Ayoub’s life sentence plunges family into endless misery

Sunday, 23 December 2012

Srinagar, Dec 23: The house was calm and when the five-year-old Darfan Ayoub saw the photograph of his father Muhammad Ayoub in a local newspaper, the boy could just utter one word: Papa……?

 Muhammad Ayoub Dar of Rawalpora is serving life-sentence at Srinagar’s Central Jail since 2009. His home on the City outskirts is inhabited by five souls but without a breadwinner.

 Ayoub’s six-year-old daughter Yuksal, a kindergarten student, waits for the return of his Papa. Ayoub’s 27-year-old sister does not agree to get married till his brother returns. Ayoub’s 82-year-old father Haji Abdul Ahad Dar has lost his memory and has one last wish: To see his son return so that he may perform his last rites.

 Ayoub’s 33-year-old wife Rouhie broke down when she heard the word Papa from Darfan. She silently pulled the newspaper from his hands and placed it under the table. On the table, a number of monochrome and color photographs of Ayoub’s marriage with Rouhie were decked. Darfan and Yuksal froze, their eyes shooting up to Ayoub’s photos.

 “I can no longer hide the truth from the children,” Rouhie said.
 “They ask me about their father and I tell them he will come soon.”

 Rouhie said Ayoub was sentenced to life on March 7, 2009 for second time.  “He had already spent 13-year term in jail before our marriage. And then he was again sentenced to life,” she said. “They falsely implicated him in the assassination case of Moulvi Mirwaiz Muhammad Farooq.”

 Rouhie and Ayoub were married in 2004. She was 25 then. “Ayoub had carved his niche in business. He had his own restaurant at Rawalpora Chowk. And when he was sentenced for life term again, the family was crumbled,” she said.

 Ayoub’s mother Hajira died due to the shock as she could not bear the life sentence of her son. “His elder sister also passed away shortly after his life sentence,” Rouhie said.

 “I have no energy left to face the challenges without him. Above is God and below are us. There is just one thing which keeps me going. That is hope.”

 Rouhie said her husband was innocent and there was no evidence against him of any sort. “I just say my Ayoub is innocent. He had nothing to do with anything. I have one thing to ask: Does law work this way?”

 Rouhie said nobody ever helped them to get Ayoub back even after going from pillar to post. “The thing is not we don’t have money or we are starving. The point is my kids are asking for their father. Ayoub’s father who has lost memory is waiting for him. And then his sister who is looking for his brother so that she gets married. We just need him back,” she said.

 Life without Ayoub, Rouhie said, is like facing a doomsday each day. “Our home is without roof as Ayoub is not there. We just hope he comes back and infuses new life in all of us,” she said.
 Ayoub’s wife said the family had applied for his parole but was not granted. “Our questions are never answered as why he was given second life sentence if he had already undergone one. We are never paid heed,” she said.

 Ayoub’s 82-year-old father Haji Abdul Ahad Dar is a loner. The moment he enters his home lobby, he gets stifled and struggles to breathe. He always remains outside, on the veranda. “I was a lion…,” he said. “But when my innocent son was put behind bars for no fault of his, I broke down.” The octogenarian said before he dies he wants to see his son back home. “I want him to perform my last rites.”

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Let's do the twist: Spiral proteins are efficient gene delivery agents

Islamabad, Dec 23 : Clinical gene therapy may be one step closer, thanks to a new twist on an old class of molecules.

A group of University of Illinois researchers, led by professors Jianjun Cheng and Fei Wang, have demonstrated that short spiral-shaped proteins can efficiently deliver DNA segments to cells. The team published its work in the journal Angewandte Chemie.

"The main idea is these are new materials that could potentially be used for clinical gene therapy," said Cheng, a professor of materials science and engineering, of chemistry and of bioengineering.

Researchers have been exploring two main pathways for gene delivery: modified viruses and nonviral agents such as synthetic polymers or lipids. The challenge has been to address both toxicity and efficiency. Polypeptides, or short protein chains, are attractive materials because they are biocompatible, fine-tunable and small.

"There are very good in vitrotransfection agents available, but we cannot use them in vivo because of their toxicity or because some of the complexes are too large," Cheng said. "Using our polypeptides, we can control the size down to the 200 nanometer range, which makes it a very interesting delivery system for in vivo applications."

A polypeptide called poly-L-lysine (PLL) was an early contender in gene delivery studies. PLL has positively charged side chains -- molecular structures that stem from each amino acid link in the polypeptide chain -- so it is soluble in the watery cellular environment.

However, PLL gradually fell into disuse because of its limited ability to deliver genes to the inside of cells, a process called transfection, and its high toxicity. Cheng postulated that PLL's low efficiency could be a function of its globular shape, as polypeptides with charged side chains tend to adopt a random coil structure, instead of a more orderly spiral helix.

