizers were artificially and massively contaminated with 16 strains of germs found in patients with cystic fibrosis (Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cenocepacia, Alcaligenes xylosoxydans). A controlled comparison was carried out of the five methods of disinfection (hypochlorite solution (0.02% active chlorine), acetic acid 3.5%, Hexanios 0.5%, washing-up detergent 0.5% and a dishwasher), tested with and without drying. Standardised bacteriological sampling took place 4 h after disinfecting. RESULTS: Following treatment, the disappearance of the germ was recorded in 84.1% of cases, and effective disinfecting (reduction>5 log CFU/mL) in another 10.6%. Disinfection failure (5.3%) was found almost only in the case of acetic acid against Staphylococcus aureus. CONCLUSION: With the exception of acetic acid, the methods of disinfecting tested in this study appeared to be effective against common bacterial pathogens in cystic fibrosis.

Key pharmacokinetic parameters of isepamicin in febrile neutropenic cancer patients and in women with acute pelvic inflammatory disease.

The pharmacokinetics (PK) of isepamicin were studied in 8 febrile neutropenic patients with hematologic malignancy and in 20 young women with acute pelvic inflammatory disease (PID). Isepamicin was given as a slow intravenous infusion over 30 min at a dose of 15 mg/kg once daily (OD). Serum levels of isepamicin were determined by fluorescence polarization immunoassay, and PK analyses were obtained based on a one-compartment open model after 24 hours (steady state) and after 7 days. On day 1, the volume of distribution (Vd) of isepamicin, for both populations, appeared about 30% higher than classically reported in healthy individuals: 0.31 and 0.36 L/kg for neutropenic and PID patients respectively. However on day 7, Vd displayed significant reduction (0.28 and 0.27 L/kg, respectively for neutropenic and PID patients). A reduction of isepamicin clearance was also observed between day 1 and day 7 (137 vs 120 mL/min and 130 vs 101 mL/min for neutropenic and PID populations, respectively). Such changes are consistent with a significant increase in the Cmax concentrations (45 vs 50 mg/L, and 38 vs 49 mg/L) and in the AUC (136 vs 158 and 137 vs 162 mg/L.h) observed after a week of treatment in neutropenic and PID patients, respectively. In conclusion, taking into account the importance of reaching early active concentrations, we recommend the use of higher loading dose of isepamicin (>15 mg/kg) in neutropenic cancer patients and in women with PID, particularly in case of a combination with a possibly ineffective antibacterial agent, in case of infection with bacteria at upper limit of susceptibility, in the presence of high infectious inoculum or in the presence of sequestered sites of infection.

Damage of tracer erythropoietin results in erroneous estimation of concentration in mouse submaxillary gland.

It has been previously reported that 1) plasma erythropoietin (Epo) titer during exposure to hypobaria is lower in nephrectomized rats and mice whose submaxillary glands (SMG) were either ablated or atrophied than in nephrectomized controls whose SMG were intact and 2) that the gland shows one of the highest levels of immunoreactive Epo (iEpo) in the body. The latter observation, however, was questioned recently when it was observed that SMG extracts degrade labeled Epo used as tracer antigen in the radioimmunoassay (RIA), thus giving invalid estimates of Epo. Since this interpretation was in turn questioned, the present study was conducted to obtain more information on the subject and make these conflicting points clear. Investigation of the reported/possible degradation of Epo by SMG homogenates was conducted via polyacrylamide gel electrophoresis followed by radioautography or by a RIA in solid phase in which there was no simultaneous incubation of the tracer antigen with the SMG homogenates. It was observed that 125I-labeled rhEpo was degraded when incubated with SMG homogenates. Degradation was rapid, being evident when incubation lasted 30 minutes, and occurred in the presence of a protease inhibitor. It showed a high degree of specificity since it did not occur when Epo was incubated with kidney homogenate or normal mouse serum. SMG homogenate did not degrade labeled thyrotrophic hormone and degraded alpha interferon (IFN-alpha) only partially. When estimates of iEpo in SMG homogenate were performed in conditions of simultaneous (SI-RIA) or nonsimultaneous (NSI-RIA) incubation of the homogenate with tracer Epo, it was observed that while estimates of Epo in plasma were similar in both types of RIA and somewhat higher in kidney homogenate in the SI-RIA than in the NSI-RIA, estimates of Epo in SMG were about 60 times higher in the former than in the latter. Therefore, it could be concluded that most of the Epo detected by standard RIA in SMG homogenate does not represent true Epo because of damage of tracer Epo which determines loss of the integrity of the RIA system.

The concentration of dietary casein required for normal mandibular growth in the rat.

To determine a suitable casein concentration for normal, undeformed mandibular growth, we placed weanling male rats on diets containing graded levels of casein between 0% and 30% for 19 days. Some weanlings were killed so that initial values could be established. Ten linear dimensions corresponding to the six skeletal units of the mandible were evaluated so that their growth rates at the end of the experimental period could be established. Other dimensions were also evaluated for study of the growth rate of the bone as a whole. The macroscopic growth of the mandible showed a sigmoidal relationship with dietary casein concentration, most of the measurements reaching a plateau at 20% casein. Within the skeletal units, four dimensions corresponding to the alveolar and symphyseal regions did not change with age and were not affected by the casein content of the diet. The remaining six dimensions-corresponding to condylar, coronoid, angular, and basal regions of the mandible-increased with age and were related positively to dietary casein concentration. Their growth patterns were not uniform, although all of them reached maximal values when the diet contained 20% casein. Therefore, deformation of the mandible appears to occur in rats fed diets with a casein concentration lower than 20%. It appears that a dietary casein concentration of 20% is required for normal, undeformed mandibular growth.