By T. Myxir. Ferris State University. 2018.
Con- tion that the agent was in contact with tainers which are not satisfactory shall the surface being sanitized generic 10 mg maxalt fast delivery. Only lowing times and intensities shall be nontoxic containers and closures shall considered a minimum: be used 10 mg maxalt free shipping. All quired documents shall be available for samples shall be free of coliform orga- official review at reasonable times. Foods (2) For chemical, physical, and radio- logical purposes, take and analyze at 130. The representtive Subpart A—General Provisions sample(s) consists of primary con- tainers of product of unit packages of §130. The plant such terms when used in regulations shall maintain records of date of sam- promulgated under the act. For ex- to substantiate the information in his ample, all regulations under section 401 petition, at a public hearing on the contemplate that the food and all arti- matter, the Commissioner may either cles used as components or ingredients (1) withdraw the regulation and termi- thereof shall not be poisonous or dele- nate the proceeding or (2) if he con- terious and shall be clean, sound, and cludes that it is in accordance with the fit for food. A provision in such regula- requirements of section 401 of the act, tions for the use of coloring or fla- continue the proceeding and introduce voring does not authorize such use evidence to substantiate such informa- under circumstances or in a manner tion. Codex Alimentarius Commission will be reviewed by the Food and Drug Ad- (2) Is used at a level no higher than ministration and will be accepted with- necessary to achieve its intended pur- out change, accepted with change, or pose in that food. All ingredients must be any deviations from the Codex stand- listed in accordance with the require- ard, and the reasons for any such devi- ments of part 101 of this chapter, ex- ations. Any such proposal shall specify nition and standard; any deviations from the Codex stand- (c) If the quantity of any ingredient ard, and the reasons for any such devi- or component fails to conform to the ations. Interested persons shall be tains a sulfiting agent or combination requested to comment on the desir- of sulfiting agents that is functional ability and need for the standard, on and provided for in the applicable the specific provisions of the standard, standard or that is present in the fin- on additional or different provisions ished food at a detectable level is mis- that should be included in the stand- branded unless the presence of the ard, and on any other pertinent points. A detectable Commissioner either shall publish a amount of sulfiting agent is 10 parts proposal to establish a food standard per million or more of the sulfite in the pursuant to section 401 of the act cov- finished food. The level of sulfite in the ering the food involved, or shall pub- finished food will be determined using lish a notice terminating consideration sections 20. All such peti- and the refinements of the "Total Sul- tions or comments are requested to in- furous Acid" procedure in the "Monier- clude a statement of any meetings and Williams Procedure (with Modifica- discussions that have been held with tions) for Sulfites in Foods," which is other interest groups. The foods prescribed food, the label shall include a state- by this general definition and standard ment informing the consumer of such of identity are those foods that sub- difference (e. Such for a standardized food defined in parts statement shall comply with the re- 131 through 169 of this chapter and that quirements of §101. The nutrient content gredients provided for by the standard claim shall comply with the require- as defined in parts 131 through 169 of ments of §101. The food shall com- eresis, extend shelf life, improve ap- ply with the relevant standard in all pearance, or add sweetness so that the other respects except as provided in product is not inferior in performance paragraphs (b), (c), and (d) of this sec- characteristics to the standardized tion. The ad- replaced or exchanged with a similar dition of nutrients shall be reflected in ingredient from another source unless the ingredient statement. Devi- through 169 of this chapter, provides ations from noningredient provisions of for the addition of such ingredient the standard of identity (e. Deviations from ingredient not be added to a substitute food under and noningredient provisions of the this section. I (4–1–10 Edition) shall be present in the product in a sig- the words or statements on the label of nificant amount. A significant amount the standardized food significantly dif- of an ingredient or component of an in- ferentiate between two or more foods gredient is at least that amount that is that comply with the same standard by required to achieve the technical effect describing the optional forms or vari- of that ingredient in the food. The statement the weight found in paragraph (a)(3) of "*Ingredient(s) not in regular lll" this