Drug-sensitive FGFR3 mutations in lung adenocarcinoma.

Background: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. Materials and methods: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models. Results: We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations. Conclusion: We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.

Experimental and theoretical rationalization of the growth mechanism of silicon quantum dots in non-stoichiometric SiN x : role of chlorine in plasma enhanced chemical vapour deposition.

Silicon quantum dots (Si-QDs) embedded in an insulator matrix are important from a technological and application point of view. Thus, being able to synthesize them in situ during the matrix growth process is technologically advantageous. The use of SiH2Cl2 as the silicon precursor in the plasma enhanced chemical vapour deposition (PECVD) process allows us to obtain Si-QDs without post-thermal annealing. Foremost in this work, is a theoretical rationalization of the mechanism responsible for Si-QD generation in a film including an analysis of the energy released by the extraction of HCl and the insertion of silylene species into the terminal surface bonds. From the results obtained using density functional theory (DFT), we propose an explanation of the mechanism responsible for the formation of Si-QDs in non-stoichiometric SiN x starting from chlorinated precursors in a PECVD system. Micrograph images obtained through transmission electron microscopy confirmed the presence of Si-QDs, even in nitrogen-rich (N-rich) samples. The film stoichiometry was controlled by varying the growth parameters, in particular the NH3/SiH2Cl2 ratio and hydrogen dilution. Experimental and theoretical results together show that using a PECVD system, along with chlorinated precursors it is possible to obtain Si-QDs at a low substrate temperature without annealing treatment. The optical property studies carried out in the present work highlight the prospects of these thin films for down shifting and as an antireflection coating in silicon solar cells.

A prospective comparative clinical study of peripheral blood counts and indices in patients with primary brain tumors.

BACKGROUND: Elevation of the neutrophil to lymphocyte ratio (NLR) has been shown to be an indicator of poor prognosis in many malignancies including recurrent glioblastoma multiforme. OBJECTIVES: This study was aimed at assessing if the NLR and other leukocyte counts and indices were deranged in treatment-naïve patients with primary brain tumors when compared with an age-matched healthy control group. MATERIALS AND METHODS: This was a prospective comparative clinical observational study by design. A healthy control population was compared with treatment-naïve patients diagnosed with intra- and extraaxial brain tumors. Leukocyte counts (neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts) as well as leukocyte ratios such as the NLR and the monocyte to lymphocyte ratio (MLR) were calculated. We also evaluated if the counts and indices were related to the tumor volume. RESULTS: In all patients with tumors, the platelet and neutrophil counts were elevated when compared to the controls. In contrast, monocyte counts and the MLR were found to be decreased in patients with tumors when compared to the controls. The subset of patients with glioblastoma showed a significant increase in NLR when compared to the controls. CONCLUSIONS: Significant changes in the neutrophil, monocyte, and platelet counts as well as NLR and MLR were observed. Prospective longitudinal studies are required to determine the prognostic and therapeutic implications of these findings.

Overcoming the effects of false positives and threshold bias in graph theoretical analyses of neuroimaging data.

Graph theory (GT) is a powerful framework for quantifying topological features of neuroimaging-derived functional and structural networks. However, false positive (FP) connections arise frequently and influence the inferred topology of networks. Thresholding is often used to overcome this problem, but an appropriate threshold often relies on a priori assumptions, which will alter inferred network topologies. Four common network metrics (global efficiency, mean clustering coefficient, mean betweenness and smallworldness) were tested using a model tractography dataset. It was found that all four network metrics were significantly affected even by just one FP. Results also show that thresholding effectively dampens the impact of FPs, but at the expense of adding significant bias to network metrics. In a larger number (n=248) of tractography datasets, statistics were computed across random group permutations for a range of thresholds, revealing that statistics for network metrics varied significantly more than for non-network metrics (i.e., number of streamlines and number of edges). Varying degrees of network atrophy were introduced artificially to half the datasets, to test sensitivity to genuine group differences. For some network metrics, this atrophy was detected as significant (p<0.05, determined using permutation testing) only across a limited range of thresholds. We propose a multi-threshold permutation correction (MTPC) method, based on the cluster-enhanced permutation correction approach, to identify sustained significant effects across clusters of thresholds. This approach minimises requirements to determine a single threshold a priori. We demonstrate improved sensitivity of MTPC-corrected metrics to genuine group effects compared to an existing approach and demonstrate the use of MTPC on a previously published network analysis of tractography data derived from a clinical population. In conclusion, we show that there are large biases and instability induced by thresholding, making statistical comparisons of network metrics difficult. However, by testing for effects across multiple thresholds using MTPC, true group differences can be robustly identified.

