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By O. Stejnar. Hanover College.

Other names include glyco- vents the proper breakdown of oligosaccharides and protein neuraminidase deficiency cheap rumalaya forte 30 pills visa spasms in upper abdomen, NEUG deficiency buy rumalaya forte 30pills with mastercard spasms temporal area, glycoproteins that contain sialic acid and the disorder is NEU or NEU1 deficiency, and neuraminidase 1 defi- ciency. Sialidosis type I sometimes is referred to as juve- characterized by the accumulation and excretion of these nile sialidosis and type II as infantile sialidosis, in substances. In addition to interfering with the lysosomal break- down of sialic acid compounds, neuraminidase defi- Lysosomal storage diseases ciency can lead to abnormal proteins. Following protein Lysosomes are membrane-bound spherical compart- synthesis, some lysosomal enzymes reach the lysosome ments or vesicles within the cytosol, the semi-fluid areas in an inactive form and require further processing for of cells. One such processing step is the neuramini- enzymes that are responsible for digesting, or hydrolyz- dase-catalyzed removal of sialic acid residues from ing, large molecules and cellular components. Lysosomal hydrolases include proteins, polysaccharides, which are long, linear that require further processing by neuraminidase include or branched chains of sugars, and lipids, which are large acid phosphatase, alpha-mannosidase, arylsulfatase B, insoluble biomolecules that are usually built from fatty and alpha-glucosidase. The smaller breakdown products from the lyso- Under conditions of neuraminidase deficiency, sialy- somes are recycled to the cytosol. These disor- fibroblasts (connective tissue cells), bone marrow cells, ders result from mutations in the genes encoding the Kupffer cells of the liver, and Schwann cells, which form hydrolytic enzymes of the lysosome. Furthermore, proteins some of the macromolecules in the lysosomes cannot be with sialic acid attachments accumulate and can be degraded and they, or their partial-breakdown products, detected in fibroblasts and in the urine. Neuraminidase exists in the lysosome in a high- molecular-weight complex with three other proteins: the Neuraminidase deficiency, particularly sialidosis enzyme beta-galactosidase, the enzyme N-acetylgalac- type II, commonly has been classified as the lysosomal tosamine-6-sulfate sulfatase (GALNS), and a multi-func- storage disease called mucolipidosis type I (ML I), for- tional enzyme called protective protein/cathepsin A merly lipomucopolysaccharidosis. Neuraminidase must be associated with PPCA symptoms of neuraminidase deficiency are similar to var- in order for the neuraminidase to reach the lysosome. However mucolipidoses Once inside the lysosome, PPCA mediates the associa- are characterized by the accumulation of large and com- plex lipid-polysaccharides. In contrast, neuraminidase tion of as many as 24 neuraminidase molecules to form deficiency leads to the accumulation of specific types of active neuraminidase. The active enzyme remains associ- short chains of sugar called oligosaccharides and of cer- ated with PPCA and beta-galactosidase, which appear to tain proteins with oligosaccharides attached to them, be necessary for protecting and stabilizing the neu- called glycoproteins. A distinct lysosomal storage disease, classify neuraminidase deficiency as an oligosaccharide neuraminidase deficiency with beta-galactosidase defi- storage disease, since it leads to the accumulation of ciency, or galactosialidosis, results from mutations in the excess oligosaccharides in various tissues throughout the gene encoding PPCA. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 803 Genetic profile and lead to the rapid degradation of neuraminidase inside the lysosome. Inheritance of neuraminidase deficiency Some mutations in the NEU1 gene lead to a com- Neuraminidase deficiency is an autosomal recessive plete absence of neuraminidase activity, with little or no disorder that can be caused by any one of a number of neuraminidase enzyme present in the lysosomes. These different mutations in the NEU1 gene encoding the lyso- mutations usually result in the severe, infantile-onset, somal neuraminidase. Other mutations result in an inactive the NEU1 gene is located on chromosome 6, rather than protein that is present in the lysosome. The disorder is reces- generally result in juvenile-onset, type II sialidosis, with sive because it only develops when both genes encoding symptoms of intermediate severity. Some mutations sig- neuraminidase, one inherited from each parent, are nificantly reduce, but do not obliterate, neuraminidase defective; however, the two defective NEU1 genes do not activity in the lysosome. If the two mutations mutated gene of this type are not completely neu- are identical, the individual is a homozygote. Individuals with one defective NEU1 gene, leading to more severe forms of neu- gene and one normal gene encoding neuraminidase may raminidase deficiency. Demographics All of the offspring of two parents with neu- Neuraminidase deficiency is an extremely rare disor- raminidase deficiency will inherit the disorder. Because of its similarities to many other disorders, it offspring of one parent with neuraminidase deficiency has been difficult to determine its frequency. In the and one parent with a single defective NEU1 gene will United States, it is estimated to occur in one out of every inherit at least one defective NEU1 gene. In Australia, the estimate is one out a 50% chance of inheriting two defective genes and, of 4. Since neuraminidase deficiency is an auto- therefore, developing neuraminidase deficiency.

