Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease is the most prevalent lethal, monogenic human disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes, it is the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, abdominal wall hernias. Over 50% of patients with ADPKD develop end stage kidney disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.

Acute loin pain Blood in the urine Ballotable kidneys Subarachnoid hemorrhage Hypertension Associated liver cysts Uremia due to kidney failure Anemia due to chronic kidney disease Increase RBC or erythropoietin secretion ADPKD is genetically heterogeneous with two genes identified: PKD1 and PKD2. Several genetic mechanisms contribute to the phenotypic expression of the disease. Although evidence exists for a two-hit mechanism explaining the focal development of renal and hepatic cysts, haploinsufficiency is more to account for the vascular manifestations of the disease. Additionally, new mouse models homozygous for PKD1 hypomorphic alleles 22 and 23 and the demonstration of increased renal epithelial cell proliferation in PKD2 +/− mice suggest that mechanisms other than the two-hit hypothesis contribute to the cystic phenotype. Large interfamilial and intrafamilial variability occurs in ADPKD. Most individuals with PKD1 mutations have kidney failure by age 70 years, whereas more than 50% of individuals with PKD2 mutations have adequate renal function at that age.

The significant intrafamilial variability observed in the severity of renal and extrarenal manifestations points to genetic and environmental modifying factors that may influence the outcome of ADPKD, results of an analysis of the variability in renal function between monozygotic twins and siblings support the role of genetic modifiers in this disease. It is estimated that 43–78% of the variance in age to ESRD could be due to heritable modifying factors, with parents as as children to show more severe disease in studies of parent-child pairs. In many patients with ADPKD, kidney dysfunction is not clinically apparent until 40 or 50 years of life. However, an increasing body of evidence suggests. Cysts form as small dilations in renal tubules, which expand to form fluid-filled cavities of different sizes. Factors suggested to lead to cystogenesis include a germline mutation in one of the polycystin gene alleles, a somatic second hit that leads to the loss of the normal allele, a third hit, which can be anything that triggers cell proliferation, leading to the dilation of the tubules.

In the progression of the disease, continued dilation of the tubules through increased cell proliferation, fluid secretion, separation from the parental tubule lead to the formation of cysts. ADPKD, together with many other diseases that present with renal cysts, can be classified into a family of diseases known as ciliopathies. Epithelial cells of the renal tubules, including all the segments of the nephron and the collecting ducts show the presence of a single primary apical cilium. Polycystin-1, the protein encoded by the PKD1 gene, is present on these cilia and is thought to sense the flow with its large extracellular domains, activating the calcium channels associated with polycystin-2, the product of gene PKD2, as a result of the genetic setting of ADPKD as explained in the genetics sub-section above. Epithelial cell proliferation and fluid secretion that lead to cystogenesis are two hallmark features in ADPKD. During the early stages of cystogenesis, cysts are attached to their parental renal tubules and a derivative of the glomerular filtrate enters the cysts.

Once these cysts expand to 2 mm in diameter, the cyst closes off from its parental tubule and after that fluid can only enter the cysts through transepithelial secretion, which in turn is suggested to increase due to secondary effects from an increased intracellular concentrations of cyclic AMP. Clinically, the insidious increase in the number and size of renal cysts translates as a progressive increment in kidney volume. Studies led by Mayo Clinic professionals established that the total kidney volume in a large cohort of ADPKD patients was 1060 ± 642ml with a mean increase of 204ml over three years, or 5.27% per year in the natural course of the disease, among other important, novel findings that were extensively studied for the first time. The diagnosis of ADPKD is performed by renal imaging using ultrasound, CT scan, or MRI. However, molecular diagnostics can be necessary in the following situations: 1- when a definite diagnosis is required in young individuals, such as a potential living related donor in an affected family with equivocal imaging data.

Blinding (punishment)

Blinding is a type of physical punishment which results in complete or nearly complete loss of vision. It torture; the punishment has been used since Antiquity. In the Byzantine Empire and many other historical societies, blinding was accomplished by gouging out the eyes, sometimes using a hot poker, by pouring a boiling substance, such as vinegar, on them. Oedipus gouged out his own eyes after accidentally fulfilling the prophecy that he would end up killing his father and marrying his mother. In the Bible, Samson was blinded upon his capture by the Philistines. Early Christians were blinded as a penalty for their beliefs. For example, St. Lucy's torturers tore out her eyes. In the Middle Ages, blinding was used as a penalty for treason or as a means of rendering a political opponent unable to rule and lead an army in war. Byzantine general Belisarius is said to have been blinded at the order of the Emperor Justinian. Vazul of the Hungarian royal House of Árpád was blinded at the order either of his cousin King Stephen I or of his queen, Gisela.

After the Battle of Kleidion of 1014, the Byzantine Emperor Basil II had captured several thousand soldiers from the Bulgarian Empire. He blinded 99 in every group; the last soldiers had only one eye gouged out, these one-eyed men were ordered to lead their blind friends back to their commander. This earned Emperor Basil II the nickname of'the Bulgar Slayer'. According to some accounts of the story, Tsar Samuel of Bulgaria died from a heart attack upon seeing the returning blind soldiers. In the 11th century, William the Conqueror used blinding as a punishment for rebellion to replace the death penalty in his laws for England. King William was accused of making the killing of a hart or hind in a royal forest into a crime punishable by blinding, but the Anglo-Saxon Chronicle claims that this was made up to tarnish the King's reputation. Henry I of England blinded William, Count of Mortain, who had fought against him at Tinchebray in 1106, he ordered blinding and castration as a punishment for thieves.

Prince Álmos and his four-year-old son Béla II of Hungary were blinded in 1113 by Álmos' brother Coloman. Blinding survives as a form of penalty in the modern era on the Indian Subcontinent. In 2003, a Pakistani court sentenced a man to be blinded after he subjected his fiancee to an acid attack resulting in loss of vision; the man who blinded Ameneh Bahrami in an acid attack was sentenced to blinding by an Iranian court in 2009. Mirror punishment Mutilation

Malaysian State Roads system

Malaysian State Roads System are the secondary roads in Malaysia. The construction of state roads in Malaysia is funded by Malaysian Public Works Department of each state; the standard of the state roads is similar with the federal roads except for the coding system, where the codes for state roads begin with state codes followed by route number, for example Johor State Route J32 is labeled as J32. If a state road crosses the state border, the state code will change, for example route B20 in Salak Tinggi, Selangor will change to N20 after crossing the border of Negeri Sembilan to Nilai; the codes assigned to each state is the same. A: Perak B: Selangor C: Pahang D: Kelantan J: Johor K: Kedah M: Malacca N: Negeri Sembilan P: Penang R: Perlis SA: Sabah T: Terengganu W: Wilayah Persekutuan Kuala Lumpur Q: Sarawak Municipal roads are not given a route number, as they are maintained by the local councils. An exception is some major roads in the capital of Selangor. For example, Persiaran Raja Muda in Shah Alam was given route number BSA-3.

Road signs in Malaysia National Speed Limits Malaysian Expressway System Malaysian Federal Roads System