NGS-based approach to determine the presence of HPV and their sites of integration in human cancer genome.

BACKGROUND: Human papilloma virus (HPV) accounts for the most common cause of all virus-associated human cancers. Here, we describe the first graphic user interface (GUI)-based automated tool 'HPVDetector', for non-computational biologists, exclusively for detection and annotation of the HPV genome based on next-generation sequencing data sets. METHODS: We developed a custom-made reference genome that comprises of human chromosomes along with annotated genome of 143 HPV types as pseudochromosomes. The tool runs on a dual mode as defined by the user: a 'quick mode' to identify presence of HPV types and an 'integration mode' to determine genomic location for the site of integration. The input data can be a paired-end whole-exome, whole-genome or whole-transcriptome data set. The HPVDetector is available in public domain for download: http://www.actrec.gov.in/pi-webpages/AmitDutt/HPVdetector/HPVDetector.html. RESULTS: On the basis of our evaluation of 116 whole-exome, 23 whole-transcriptome and 2 whole-genome data, we were able to identify presence of HPV in 20 exomes and 4 transcriptomes of cervical and head and neck cancer tumour samples. Using the inbuilt annotation module of HPVDetector, we found predominant integration of viral gene E7, a known oncogene, at known 17q21, 3q27, 7q35, Xq28 and novel sites of integration in the human genome. Furthermore, co-infection with high-risk HPVs such as 16 and 31 were found to be mutually exclusive compared with low-risk HPV71. CONCLUSIONS: HPVDetector is a simple yet precise and robust tool for detecting HPV from tumour samples using variety of next-generation sequencing platforms including whole genome, whole exome and transcriptome. Two different modes (quick detection and integration mode) along with a GUI widen the usability of HPVDetector for biologists and clinicians with minimal computational knowledge.

A genetic model for gallbladder carcinogenesis and its dissemination.

Gallbladder cancer, although regarded as the most common malignancy of the biliary tract, continues to be associated with a dismal overall survival even in the present day. While complete surgical removal of the tumour offers a good chance of cure, only a fraction of the patients are amenable to curative surgery owing to their delayed presentation. Moreover, the current contribution of adjuvant therapies towards prolonging survival is marginal, at best. Thus, understanding the biology of the disease will not only enable a better appreciation of the pathways of progression but also facilitate the development of an accurate genetic model for gallbladder carcinogenesis and dissemination. This review provides an updated, evidence-based model of the pathways of carcinogenesis in gallbladder cancer and its dissemination. The model proposed could serve as the scaffolding for elucidation of the molecular mechanisms involved in gallbladder carcinogenesis. A better understanding of the pathways involved in gallbladder tumorigenesis will serve to identify patients at risk for the cancer (and who thus could be offered prophylactic cholecystectomy) as well as aid oncologists in planning the most suitable treatment for a particular patient, thereby setting us on the vanguard of transforming the current treatment paradigm for gallbladder cancer.

Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation.