"We never studied the connections of conformation with transfection efficiency, because we were never able to synthetically make materials containing both cationic charge and a high percentage of helical structures," Cheng said. "This paper demonstrated for the first time that helicity has a huge impact on transfection efficiencies."

Earlier this year, Cheng's group developed a method of making helical polypeptides with positively charged side chains.

To test whether a helical polypeptide could be an efficient gene delivery agent, the group assembled a library of 31 helical polypeptides that are stable over a broad pH range and can bond to DNA for delivery. Most of them outperformed PLL and a few outstripped a leading commercial agent called polyethyleneimine (PEI), notorious for its toxicity although it is highly efficient. The helical molecules even worked on some of the hardest cells to transfect: stem cells and fibroblast cells.

"People kind of gave up on polypeptide-based materials for gene deliveries because PLL had low efficiency and high toxicity," Cheng said. "The polypeptide that we designed, synthesized and used in this study has very high efficiency and also well-controlled toxicities. With a modified helical polypeptide, we demonstrated that we can outperform many commercial agents."

The polypeptides Cheng and his co-workers developed can adopt helical shapes because the side chains are longer, so that the positive charges do not interfere with the protein's winding. The positive charges readily bind to negatively charged DNA, forming complexes that are internalized into cellular compartments called endosomes. The helical structures rupture the endosomal membranes, letting the DNA escape into the cell.

To confirm that the spiral polypeptide shape is the key to transfection, the researchers then synthesized two batches of the most efficient polypeptide: one batch with a helical shape, one with the usual random coil. The helical polypeptide far exceeded the random-coil polypeptide in both efficiency and stability.

"This demonstrates that the helicity is very important, because the polymer has exactly the same chemical makeup; the only difference is the structure," said Cheng, who also is associated with the Institute for Genomic Biology and the Beckman Institute for Advanced Science and Technology, both at the U. of I.

Next, the researchers plan to further explore their helical polypeptides' properties, especially their cell-penetrating abilities. They hope to control sequence and structure with precision for specific applications, including gene delivery, drug delivery, cell-membrane penetration and antimicrobial action.

The National Science Foundation and the National Institutes of Health supported this work. Fei Wang is a professor of cell and development biology and of bioengineering. Postdoctoral researchers Nathan Gabrielson, Lichen Yin and Dong Li and graduate student Hua Lu were co-authors of the paper.ScienceDaily (Dec. 15, 2011) — A team of scientists and clinicians, led by researchers at King's College London and St George's, University of London, are calling for a review of penicillin dosing guidelines for children, that have remained unchanged for nearly 50 years.

The call comes as a study published in the British Medical Journal indicates some children may not be receiving effective doses, which could potentially lead to failed treatment and contribute to antibiotic resistance.
Oral penicillins (such as amoxicillin) account for nearly 4.5 million of the total 6 million annual prescriptions for antibiotics given to treat childhood bacterial infections each year in the UK.

Current dosing guidelines for penicillin are provided by the British National Formulary for Children (BNFC) and are mainly based on age bands. The doses given have not changed in almost 50 years. But the dose of penicillin needed is determined by a child's weight, and the guidelines have not taken into account the increase in the average weight of children over time. The experts say reviewing these guidelines is essential, to ensure all children who require penicillin are receiving effective doses.

The review was led by Dr Paul Long from the Institute of Pharmaceutical Science at King's College London and Professor Mike Sharland at St George's, University of London on behalf of the improving Children's Antibiotic Prescribing Research Network (iCAP). 
The team carried out a literature review of evidence, including all the historic archives of the Royal Pharmaceutical Society and the British Medical Association, to understand the origins of the current dosing guidelines. They found that prescribing based on age bands had first been suggested in the early 1950s, based on the results of oral dosing studies. Following these findings, a general recommendation to use age banding for all antibiotics in children was published in the BMJ in 1963, and these same recommendations remain in use today.

The researchers found that the age band guidelines set in 1963 were accompanied by average weights, and doses are based on fractions of the widely used adult doses. The BNFC structured dosing bands are: birth to 1 year (10kg); 2 years (13kg); 5 years (18kg); and 10 years (30kg). However, according to the Health Survey for England 2009, the average weight today of a 5 year old is 21kg and a 10 year old is 37kg, indicating that average weights today are up to twenty percent higher than in 1963.

Under-dosing is potentially a problem for children, as this could lead to sub-therapeutic concentrations.

The researchers also noted that adult penicillin recommendations have been re-evaluated taking modern weights into consideration, and penicillin doses have consequently increased. But UK recommendations for children have not been reassessed in the same way.