section. The difference shall be (fill in name of the traditional stand- considered to be the weight of water re- ardized food) or "*Ingredient(s) in ex- quired to fill the container. If the container as filled in paragraph (b)(4) quantity of the contents of the con- of this section to the level of the food tainer is less than 1 pound, the state- found in paragraph (b)(2) of this sec- ment is in 12-point type; if such quan- tion, weigh the container with remain- tity is 1 pound or more, the statement ing water, and determine the weight of is in 14-point type. Such statement is the remaining water by subtracting the enclosed within lines, not less than 6 weight of the container found in para- points in width, forming a rectangle; graph (b)(3) of this section. Such statement or (b)(4) of this section, and multiply by statements, with enclosing lines, are 100. The result shall be considered to be on a strongly contrasting, uniform the percent of the total capacity of the background, and are so placed as to be container occupied by the food. The words "Below Standard in packs of food varying from applicable Quality" constitute the first line, and definitions and standards of identity the second immediately follows. If such quantity is 1 pound the sole purpose of the tests is to ob- or more, the type of the first line is 14- tain data necessary for reasonable point, and of the second, 10-point. Such grounds in support of a petition to statement is enclosed within lines, not amend food standards, that the tests less than 6 points in width, forming a are necessary to the completion or con- rectangle. Such statement, with en- clusiveness of an otherwise adequate closing lines, is on a strongly con- investigation, and that the interests of trasting, uniform background, and is so consumers are adequately safeguarded; placed as to be easily seen when the permits for such tests shall normally name of the food or any pictorial rep- be for a period not to exceed 15 months. The Food and Drug Administra- ingredient, a description of its prop- tion will therefore refrain from recom- erties and basis for concluding that it mending regulatory proceedings under is not a deleterious substance. Drug Administration shall be notified (10) The period during which the ap- in writing of the date on which the test plicant desires to introduce such food period begins as soon as it is deter- into interstate commerce, with a state- mined. If a period longer file with the Team Leader, Conven- than 15 months is requested, a detailed tional Foods Team, Division of Stand- explanation of why a 15-month period ards and Labeling Regulations, Office is inadequate shall be provided. The extended market test period to the applicant for interstate ship- shall not begin prior to the publication ment of such food. Any interested person (f) The terms and conditions of the who accepts the invitation to partici- permit may be modified at the discre- pate in the extended market test shall tion of the Food and Drug Administra- notify the Food and Drug Administra- tion or upon application of the per- tion in writing of that fact, the amount mittee during the effective period of to be distributed, and the area of dis- the permit. The application for an extension shall be Subpart B—Food Additives in filed not later than 3 months prior to Standardized Foods the expiration date of the permit and shall be accompanied by a petition to §130. If use in foods for which definitions the Food and Drug Administration con- and standards of identity are estab- cludes that it will be in the interest of lished. Cream contains not less than 18 posal for a food additive regulation, percent milkfat. Milk is the lacteal se- culated by subtracting the milk fat cretion, practically free from colos- content from the total solids content trum, obtained by the complete milk- as determined by the method "Total ing of one or more healthy cows.
Adverse Efects Hypotension trusted maxalt 10mg, cough cheap 10mg maxalt free shipping, asthenia, dizziness, headache, angioneurotc edema, hypersensitvity reactons, erythema multforme, toxic epidermal necrolysis, Stevens Johnson syndrome, hepatc necrosis, pancreatts, pancytopenia, thrombocytopenia. Precautons Impaired pulmonary functon; hypothyroidism; renal impairment; ischaemic heart disease; impaired cerebral circulaton; hyponatraemia; raised intracranial pressure; elderly; hypothermia; monitor blood pressure and blood-cyanide concentraton; also blood-thiocyanate concentraton if given for more than 3 days; avoid sudden withdrawal (reduce infusion over 15-30 min to avoid rebound efects); pregnancy (Appendix 7c); lactaton; interactons (Appendix 6b); hepatc impairment (Appendix 7a). Adverse Efects Severe hypotension; efects associated with over-rapid reducton in blood pressure include headache; dizziness; retching; abdominal pain; perspiraton; palpitatons; apprehension; retrosternal discomfort; rarely, reduced platelet count; acute transient phlebits; muscle twitching; hypothyroidism; increased