Although 75% of endometrial cancers are treated at an early stage, 15% to 20% of these recur. We performed an integrated analysis of genome-wide expression and copy-number data for primary endometrial carcinomas with extensive clinical and histopathological data to detect features predictive of recurrent disease. Unsupervised analysis of the expression data distinguished 2 major clusters with strikingly different phenotypes, including significant differences in disease-free survival. To identify possible mechanisms for these differences, we performed a global genomic survey of amplifications, deletions, and loss of heterozygosity, which identified 11 significantly amplified and 13 significantly deleted regions. Amplifications of 3q26.32 harboring the oncogene PIK3CA were associated with poor prognosis and segregated with the aggressive transcriptional cluster. Moreover, samples with PIK3CA amplification carried signatures associated with in vitro activation of PI3 kinase (PI3K), a signature that was shared by aggressive tumors without PIK3CA amplification. Tumors with loss of PTEN expression or PIK3CA overexpression that did not have PIK3CA amplification also shared the PI3K activation signature, high protein expression of the PI3K pathway member STMN1, and an aggressive phenotype in test and validation datasets. However, mutations of PTEN or PIK3CA were not associated with the same expression profile or aggressive phenotype. STMN1 expression had independent prognostic value. The results affirm the utility of systematic characterization of the cancer genome in clinically annotated specimens and suggest the particular importance of the PI3K pathway in patients who have aggressive endometrial cancer.

Significant regional inequalities in the prevalence of intellectual disability and trends from 1990 to 2019: a systematic analysis of GBD 2019.

AIMS: Policymakers and researchers have little evidence on prevalence rates of intellectual disability (ID) or their changes over time to tailor healthcare interventions. Prevalence rates and trends of ID are especially lacking in regions with lower socio-demographic development. Additionally, the assessment of inequalities in the prevalence of ID across regions with varying socio-demographic development is understudied. This study assessed variations in prevalence rates of ID from 1990 to 2019 and the related inequalities between low and high socio-demographic index (SDI) regions. METHODS: This study used global data from 1990 to 2019 for individuals with ID from the 2019 Global Burden of Diseases study. Data analyses were performed from September 2021 to January 2022. Prevalence for individuals with ID was extracted by sex, age groups and SDI regions. Annual percentage change (APC) was estimated for each demographic group within SDI regions to assess their prevalence trends over 30 years. Relative and absolute inequalities were calculated between low and high SDI regions for the various age groups. RESULTS: In 2019, there were 107.62 million (1.74%) individuals with ID, with an APC of -0.80 (-0.88 to -0.72). There was a slightly higher prevalence among males (1.42%) than females (1.37%). The highest prevalence rates were found in the low-middle SDI regions (2.42%) and the lowest prevalence rates were in the high SDI regions (0.33%). There was a large reduction in the prevalence rate between the youngest age group v. the oldest age group in all the SDI regions and at all time points. The relative inequalities between low and high SDI regions increased over three decades. CONCLUSIONS: While an overall decrease in global prevalence rate for ID was found, relative inequalities continue to increase with lower SDI regions needing more comprehensive support services. The demographic trends indicate a significantly higher mortality rate among those with ID v. the rest of the population. Our study highlights the necessity for policies and interventions targeting lower SDI regions to mobilise resources that better support individuals with ID and achieve sustainable development goals proposed by the United Nations.

Do COMT, BDNF and NRG1 polymorphisms influence P50 sensory gating in psychosis?

BACKGROUND: Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. METHOD: The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. RESULTS: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. CONCLUSIONS: The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle.

The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis.

BACKGROUND: Morphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis. METHOD: A total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family. RESULTS: The results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes. CONCLUSIONS: Abnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present.

Cognitive dysfunction in an urban Indian population--some observations.

There is no prospective study of mild cognitive impairment (MCI) in India. This study aims to determine the prevalence rate of dementia and to prospectively analyze a group of patients with MCI. A door-to-door cross-sectional cluster survey was conducted in Kolkata, India, among those aged >50 years to estimate the prevalence rate of dementia. Then annual assessment of cognitive function using a validated questionnaire battery was undertaken among 21 elderly individuals with memory complaints for 4 consecutive years. A total of 53,907 persons were surveyed. The crude prevalence rates of dementia were 0.62% (95% CI 0.44-0.84) and 1.25% (95% CI 0.87-1.74) among those >50 and >60 years of age, respectively. The weighted prevalence rate among those above 50 years was 0.95% (95% CI 0.68-1.29). Alzheimer's disease was the commonest subtype (55%) followed by vascular dementia (36%). In a prospective study, MCI remained static, converted to dementia or reverted to normalcy. There was also transition from one subtype of MCI to another. A similar outcome of MCI is also noted in Western nations. However, the prevalence rate of dementia in Eastern India remained quite low.

