BACKGROUND AND OBJECTIVES: The rare single gene mutations resulting in early onset extreme obesity and hyperphagia have led to the discovery of the central leptin-dependent melanocortin signaling regulating energy homeostasis, food intake and body weight. Energy imbalance is known to influence other physiological mechanisms such as neuroendocrine, reproductive, metabolic and immune functions. Excessive obesity has also been shown to impact bone formation and mineralization as evidenced mainly through imaging techniques. However, the effects of obesity on bone metabolism have remained controversial and often conflicting in various reports presumably due to the heterogeneity of the disease and differences in age, sex and ethnicity of subjects under investigation. Monogenic obesity provides an exceptionally unique paradigm to study the physiological phenotype in relation to specific energy-impaired states in the human. In view of the foregoing, the present study aims to first identify cases of monogenic obesity by screening, a group of children with early onset severe obesity from consanguineous families and subsequently to assess bone metabolism in affected individuals using specific bone turnover biomarkers. In addition, associated changes in metabolic hormone levels are recorded. MATERIALS AND METHODS: Initially, 130 unrelated severely obese children from consanguineous families were recruited from the central Punjab province of Pakistan. The subjects, 0.3-13 years of age, had a body weight percentile >97 and a BMI SDS for age ≥3.0. Anthropometric data and information about family and medical history were recorded. In the first phase of investigation, DNA of all subjects was screened for leptin (LEP) and melanocortin-4 receptor (MC4R) genes mutations, in the coding regions. Subjects found negative for these mutations were subsequently screened by microdroplet PCR targeted against a panel of 27 known obesity associated genes and next generation sequencing. Serum from subjects identified with monogenic obesity and from a control group of 26 age-matched children with normal body weight, was analyzed for bone specific turnover biomarkers, osteocalcin (OC), osteopontin (OPN), osteoprotegerin (OPG) and sclerostin (SOST) using multiplex analyte profiling. In addition, serum levels of leptin, insulin and cortisol were assessed by enzyme linked immunosorbent assay (ELISA). Thyroid stimulating hormone (TSH) and thyroid hormones (T3 and T4) were determined by electro-chemiluminescence immunoassay (ECLIA). RESULTS: The two-step genetic analysis of 130 children with morbid obesity, identified 42 probands with lossof- function homozygous mutations in LEP, leptin receptor (LEPR), or MC4R genes. Amongst these, 23 probands were identified with mutations in LEP, 11 with mutations in LEPR and 8 children with mutations in the MC4R gene. Eleven of the 18 variants identified in the 3 genes associated with obesity, are reported here for the first time. Bone metabolism in affected subjects, was assessed by specific serum bone turnover markers. Serum levels of bone formation indicators, osteocalcin and osteopontin, were significantly lower in LEP and LEPR deficient subjects compared with controls. In contrast, in MC4R deficient children, levels of these two biomarkers were remarkably raised over values observed for all other groups. Serum concentration of bone resorption biomarkers, osteoprotegerin and sclerostin, for the three mutant groups were not remarkably different from the values of normal weight subjects. However, mean sclerostin levels in children with MC4R mutations tended to be lower than those with LEP and LEPR defects and of the control group. As expected, leptin levels were undetectable in subjects with LEP mutations. Hyperleptinemia was more pronounced in subjects with LEPR deficiency compared to those with MC4R deficiency. Insulin levels though raised in all affected subjects were significantly higher in children with MC4R deficiency whereas serum cortisol concentrations were significantly elevated in LEP deficient children compared to all other groups. Interestingly, TSH, T3 and T4 levels in all affected subjects were unremarkable and within the normal range. CONCLUSIONS: The present data in conformity with previous reports in this population, demonstrate a relatively high prevalence (32%) of monogenic obesity among severely obese children. Eighteen different known or novel loss-of-function mutations were identified in LEP, LEPR and MC4R genes. Assessment of bone metabolism in affected subjects revealed a consistent deficit in bone formation in subjects with leptin or leptin receptor deficiency. These results indicate an impaired osteogenic activity and further support a substantial role of leptin in bone homeostasis. Remarkably, opposite alterations in bone turnover presumably due to an up-regulation of bone formation, were associated with MC4R deficiency. The present data advocate investigation of bone health preferably using a combination of imaging and biochemical techniques in cases of severe obesity for individualized management or treatment.