anaerobic metabolism. Adverse efects associated with excessive concentraton of cyanide metabolite include tachycardia; sweatng; hyperventlaton; arrhythmias; marked metabolic acidosis (discontnue infusion and give antdote). Terazosin Pregnancy Category-C Schedule H Indicatons Mild to moderate hypertension, benign prostatc hyperplasia. Dose Hypertension: Adult-Initally 1 mg at bedtme (compliance with bedtme dose is important, see precautons), gradually increase at 7 day intervals. Benign prostatc hyperplasia: Adult- 1 mg at bedtme, gradually increase at 7-day interval. Precautons First dose syncope (should be taken just before retring to bed), kidney disease, liver disease, elderly, pregnancy (Appendix 7c), lactaton, interactons (Appendix 6a). Adverse efects Dizziness, drowsiness, fatgue, dyspnoea, blurred vision, postural hypotension, asthenia, nasal congeston, miosis, chest pain, urinary frequency, weight gain, thrombocytopenia, decreased libido, back pain and pain in extremites. Antplatelet drugs also help to inhibit thrombus formaton by decreasing platelet aggregaton. Thrombolytcs (fbrinolytcs) such as streptokinase are used to break up thrombi; they are used to treat acute myocardial infarcton, extensive deep vein thrombosis, major pulmonary embolism and acute arterial occlusion. Myocardial Infarcton: Management of myocardial infarcton includes two phases: • inital management of the acute atack • long-term management, including preventon of further atacks 1. Inital Management: Oxygen should be given to all patents, except those with severe chronic obstructve pulmonary disease. Pain and anxiety are relieved by slow intravenous injecton of an opioid analgesic such as morphine. Metoclopramide may also be given by intramuscular injecton to prevent and treat nausea and vomitng caused by morphine. Acetylsalicylic acid 150-300 mg by mouth (preferably chewed or dispersed in water) is given immediately for its antplatelet efect. Thrombolytc drugs such as streptokinase help to restore perfusion and thus relieve myocardial ischaemia; they should ideally be given within 1 h of infarcton (use afer 12 h requires specialist advice). Early administraton of beta-blockers such as atenolol have been shown to reduce both early mortality and the recur- rence rate of myocardial infarcton; inital intravenous admin- istraton is followed by long-term oral treatment (unless the patent has contraindicatons). If arrhythmias occur, they should be treated aggressively, but the likelihood decreases rapidly over the frst 24 h afer infarcton. Ventricular fbrillaton should be treated imme- diately with a defbrillator; if this is inefectve alone, the antarrhythmic drug lidocaine should be given. Long-term Management Acetylsalicylic acid should be given to all patents in a dose of 75-150 mg daily by mouth, unless it is contraindicated. Treatment with beta-blockers should be contnued for at least 1 year and possibly for up to 3 years. Stroke: Stroke (cerebrovascular accident) may be ischaemic or haem- orrhagic; precise diagnosis is essental, as management for the two types of stroke is quite diferent. Primary preventon of both types of stroke includes reducton of high blood pressure, stopping smoking, weight reducton and cholesterol reducton. Atrial fbrillaton, acute myocardial infarcton and valvular disease may produce embolism and ischaemic stroke. Prophylaxis in patents at risk of ischaemic stroke includes oral antcoagulants such as warfarin and antplatelet drugs such as acetylsalicylic acid. Treatment of acute ischaemic stroke includes use of acetylsalicylic acid, antcoagulants such as heparin and of thrombolytcs, such as streptokinase. Long-term therapy with acetyl- salicylic acid reduces the risk of having another stroke. Antplatelet and thrombolytc drugs are not used in the management of haemorrhagic stroke, as they may exacerbate bleeding. Acetylsalicylic acid is normally given for at least one year afer coronary artery bypass surgery. It is also given to patents with prosthetc heart valves who have had cerebral embolism despite warfarin treatment. Contraindicatons Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitaton, actve bleeding, serious gastrointestnal bleeding within 3 months, previous cerebrovascular accident or actve intracranial process, thrombocytopenia, severe uncontrolled hypertension, aortc dissecton, acute pericardits. Precautons Monitor platelet count for thrombocytopenia; interactions (Appendix 6c); pregnancy (Appendix 7c). Dose Oral Adult-Prophylaxis of cerebrovascular disease or myocardial infarcton: 75 to 100 mg daily. Adverse Efects Bronchospasm;gastrointestnalhaemorrhage (rarely, major); also other haemorrhage (for example subconjunctval); urtcaria; hepatomegaly. Alteplase Pregnancy Category-C Schedule H Indicatons Acute myocardial infarcton, acute massive pulmonary embolism, acute ischaemic stroke. Dose Intravenous Acute myocardial infarcton Adult: The recommended total dose is 100 mg. Heparin therapy to be insttuted or reinsttuted near the end of