Importance of a Population Policy in Pakistan

The primary purpose of this lecture is to make a case for an integrated and effective population policy in Pakistan. An effective population policy is critical in its own right. It is also essential for maximising the positive outcome of all of Pakistan’s development efforts. Despite some very modest progress, the overall population growth rate is still so high that it warrants serious concern. Among the top ten contributors to world population growth during 1995–2000, Pakistan stood third in absolute number, and was Number One in rate of growth. The average total fertility rate per woman of 5.2 in Pakistan, as compared to 2.4 in Indonesia, 2.9 in Iran, and 3.1 in India, is indeed problematic and requires an appropriate policy response. A broader view of population growth and economic development is suggested instead of a narrow family planning focus. Thus family planning programmes (supply-side) would be effective only when the population at large has the desire or motivation for smaller families (demand-side). It is shown that the demand-side of the equation is influenced by a host of social, cultural, religious, educational, and other factors. For purposes of this paper, all these are taken together and termed the knowledge factor. It is suggested that a successful population policy must have a clear focus on increasing the knowledge factor in the country through education and advocacy. Based on the policy experiences of other developing countries and the recent demographic realities in Pakistan, an effective population policy must address the following three objectives: (a) reduction in the rate and incidence of unwanted fertility; (b) reduction in demand for large-size families; and (c) greater investment in adolescents to tackle the population momentum problem. The lecture concludes that Pakistan still has a population problem that it must deal with by a comprehensive and effective population programme. Failure to do so would magnify the current problems which are a result of previous policy neglect.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Importance of a Population Policy in Pakistan (The Mahbub ul Haq Memorial Lecture)

The primary purpose of this lecture is to make a case for an integrated and effective population policy in Pakistan. An effective population policy is critical in its own right. It is also essential for maximising the positive outcome of all of Pakistan’s development efforts. Despite some very modest progress, the overall population growth rate is still so high that it warrants serious concern. Among the top ten contributors to world population growth during 1995-2000, Pakistan stood third in absolute number, and was Number One in rate of growth. The average total fertility rate per woman of 5.2 in Pakistan, as compared to 2.4 in Indonesia, 2.9 in Iran, and 3.1 in India, is indeed problematic and requires an appropriate policy response. A broader view of population growth and economic development is suggested instead of a narrow family planning focus. Thus family planning programmes (supply-side) would be effective only when the population at large has the desire or motivation for smaller families (demand-side). It is shown that the demand-side of the equation is influenced by a host of social, cultural, religious, educational, and other factors. For purposes of this paper, all these are taken together and termed the knowledge factor. It is suggested that a successful population policy must have a clear focus on increasing the knowledge factor in the country through education and advocacy

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

International audienceIn 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field