Road Train Elphinstone Easyloader

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Folding Log Trailer

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Transport Schmiedepresse / forging press Bohnet Schwertransporte

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Amazing Future Truck

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Arrivée du premier tram-train Avanto à Mulhouse et déchargement.

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Nadměrný náklad Hradec Králové - Mělník

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Ditched Kenworth Log Truck Recovery

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Overview of sphingolipidosis (Lipid storage Diseases)

he sphingolipidosis (lipid storage diseases) are a group of inherited diseases that are caused by a genetic defect in the catabolism of lipids containing sphingosine. They are part of a larger group of lysosomal disorders and exhibit several constant features:

(1) Complex lipids containing ceramide accumulate in cells, particularly neurons, causing neuro degeneration and shortening the life span.

(2) The rate of synthesis of the stored lipid is normal.

(3) The enzymatic defect is in the lysosomal degradation pathway of sphingolipids.

(4) The extent to which the activity of the affected enzyme is decreased is similar in all tissues.

There is no effective treatment for many of the diseases, although some success has been achieved with enzyme replacement therapy and bone marrow transplantation in the treatment of Gaucher’s and Fabry’s diseases. Other promising approaches are substrate deprivation therapy to inhibit the synthesis of sphingolipids and chemical chaperone therapy. Gene therapy for lysosomal disorders is also currently under investigation.

Disease	Enzyme Deficiency	Lipid Accumulating	Clinical Symptoms
Tay Sach’s Disease	Hexosaminidase A	GM2 Ganglioside	Mental retardation, blindness, muscular weakness
Fabry’s disease	α-Galactosidase	Globotriaosylceramide	Skin rash, kidney failure (full symptoms only in males; X-linked recessive).
Metachromatic leukodystrophy	Arylsulfatase A	Sulfogalactosylceramide	Mental retardation and Psychologic disturbances in adults; demyelination.
Krabbe’s disease	β-Galactosidase	Galactosylceramide	Mental retardation; myelin almost absent.
Gaucher’s disease	β -Glycosidase	Glucosyl ceramide	Enlarged liver and spleen, erosion of long bones, mental retardation in infants.
Niemann-Pick disease	Sphingomyelinase	Sphigomyelin	Enlarged liver and spleen, mental retardation; fatal in early life.
Farber’s disease	Ceramidase	Ceramide	Hoarseness, dermatitis, skeletal deformation, mental retardation; fatal in early life

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Hyperlipoproteinemia

 A) Primary Hyperlipoproteinemia

TYPE	CLASSIFICATION	BIOCHEMICAL DEFECT	INHERITANCE	PLASMA LIPIDS AND LIPOPROTEINS	CLINICAL FEATURES
I.	Familial lipoprotein lipase deficiency(Hyperchylomicronemia)	Deficiency of lipoprotein lipase. A variant of this diseases can be produced by deficiency of apo CII.	Autosomal recessive	TG↑, cholesterol may also be increased, Chylomicrons ++, VLDL↑, HDL and LDL ↓.Refrigeration test confirms the presence of chylomicrons in serum	Present in early childhood, Eruptive xanthomas, Recurrent abdominal pain, no premature cardiovascular disease
II.	Familial Hypercholesterolemia(FHC)	No enzyme deficiency but there is increased synthesis of apo- B protein and there is impaired degradation of LDL	Autosomal dominant	LDL ↑, total cholesterol ↑, VLDL  and TG are also raised	Xanthomas, corneal arcus, increased risk of premature Cardiovascular disease.
III.	Familial Dysbeta lipoproteinemiaAlso called- Broad beta disease , ‘Remnant removal disease”	Increase concentration of apo-E, increased synthesis of Apo B, conversion of normal VLDL to IDL and its degradation without conversion to LDL. Defect in Remnant removal.	Autosomal dominant	LDL↑, VLDL↑, actual rise in IDL which appears as Broad beta band on electrophoresis. TG↑, cholesterol may also be increased.	Tuberous and Palmar xanthomas, increased risk of premature Cardiovascular disease and peripheral vascular disease.
IV.	Familial Hypertriglyceridemia(FHTG)	Increased synthesis  and decreased catabolism of endogenous TGs	Autosomal dominant	Hyper pre beta lipoproteinemia VLDL↑, TG and cholesterol also↑, α and β-lipoproteins are subnormal (HDL↓ and LDL↓). There is associated impaired Glucose Tolerance	Presents in early childhood, and is commonly associated with CHD, Diabetes Mellitus, Alcoholism and  obesity
V.	Combined Hyperlipidemia	Usually secondary to other disorders like obesity, excessive alcohol intake, renal failure and pancreatitis etc. Exact biochemical defect is not known	Autosomal dominant	Complex lipoprotein pattern, Increase in both chylomicrons and pre β-lipoproteins (VLDL), TG and cholesterol also↑↑, α and β-lipoproteins are subnormal (HDL↓ and LDL↓).	Xanthomas are frequently present impaired glucose tolerance, frequently found associated with CHD, Diabetes Mellitus, Alcoholism and  obesity