or immediately following the alteplase infusion when the partal thromboplastn tme returns to twice normal or less. Acute ischemic stroke Adult: Use recommended within frst 3 h of onset of the symptoms. Caution in recent surgery or invasive procedures, diabetic hemorrhagic retinopathy, severe hepatic and renal impairment, pregnancy (Appendix 7c), lactation, children, elderly, interactions (Appendix 6c). Adverse Efects Hemorrhage including intracranial, gastrointestnal or genitourinary bleeding, transient hypotension, reperfusion dysrythmias, cerebral edema, seizures, allergic-type reactons, nausea, vomitng. Storage Store protected from heat, light and moisture at room temperature (<30°C) or under refrigeraton. Clopidogrel* Pregnancy Category-B Schedule H Indicatons Prophylaxis in thromboembolic disorders including myocardial infarcton, peripheral arterial disease and stroke, acute coronary syndrome. Contraindicatons Hypersensitvity, actve pathological bleed- ing such as peptc ulcer or intracranial hem- orrhage, coagulaton disorders, lactaton.
Subsequent to the above Notification maxalt 10mg for sale, representations have been received from various Drug Manufacturers Associations requesting for exemption from registration requirements of the Drugs & Cosmetics Act for imports under the Advance Licensing Scheme buy 10 mg maxalt overnight delivery. The requests have been considered and It has been decided that import of approved & unapproved drugs under the Advance Licensing Scheme will not be subjected to the Registration procedure and the imports will be permitted subject to the following conditions: i. Import license will only be given against an existing valid export order and to the extent raw material is required as per that order. A copy of the license would be endorsed to the Drug Controller and the concerned State Drug Controller. Any violation is punishable under the Foreign Trade Development and Regulation Act and the Customs Act. The Drug Controller could also make provisions for penalizing the Drug Manufacturing Units in terms of suspension or cancelling of his license. Export obligation will be fulfilled within a period of six months from the date of issuance of the license. However, if they make supplies to the domestic market, they will have to follow the formalities of registration as under the Drugs & Cosmetics Act. Representations have also been received regarding issuance of Form-10 under the Drugs & Cosmetics Act for manufacturers. It is clarified that Form -9 issued by the registered manufacturers should also be accepted for the purpose of issuing Form-10 license under the Drugs & Cosmetics Act. In addition as far as imports of drugs/raw materials for purposes of (i) clinical trials & (ii) for formulation development is concerned, it is clarified that exemption in such cases will be permitted on case to case basis. The exemption from registration procedure of the Drugs & Cosmetics Act will not only cover those drugs listed in Notification No. The Licensing Authority will make an endorsement on the licence that the exemption has been granted in terms of Policy Circular No. All importers making imports against advance licences, which have not been issued in terms of Policy Circular No. The export obligation period for the advance licences issued as per Policy Circular No. I) shall however be applicable for advance licences issued under Policy Circular 9 dated 30. Na M E Lan sh Shel Shel Batc i t N me din elf f f h t a o & ( g Lif Life Life wise l. That we shall arrange for inspection of the goods as soon as they arrive in the go-down and follow the instructions of representative of the O/o. Assistant Drugs Controller (I), with regard to drawing of samples for test, rectification of labelling defects etc. That we shall not dispose of the said goods without the consent of the Collector of Customs or any Officer on his behalf in writing. That we shall return the said goods in whole or in part as the Collector of Customs or any officer on his behalf may direct within ten days of receipt of a notice from the Collector of Customs or any officer on his behalf to return the goods. That we shall reship or surrender the said goods within two months of the receipt of any order to that effect from the Collector of Customs or any officer in his behalf. Any amount due under this bond may be recovered in the manner laid down in the subsection of the Section 142 of the Customs Act, 1962 without prejudice to any other mode or recovery. The undertakings referred to above is given in view of rule 40 of the drugs and Cosmetics Rules 1945. We hereby undertake: 1) That we shall arrange for inspection of the goods as soon as they arrive in our go-down by a representative of Asst. Drugs Controller (India) and obey his instructions as regards drawing samples under proper conditions and rectification of labelling defects if any etc 2) That we shall not dispose of the said goods without the consent of the Collector of Customs or any officer on his behalf in writing. Any