ﷺ تضمین بر مشہورِ زمانہ نعت بہ قلمِ نصیر احمد اخترؔ دمِ عیسیٰؑ نہیں دیکھا ! یدِ بیضا نہیں دیکھا ! جہاں میں چشمِ جبرائیلؑ نے کیا کیا نہیں دیکھا
جمالِ ماہِ کنعاؑں کا حسیں جلوہ نہیں دیکھا! ! جہاں دیدہ نگا ہوں نے بہت ڈھونڈا نہیں دیکھا زمانے میں محمد مصطفیٰؐ جیسا نہیں دیکھا ستاروں کی ضیاؤں سے زمینِ ثور کہتی ہے قمر کی دلکشی پر خوب کر کے غور ، کہتی ہے
فلک پرکہکشاں پھر پھیل کر ہر طور کہتی ہے نگاہِ آسماںؐ لیتی ہے بوسے اور کہتی ہے بہت دیکھے ہیں لیکن اُنؐ سا نقشِ پا نہیں دیکھاا فلک کی عظمتیں قربان اس کے ذرّے ذرّے پر قطار اندر قطار آتے ہیں قدسی آستانے پر
فدا ہے رفعتِ سدرہ اسی پرنور خطّے پر فرشتے سر نگوں پائے گئے آقاؐ کے روضے پر رسولوں میں بھی کوئی اُنؐ کا ہم پایہ نہیں دیکھا کوئی عنصر نہیں دوئی کا اس منظر سہانے میں کرن سورج کی ہے ناکام اس کی مثل لانے میں
زمیں پر چلنے پھرنے میں’ دنیٰ ‘‘تک آنے جانے میں مُسلم آپؐ کی یکتائی ہے سارے زمانے میں کہیں چشمِ فلک نے آپؐ کا سایہ نہیں دیکھا
ﷺ تضمین بر مشہورِ زمانہ نعت بہ قلمِ نصیر احمد اخترؔ دمِ عیسیٰؑ نہیں دیکھا ! یدِ بیضا نہیں دیکھا ! جہاں میں چشمِ جبرائیلؑ نے کیا کیا نہیں دیکھا
جمالِ ماہِ کنعاؑں کا حسیں جلوہ نہیں دیکھا! ! جہاں دیدہ نگا ہوں نے بہت ڈھونڈا نہیں دیکھا زمانے میں محمد مصطفیٰؐ جیسا نہیں دیکھا ستاروں کی ضیاؤں سے زمینِ ثور کہتی ہے قمر کی دلکشی پر خوب کر کے غور ، کہتی ہے
فلک پرکہکشاں پھر پھیل کر ہر طور کہتی ہے نگاہِ آسماںؐ...
هدفت الدراسة للوقوف على الوضع اللغوي في المملكة العربية السعودية والتعرف على القرارات الرسمية وخطاباتها التواصلية في تدبير مشكلات اللغة. ولتحقيق هدف الدراسة فقد استخدم الباحث المنهج الوصفي، وتوصل الباحث إلى مجموعة من النتائج أهمها أنَّ القرارات الخاصة باللغة العربية غطَّت جميع نواحي الحياة الخاصة بالمجتمع السعودي تقريبًا؛ وذلك لأنها اللغة الأم لهذه المنطقة ولأن تفشي غيرها من اللغات يؤثر سلبًا على هذه اللغة وعلى عادات وتقاليد أهل هذه البقعة الفاضلة من هذه الأرض.
Teaching reading in the early years is highly emphasised especially in an EFL context like Pakistan; however, its assessment is often neglected. The current study is based on the concept that assessment is an integral part of the teaching and learning process and it should facilitate the child’s learning. The purpose of this study is to explore classroom-based assessment strategies to assess the reading skills of young children. To serve the purpose of the study, a Collaborative Action Research approach was employed, in which the researcher worked in collaboration with the teacher to apply reading assessment strategies in the classroom. The study comprised three phases starting from the pre-intervention in which the existing assessment practices were explored, then the intervention phase where different strategies were applied and last was the post- intervention phase in which the teacher assessed the children independently. As a research participant, one English teacher who had at least three years of experience of teaching young children was selected along with four students of 6-7 years as a focused group. The findings of the study confirmed that the assessment strategies ‘observation and retelling stories’ have the potential to assess the reading skills of young children, especially their understanding of reading as a meaning-making process. It was also revealed that these assessment strategies allowed the teacher to monitor students’ progress as well as guide her own teaching practice. Moreover, classroom-based assessment was found to be promising in providing a teacher a rich picture of children’s reading development by gathering and interpreting the assessment information. However, a teacher’s own education of assessment and time pressure hindered the implementation of classroom-based assessment. It is recommended that classroom-based assessment must be included as a part of teacher development programmes so that students’ learning could be supported during the course of the teaching learning process through effective use of assessment.