Dr Paul Long, Senior Lecturer in Pharmacognosy at King's College London, said: 'We were surprised at the lack of evidence to support the current oral penicillins dosing recommendations for children, as it is such a commonly used drug. Children's average size and weight are slowly but significantly changing, so what may have been adequate doses of penicillin 50 years ago are potentially not enough today.

'It is important to point out that this study does not provide any clinical evidence that children are receiving sub-optimal penicillin doses that lead to harm, and we want to reassure parents of that. But what we are saying is that we should ensure that children with severe infections who need these antibiotics the most are still receiving an effective dose.

'In the long-term we are concerned that under-dosing could lead to penicillin-resistance in both individuals and wider communities, which is a very serious issue, given the number of prescriptions of this medicine given every year for common childhood infections.

'If we want to be sure that we are treating childhood bacterial infections effectively, the evidence base behind these prescribing guidelines needs to be improved, and the recommended doses reviewed accordingly.'

Professor Mike Sharland from St George's, University of London, and co-author of the study said: 'Although there is now a very formal process of determining the right dose for new drugs being licensed for use in children, we also need to check more carefully that the guidelines are still correct for older drugs that have been used for a long time. We are not saying the current doses are wrong or unsafe and parents should always give the medicine at the doses prescribed by their GP. We are saying that we need to develop a clearer system to check the doses used for older medicines.'

Simon Keady, Royal Pharmaceutical Society spokesperson on children's medicines, said: 'This research and its outcomes clearly demonstrates the importance of continued work in the field of paediatrics as further evidence and experience is gathered. The use of penicillins over many years for a wide variety of conditions should not stop us from continuing to identify the most appropriate dose which gives us the most effective outcomes. The work clearly shows that the focus should not always be about new drugs but also looking at where we have historically centred dosing around age bands.'

NICE (National Institute for Health and Clinical Excellence) guidance on Upper Respiratory Tract Infections (URTIs) suggests that the majority of minor URTI's in children are viral and will resolve on their own without the need for antibiotics. Therefore, the authors also suggest that not only do the effective doses for children of all ages and weights need to be determined, but there is the need to target more clearly which children will really benefit most from antibiotics.

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Scientists may be able to double efficacy of radiation therapy

Islamabad, Dec 23 : Scientists may have a way to double the efficacy and reduce the side effects of radiation therapy.

Georgia Health Sciences University scientists have devised a way to reduce lung cancer cells' ability to repair the lethal double-strand DNA breaks caused by radiation therapy.

"Radiation is a great therapy -- the problem is the side effects," said Dr. William S. Dynan, biochemist and Associate Director of Research and Chief, Nanomedicine and Gene Regulation at the GHSU Institute of Molecular Medicine and Genetics. "We think this is a way to get the same amount of cancer cell death with less radiation or use the same amount and maybe cure a patient that could not be cured before."

Radiation therapy capitalizes on radiation's ability to kill cells by causing double-strand breaks in DNA. But the fact that varying levels of radiation are essentially everywhere -- food, air, the ground, etc. -- means all cells, including cancer cells, have internal mechanisms to prevent the lethal breakage.

GHSU scientists are targeting the natural defense mechanisms by packaging a piece of an antibody against one of them with folate, which has easy access to most cells, particularly cancer cells. Many cancers, including the lung cancer cells they studied, have large numbers of folate receptors so that cancer cells get a disproportionate share of the package.

Previous efforts to destroy cancer cells' ability to avoid radiation damage have focused on receptors on their surface, said Dr. Shuyi Li, molecular biologist, pediatrician and corresponding author on the study in the International Journal of Radiation Oncology.

To get a more direct hit, the scientists took advantage of folate receptors as a point of entry by chemically binding folate with the small piece of their antibody, ScFv 18-2. The package heads straight for the cell nucleus where a different chemical environment breaks the bond, freeing ScFv 18-2 to attack the regulatory region of DNA-dependent protein kinase, an enzyme essential to DNA repair.

"We are joining a targeting molecule with a cargo," said Dynan. "This strategy targets one of the key enzymes so it's harder to repair," Li said. This makes cancer cells more vulnerable to radiation.
Dynan and Li say the approach could be used to deliver any number of drugs directly inside cancer cells. Future studies include looking at other cell entry points as well as other targets to ensure they have the most effective package. Studies to date have been in human lung cancer cells in culture, so next steps also need to include animal studies.

Their approach mimics a natural process called endocytosis in which cells engulf proteins and other substances they want to let inside but can't fit through normal doorways.

Folate receptors already are being used as direct entry points for chemotherapeutic drugs, including clinical studies of a new strategy for ovarian cancer. GHSU is participating in clinical trials of a therapy that pairs an agent too toxic to be delivered through the bloodstream with folate to better target one of the most deadly cancers.