amount due under this bond may be recovered in the, manner laid down in subsection of the Section 142 of the Customs Act, 1962 without prejudice to any other mode of recovery. The undertakings referred to above is given in view of Rule 40 of the Drugs and Cosmetics Rules, 1945. That we shall label the goods mentioned above as required under the above rules within a month or such extended period as the Collector of Customs or any officer on his behalf may allow. That we shall not dispose of the said goods without the consent of the Collector of Customs or any officer on his behalf in writing. That we shall return the said goods in whole or in part us the Collector of Customs or any officer on his behalf nay direct within ten days of receipt of a notice from the Collector of Customs or any officer on his behalf to return the goods. That we shall reship or surrender the said goods within two months of the receipt of any order to that effect from the Collector of Customs or any Officer on his behalf. Any amount due under this bond may be recovered in the, manner laid down in subsection of the Section 142 of the Customs Act, 1962 without prejudice to any other mode of recovery. The undertakings referred to above is given in view of Rule 40 & 96 of the Drugs and Cosmetics Rules, 1945. Office of the Assistant Drugs Controller (India) Mumbai / Kolkata / Chennai / Delhi Ahmadabad / Hyderabad/Cochin Date: 1. The importers, may however please be given the option to have the goods wither reshipped to the country of origin or have them destroyed in the presence of Assistant Drugs Controller (India) or a Custom Officer, provided under Rule 41 ( 1) of the Drugs and Cosmetics Rules. The goods are lying in the docks /air-shed/ were cleared on a Letter of Undertaking for test pending the receipt of the test report. Office of the Assistant Drugs Controller (India) Mumbai / Kolkata / Chennai / Delhi Ahmadabad / Hyderabad/Cochin Dt. A sample of the subject drug sent for test under Rule 40 of the Drugs and cosmetics Rule from a consignment imported by M/s……………………………………………………… (Name and full address of the importers), has since been reported by the Director, C. Value ……………………………………………………………………………………………… The Customs authorities have been advised to take necessary action under Rule 41(1) of the Drugs and Cosmetics Rules in respect of the above goods which are lying in the Docks / were cleared on Letter of undertaking for test. The import of these goods are prohibited under Section 10(a) of the Drugs and Cosmetics act read with Section 11 of the same act and liable to absolute confiscation under Section 111 (d) of the Customs act, 1962. You are hereby required to show cause why action should not be taken to confiscate the goods under Section…………………………………of the Customs Act. You are required to indicate whether you would like to re-export the goods to the country of origin as per option given in rule 41 (1) of the Drugs and Cosmetics Rules, 1945. You are further required to show cause why a personal penalty should not be imposed on you under the aforesaid section. Your written explanation should be presented within …………………day hereof to the undersigned along with all the documentary evidence.
At this stage of research purchase 10 mg maxalt with mastercard, three-dimensional information of inhibitors bound to the enzyme along with information pertaining to the fexibility of the active site have provided suffcient data to search for potential nonpeptide lead compounds purchase maxalt 10mg free shipping. From a generic chemical library, compounds that can ft and favorably electronically interact with the active site are searched through computer-assisted docking simulations, namely, vir- tual high throughput screening. These potential lead compounds are then synthesized and processed by high throughput assay screening to verify for activating or inhibitory activity toward or against the enzyme. Essentially, high throughput assay screening is an automated assaying method of a large library of potential lead compounds in microtiter plates. Once lead compounds are identifed, the compounds are structurally refned under rational drug optimization to derive potent compounds with desired pharmacodynamic and pharmacokinetic properties. Cellular and animal experiments are performed to confrm the expected pharmacodynamics and pharmacokinetics, as well as to examine for any unexpected adverse drug effects. Clinical trials are divided into four phases in which the drug is administered to volunteer trial participants. Because the tests are ethically conducted on living humans, there are extensive rules and standards governing the trials and their evalua- tions. Throughout the clinical phases, safety, effectiveness, adverse risks, and adverse reactions associated with the investigational drug in human are continuously moni- tored. In other words, the pharmacodynamic properties of the drug are diligently kept under close watch. In phase I clinical trials, low doses of the investigational new drug