Probing pairing symmetry in multi-band superconductors by quasiparticle interference.

We study momentum and energy dependencies of the quasiparticle interference (QPI) response function in multiband superconductors in the framework of the strong-coupling Eliashberg approach. Within an effective two-band model we study the s± and s++ symmetry cases, corresponding to opposite or equal signs of the order parameters in the bands. We demonstrate that the momentum dependence of the QPI function is strikingly different for s± and s++ symmetries of the order parameter at energies close to the small gap. At the same time, the QPI response becomes indistinguishable for both symmetries at higher energies around the large gap. This result may guide future experiments on probing pairing symmetry in iron pnictides as well as in other unconventional superconductors.

Regulation of N-linked glycoprotein assembly in uteri by steroid hormones.

The effects of the steroid hormones 17 beta-estradiol (E2) and progesterone on N-linked glycoprotein assembly in ovariectomized mice have been examined. Both priming and nidatory E2 markedly stimulate [3H]mannose incorporation (3- to 6-fold) into uterine glycoproteins, whereas uterine bulk protein synthesis is not stimulated under the same conditions. Progesterone alone stimulates glycoprotein synthesis modestly (1.5-fold) over that in oil-injected controls, but antagonizes the action of E2 when coinjected with the estrogen. The E2 effect is not systemic, because livers from these same animals do not display an increase in glycoprotein synthesis. When mice were injected with tamoxifen or clomiphene, two drugs that mimic E2 actions in uteri without inducing the full extent of cell proliferation that normally accompanies E2 treatment, a similar enhancement of uterine glycoprotein synthesis was observed. Although mannosylphosphoryldolichol synthase activity rose in parallel with glycoprotein synthesis during E2 priming, the apparent activities of two other enzymes involved in the assembly of N-linked glycoproteins, namely chitobiosylpyrophosphoryldolichol synthase and oligosaccharyltransferase, remained relatively unchanged. Furthermore, the apparent in vivo rate of dolichol phosphorylation was not altered during E2 priming. Supplementation of uterine tissue slices with dolichylphosphate failed to enhance the rate of protein glycosylation in vivo. In addition, changes in the pool sizes of GDP-mannose did not correlate with changes in the in vivo rate of glycoprotein synthesis. Collectively, these observations indicate that the E2-dependent increase in glycoprotein synthesis is not likely to be due to increased enzyme activities for oligosaccharide assembly or transfer to protein, increased dolichylphosphate availability, or increased sugar nucleotide availability. To study the effects of E2 on the production of specific glycoproteins, the pattern of [3H]mannose-labeled glycoproteins produced as a function of days of E2 priming was examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Estrogen priming induced the secretion of 9-11 [3H]mannose-labeled glycoproteins by uteri; however, the pattern of tissue-associated glycoproteins remained constant throughout this interval. It appears, therefore, that estrogen priming induces the secretion of a few specific glycoproteins while generally enhancing the production of most tissue-associated glycoproteins. Most (70%) of the [3H]mannose-labeled oligosaccharide chains of these glycoproteins were of the polymannose type.(ABSTRACT TRUNCATED AT 400 WORDS)

Theophylline kinetics in chronic obstructive airway disease in the elderly.