B) Secondary Hyperlipoproteinemia

S. .No	Disease	Serum total Cholesterol	Serum triglycerides
1.	Diabetes Mellitus	Increased	Increased
2.	Nephrotic syndrome	Increased	Increased
3.	Hypothyroidism	Increased	Increased
4.	Biliary obstruction	Increased	Normal
5.	Pregnancy	Increased	Normal
6.	Alcoholism	Normal	Increased
7.	Oral contraceptives	Normal

Hypolipoproteinemia

Disease	Biochemical defect	Inheritance	Laboratory findings	Clinical manifestations
Familial Hypobetalipoproteinemia	Inability to synthesize ApoB100 and Apo-B48	Autosomal dominant	LDL between 10 to 50 % of normal, Cholesterol low but Triglycerides and Chylomicrons normal.	Mostly asymptomatic, but there is decreased risk of CHD
Abetalipoproteinemia	No synthesis or secretion  of Apo B containing lipoproteins	Rare inherited disease	VLDL↓, LDL↓↓, B-100↓, B-48↓, decrease in TG and a marked ↓in Serum total cholesterol, prolonged prothrombin time.	Malabsorption, mental and physical retardation, acanthocytosis, Atypical retinitis pigmentosa, fatty infiltration of intestinal mucosal cells and liver.
Hypoalphalipoproteinemia	Not known	Autosomal dominant	HDL↓, Cholesterol and TGs normal	Increased risk of CHD
Familial Alpha lipoprotein deficiency(Tangier’s disease)	Deficiency of alpha lipoprotein. Cholesteryl esters are deposited in the reticulo endothelial system, but functions of major organs are not affected	Autosomal recessive	Low or absent HDL, Lack of Alpha band on electrophoresis.	Orange yellow tonsils and adenoids, muscle weakness, atrophy, recurrent peripheral neuropathies and depressed tendon reflexes. The pharyngeal and rectal mucosa is also orange colored.(The orange color is due to deposition of cholesteryl esters.) There is increased predisposition to Atherosclerosis.

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Regulatory Mechanisms- Lipid Metabolism

Enzyme	Pathway	Effect of substrate concentration	Allosteric Modification/ Fed back Inhibition	Induction/ Repression	Clinical Significance
Acetyl co A Carboxylase	Fatty acid synthesis	Activity increases during well fed state Activity decrease during fasting	Activator- Citrate, ATP Acetyl co A Insulin-by causing de phosphorylation by stimulating protein phosphatase Inhibitors- Long chain fatty acids, Epinephrine, Glucagon- via changes in phosphorylation state through c AMP mediated phosphorylation cascade	Induced byInsulin Repressed byGlucagon	Activity decreases in diabetes Mellitus
Carnitine Acyl Transferase	Carnitine shuttle	Activity low in fed state, high during fasting	Activated byGlucagon through lipolysis and provision of fatty acids for oxidation Inhibited by insulin and malonyl co A		Inherited CAT-I deficiencyaffects only the liver, resulting in reduced fatty acid oxidation and ketogenesis, with hypoglycemia.
HMG co A Reductase	Cholesterol synthesis	Activity low in fasting state,	Activated by Insulin, Thyroid hormone Inhibited by –Glucagon, Glucocorticoids,(By reversible phosphorylation) Dietary cholesterol (Hepatic synthesis) Mevalonate and cholesterol ,the products of pathway	Expression of HMG COA reductase is regulated by sterol regulatory element binding protein Also induced by Insulin	Activity high in Diabetes mellitus die to availability of excess Acetyl co A. Activity inhibited by Statins used as cholesterol lowering drugs.

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