are given to healthy individuals and gradually increased to investigate for the safety and tolerabil- ity of the drug. The investigators examine for pharmacokinetic properties in healthy individuals to assess drug bioavailability and isolate potential drug distribution problems, so as to determine safe and tolerable dosage levels. The main focus of the trials is to determine the most appropriate method of drug delivery and its associated therapeutic dosage. Hence, this phase looks at the pharmaceutics of the drug in patients afficted with the targeted disease. Investigators and patients are randomized and double-blinded to provide the primary basis for the beneft-versus-risk assessment for the new drug, while comparing the drug with conventional treatments. Once the manufacturing process and clinical trials are reviewed by the agency, the drug may be approved for marketing. Phosphates are important in signal transduction because they regulate the proteins to which they are attached. Protein kinases modify peptides or proteins by attach- ing a phosphate group to one of the three amino acids that have a free hydroxyl group, namely, serine, threonine, and tyrosine. Certain protein kinases, such as histi- dine kinase, may phosphorylate other amino acids. Owing to their important effect on cell growth, movement, and death, the activity of protein kinases is highly regulated by several mechanisms. A deregulation of protein kinase activity often causes cell proliferation diseases such as cancer. These inhibitors are either of monoclonal antibody or small molecule class, and none of them seems to have been derived from peptides. While protein kinases add a phosphate group to serine, threonine, tyrosine, or histidine, protein phosphatases remove the phosphate group. Protein phosphatases catalyze the removal of the phosphate thus reversing the regulatory effect of phos- phates. As far as we are aware, there is currently no protein phosphatase modulating drug on the pharmaceutical market. Belonging to the hydrolase category, peptidases, as their names suggest, catalyze the hydrolysis of a peptide bond. Semantically, considering that proteins are longer peptides, the terms protease and peptidase are often used interchangeably to denote an enzyme that breaks down a protein or peptide. Proteases are classifed as serine, threonine, cys- teine, aspartic acid, glutamic acid, and metalloprotease, to denote the participation of the active site amino acid(s) within the enzyme or metal ion, during the hydrolysis of a substrate. We will examine a few of these enzymes that are used in common assay tests, commer- cial products and as therapeutic agents. Use of serine protease as therapeutic agents and their importance in blood coagulation will be discussed separately in Section 5. Bromelain refers to two cysteine proteases, fruit and stem bromelain, found in the respective parts of the pineapple, Ananas comosus. Chymosin, also known as rennin (with two n’s), is an aspartic protease found in rennet, a natural complex of enzymes produced in infant mammalian stomach to cur- dle ingested mother’s milk thus allowing longer residence in the bowels, and thereby improving absorption of the milk-product. Chymosin catabolyses K-casein between Phe105 and Met106 to produce an insoluble 1–105 fragment, which forms a curd in the presence of calcium, and a soluble frag- ment 106–169 fragment, which becomes a part of the whey. The catabolytic effects of chymosin are exploited in the making of cheese, curd, and junket. In other words, collagenase is used to break down the collagen that binds dead tissues together. Papain is a cysteine protease found in papaya, Carica papaya, and mountain papaya, Vasconcellea cundinamarcensis. In the laboratory, papain is used to dis- sociate cells in the frst step of cell culture preparation. For thousands of years in South America, papain is used to break down tough meat fbers and is also currently marketed as a meat tenderizer, digestive aid and used in breweries. Topically papain is used as a home remedy treatment to digest protein toxins in the venom of jellyfsh, bee, wasp stings, and mosquito bites. Papain is also found as an ingredient in various enzymatic debriding preparations to remove dead or contaminated skin tissues for medical and cosmetic purposes, as shampoo, as enzyme cleaners for soft contact lenses, as tooth whitener in much diluted form and as dental caries removal in more concentrated form. Dis- covered in 1836 by Theodor Schwann, the aspartic protease has found success as a digestive aid . The discovery of a potent inhibitor of pepsin, pepstatin, would popularize substrate-based inhibitory peptide drug design (Section 5. Pregnancy-associated plasma protein A, also known as pappalysin 1, is a metallo- protease used as a biochemical marker for Down’s syndrome in prenatal screening. Low plasma level of pregnancy-associated plasma protein A has been positively cor- related with aneuploid fetuses that may develop to babies with Down’s syndrome.