Theophylline kinetic studies, serial spirometric function tests, and arterial blood gas determinations were performed in 39 adult men with stable chronic obstructive airway disease (COPD). Subjects were given an intravenous aminophylline loading dose of 5.6 mg/kg and a maintenance dose of 0.9 mg/kg/hr for 6 hours. Elderly (greater than 60 years old) nonsmoking subjects had 36% lower theophylline clearance (Cl) and a 40% longer serum theophylline elimination t1/2 than did middle-aged (less than 60 years old) nonsmoking subjects (mean +/- SE; clearances of 32.6 +/- 3.2 [n = 13] and 50.7 +/- 8.5 ml/kg/hr [n = 8] and t1/2s of 11.0 +/- 0.8 and 7.4 +/- 0.8 hours, respectively). There were also differences in Cl and t1/2 between elderly and middle-aged subjects in both the smoking and nonsmoking groups: elderly group, Cl = 43.6 +/- 3.7 mg/kg/hr and t1/2 = 9.0 +/- 0.7 hours; middle-aged group, Cl = 57.6 +/- 6.0 mg/kg/hr and t1/2 = 6.7 +/- 0.6 hours). There was consistent improvement in spirometric functions in both nonsmoking and smoking elderly subjects: percent changes in forced expiratory volume in 1 second of 19% to 25%; in forced vital capacity of 25% to 31%; in forced expiratory flow at 25% to 75% of vital capacity of 59% to 67%; and in maximum mid-flow time of -25% to -30%, at serum theophylline concentrations of 10 to 13 mg/L (group mean). We conclude that elderly nonsmoking subjects with COPD cleared theophylline more slowly than did middle-aged, nonsmoking subjects with COPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-course chemotherapy for tuberculosis with mainly twice-weekly isoniazid and rifampin. Community physicians' seven-year experience with mainly outpatients.

The general medical community in the United States has been rather slow in adopting short-course bactericidal chemotherapy for tuberculosis despite the clear demonstration of the advantage by several carefully controlled clinical trials. Reported herein is experience between January 1976 and December 1982 in 1,028 patients with bacteriologically proved pulmonary tuberculosis treated for nine months with isoniazid (300 mg) and rifampin (600 mg) daily for one month followed by twice-weekly isoniazid (900 mg) and rifampin (600 mg) for the other eight months. They were treated by 45 local practitioners and supervised by public health nurses through 60 Arkansas Department of Health chest clinics in the state. Outpatient therapy was mostly self-administered in the routine treatment program. Overall success was achieved in 95 percent of the 751 patients who completed therapy; in 21 (2.8 percent), sputum cultures failed to convert to negative, and 15 (2.1 percent) have had relapse since therapy was stopped. Therapy could not be completed in 26.9 percent due to deaths, drug toxicities, relocation, refusal, etc. Of 21 bacteriologic failures, 18 patients developed isoniazid resistance and were treated with additional two bactericidal drugs. Most of the relapses (nine of 15) occurred within 12 months after chemotherapy was stopped. However, four relapses occurred quite late during follow-up. Only three of 15 patients with relapse showed isoniazid resistance. Side effects of the drugs were encountered in 10.3 percent, but major toxicities occurred in 3.2 percent (hepatitis in 2.6 percent, hematologic effects in 0.6 percent). Clinical surveillance for toxicity is preferred over routine and regular biochemical monitoring. Patient acceptance of the regimen was excellent, and compliance was good. Short-course chemotherapy is effective, with low drug toxicity, reduced cost of drugs, and ease of direct supervision when needed, and is acceptable to patients in routine treatment.

Short-course chemotherapy for tuberculosis in children.