Dynan is the Georgia Research Alliance Eminent Scholar in Molecular Biology. Dynan and Li are both faculty members in GHSU's Medical College of Georgia. Dynan also is a faculty member in the College of Graduate Studies.

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Penicillin doses for children should be reviewed

Islamabad, Dec 23 : A team of scientists and clinicians, led by researchers at King's College London and St George's, University of London, are calling for a review of penicillin dosing guidelines for children, that have remained unchanged for nearly 50 years.

The call comes as a study published in the British Medical Journal indicates some children may not be receiving effective doses, which could potentially lead to failed treatment and contribute to antibiotic resistance.

Oral penicillins (such as amoxicillin) account for nearly 4.5 million of the total 6 million annual prescriptions for antibiotics given to treat childhood bacterial infections each year in the UK.

Current dosing guidelines for penicillin are provided by the British National Formulary for Children (BNFC) and are mainly based on age bands. The doses given have not changed in almost 50 years. But the dose of penicillin needed is determined by a child's weight, and the guidelines have not taken into account the increase in the average weight of children over time. The experts say reviewing these guidelines is essential, to ensure all children who require penicillin are receiving effective doses.

The review was led by Dr Paul Long from the Institute of Pharmaceutical Science at King's College London and Professor Mike Sharland at St George's, University of London on behalf of the improving Children's Antibiotic Prescribing Research Network (iCAP).
The team carried out a literature review of evidence, including all the historic archives of the Royal Pharmaceutical Society and the British Medical Association, to understand the origins of the current dosing guidelines. They found that prescribing based on age bands had first been suggested in the early 1950s, based on the results of oral dosing studies. Following these findings, a general recommendation to use age banding for all antibiotics in children was published in the BMJ in 1963, and these same recommendations remain in use today.

The researchers found that the age band guidelines set in 1963 were accompanied by average weights, and doses are based on fractions of the widely used adult doses. The BNFC structured dosing bands are: birth to 1 year (10kg); 2 years (13kg); 5 years (18kg); and 10 years (30kg). However, according to the Health Survey for England 2009, the average weight today of a 5 year old is 21kg and a 10 year old is 37kg, indicating that average weights today are up to twenty percent higher than in 1963.

Under-dosing is potentially a problem for children, as this could lead to sub-therapeutic concentrations.

The researchers also noted that adult penicillin recommendations have been re-evaluated taking modern weights into consideration, and penicillin doses have consequently increased. But UK recommendations for children have not been reassessed in the same way.

Dr Paul Long, Senior Lecturer in Pharmacognosy at King's College London, said: 'We were surprised at the lack of evidence to support the current oral penicillins dosing recommendations for children, as it is such a commonly used drug. Children's average size and weight are slowly but significantly changing, so what may have been adequate doses of penicillin 50 years ago are potentially not enough today.

'It is important to point out that this study does not provide any clinical evidence that children are receiving sub-optimal penicillin doses that lead to harm, and we want to reassure parents of that. But what we are saying is that we should ensure that children with severe infections who need these antibiotics the most are still receiving an effective dose.

'In the long-term we are concerned that under-dosing could lead to penicillin-resistance in both individuals and wider communities, which is a very serious issue, given the number of prescriptions of this medicine given every year for common childhood infections.

'If we want to be sure that we are treating childhood bacterial infections effectively, the evidence base behind these prescribing guidelines needs to be improved, and the recommended doses reviewed accordingly.'

Professor Mike Sharland from St George's, University of London, and co-author of the study said: 'Although there is now a very formal process of determining the right dose for new drugs being licensed for use in children, we also need to check more carefully that the guidelines are still correct for older drugs that have been used for a long time. We are not saying the current doses are wrong or unsafe and parents should always give the medicine at the doses prescribed by their GP. We are saying that we need to develop a clearer system to check the doses used for older medicines.'

Simon Keady, Royal Pharmaceutical Society spokesperson on children's medicines, said: 'This research and its outcomes clearly demonstrates the importance of continued work in the field of paediatrics as further evidence and experience is gathered. The use of penicillins over many years for a wide variety of conditions should not stop us from continuing to identify the most appropriate dose which gives us the most effective outcomes. The work clearly shows that the focus should not always be about new drugs but also looking at where we have historically centred dosing around age bands.'

NICE (National Institute for Health and Clinical Excellence) guidance on Upper Respiratory Tract Infections (URTIs) suggests that the majority of minor URTI's in children are viral and will resolve on their own without the need for antibiotics. Therefore, the authors also suggest that not only do the effective doses for children of all ages and weights need to be determined, but there is the need to target more clearly which children will really benefit most from antibiotics.

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