Short-course, largely twice-weekly chemotherapy for tuberculosis was introduced in the United States for treatment of adults with pulmonary disease by the Arkansas State Department of Health in 1976. Since 1977, 50 children with tuberculosis have been treated with rifampin, 10 to 20 mg/kg, and isoniazid, 10 to 20 mg/kg daily for one month followed by 10 to 20 mg/kg of rifampin and 20 to 40 mg/kg of isoniazid twice a week for another 8 months. Ages ranged from 4 months to 15 years with a median age of 3 years. A presumptive diagnosis of tuberculosis was made on the basis of 10 mm or more of induration to 5 TU of purified protein derivative and a chest film or other findings compatible with tuberculosis. Three children had extrapulmonary disease (two had cervical adenitis, one had tuberculosis arthritis). Of the 47 children with pulmonary disease, 32 were asymptomatic. The results were excellent. Symptoms cleared in 1 to 2 months. Most pulmonary infiltrates had cleared by 10 months, but hilar adenopathy rarely cleared in less than 2 years. Drug toxicity occurred in only one patient (vomiting of rifampin). This treatment appears to be safe, effective, inexpensive, short and simple enough to ensure cooperation or to allow personnel to administer drugs directly to children from socially disorganized families.

Age-related release of prolactin by the pituitary and the pituitary-hypothalamic complex in vitro: an attempt to describe the development of the hypothalamic prolactin-inhibiting and -releasing activities in male rats.

We have recently demonstrated that the pituitary hypothalamic complex (PHC) is a good model for studying interactions between the hypothalamus and pituitary in vitro. The amount of prolactin secreted by the PHC is an index of prolactin secreted by the pituitary in the presence of hypothalamic control, while the amount released by the whole pituitary alone is an index of prolactin secreted in the absence of hypothalamic control. The amount of prolactin secreted by the PHC has been regarded as an index of hypothalamic prolactin-releasing activity (HPRA), while the difference in the amounts of prolactin secreted by the whole pituitary and the PHC is the hypothalamic prolactin-inhibiting activity (HPIA). Attempts were made to correlate HPRA and HPIA to the development of serum concentrations of prolactin from days 7 to 77 in male rats. The HPRA increased steadily from days 7 to 56, decreased significantly on day 63 and thereafter remained unchanged until day 77. The HPIA was low on days 7 and 14 and increased steadily up to day 49, with no further significant variations. The developmental patterns of HPRA and HPIA were comparable up to day 49. Serum concentrations of prolactin increased significantly until day 28 and remained fairly constant until day 49. The weight of the pituitary gland increased from 1.0 +/- 0.03 mg (mean +/- S.E.M.) on day 7 to 7.76 +/- 0.32 mg on day 63 and remained unchanged thereafter. The weight of the hypothalamic islet was 31.5 +/- 2.88 mg on day 7, 34.83 +/- 1.45 mg on day 14 and 50.4 +/- 4.01 mg on day 21. After day 21 the weights of the hypothalamic islets were not significantly altered, except on day 49. It was concluded that serum concentrations of prolactin are regulated by interaction or competition between HPRA and HPIA at the level of the pituitary.

Ontogeny of serum and pituitary gonadotrophins in male rats treated with low doses of 5 alpha-dihydrotestosterone.

The effect of s.c. daily injections of 10 or 1000 ng 5 alpha-dihydrotestosterone (DHT)100 g body weight from birth to day 21, or from days 26 to 117 of age, on the changes in concentration of serum and pituitary gonadotrophins was investigated in male rats. Treatment with 10 ng DHT from days 1 to 21 depressed serum FSH, but not LH, at day 7, while 1000 ng DHT depressed both serum LH and FSH. Treatment with both doses of DHT reduced pituitary levels of LH and FSH at day 7, with FSH being more depressed than LH. Treatment with 10 ng DHT from days 26 to 117 increased serum FSH from days 82 to 117, while 1000 ng DHT did not have this effect. Treatment with 1000 ng, but not 10 ng, DHT between days 26 and 117 reduced pituitary levels of LH and FSH at day 40. Rats treated with the two doses of DHT from days 26 to 117 showed a difference in the responsiveness of the pituitary to LH-releasing hormone (LHRH). Treatment with 10 ng DHT enhanced LHRH-induced release of LH without affecting FSH release, while 1000 ng DHT depressed LHRH-induced release of FSH but not of LH. These findings support the view that DHT may play a modulatory role in the ontogeny of serum gonadotrophins and the responsiveness of the pituitary to LHRH during the onset of puberty in the male rat.