Other maternal risk factors that may prove important include good control of diabetes purchase rumalaya forte 30pills on line muscle relaxant menstrual cramps, reduction of obesity and infections discount rumalaya forte 30 pills without a prescription zyprexa spasms, vitamin supplementation (folate, inos- itol, and vitamin B12), and avoidance of over-heated environments like saunas. Additionally, mothers taking valproate and carbamazapine antiepileptic medications should discontinue use or take other medications if possible to eliminate the increased risk. It may be possible in some cases to identify mothers with inheritable genetic predispositions and counsel them during the preconception period in preparation for possible treatment during pregnancy. Several possible medications could be devel- oped to provide genetic targeting during early fetal development. Tools for targeting candidate genes at the DNA, RNA, or protein level are all plausible possibilities. These tools could target defects in genes involved in proper neural tube patterning, folate-dependent and -independent mechanisms, or healing mechanisms. The next decade certainly will see attempts at in vitro correction of genetic defects during the blastocyst stage or manipulation of these genes in utero via delivery systems like viral vectors. Several studies with animal models have elucidated some of the genes involved in the induction of proper neural tube development, for example, Wnt-1, Gnot1 (a notochord family homeobox gene), HOX-1, and activin. The neural tube-inducing prop- erties of sonic and bone morphogenic protein genes are also under intense investi- gation. Alterna- tively, embryonic stem cell lines with normal genes may be introduced into target embryos by blastocyst injection, producing chimeras expressing enough of the nor- mal gene to ameliorate the defective phenotype. Interestingly, folate, the earliest magic pill, has been shown to prevent NTD in the Sp and other mouse models with mutations in Cart1 and crooked tail genes. Currently available viral vectors could be designed to transfect fetal cells with the normal MTHFR gene. Hyperhomocysteinemia may also be due to reduced folate-dependent homocysteine remethylation, which provides another interesting mechanism for treating NTD. Cytosine methylation on CpG dinucleotides of genomic DNA is one of many forms of DNA modifications that help maintain stability of numerous regions of genomic DNA. The areas of methylation that change during embryogenesis are at transposable element inser- tion sites in the genome that underlie epigenetic-induced phenotypic variability. It is hypothesized that such a mechanism may underlie the corrected NTD phenotype in folate supplementation. Another compound that prevented folate resistance NTD in the curly tail mouse and recently in humans is inositol. All these therapeutic measures are meant to prevent or correct defects early enough in devel- opment to prevent NTDs. Most forms of what we can designate as “magic repairs” are applied during intrauterine development or after birth. Both paradigms are designed to minimize further risk, prevent progressive functional loss, and possibly reverse neurological deterioration. Clearly, in the case of an open NTD, reversal of paralysis or sacral dysfunction is not expected or attained. For example, fetal ultrasonography revealed that human fetuses with myelomeningoceles retained lower extremity movements early in gestation and that the movements were lost by term. Parameters undergoing study include optimal timing, neurological recovery, and effects of repairs on associated hydrocephalus and Chiari II malformations. The study is comparing two approaches to the treatment of babies with spina bifida: surgery before birth (prenatal surgery) and the standard closure surgery after birth (postnatal surgery). Furthermore, when it appeared that spinal cord function was present to a degree, it was less than predicted based on data from the animal models. If the placode retains normal patterning and is simply un-neurulated, a repair may be effective in preventing secondary injury. Conversely, George and Cummings characterized the placode as having abnor- mal patterning along the dorsoventral and rostrocaudal axes indicative of a change © 2005 by CRC Press LLC in pattern determination and a paucity of maturing neurons with evidence of signif- icant inflammatory infiltrate, gliosis, and fibrosis consistent with secondary injury. All mammals except mice had spina bifida lesions in which the skin, muscle, lamina, and dura were opened, but the spinal cord itself was not dis- turbed. These surgical models represent a reopening mechanism of a closed neural tube that has not been shown to appear in humans, but was reported in curtailed mouse mutants. However, transforming growth factor-beta and hyaluronic acid-rich wound matrix play pivotal roles in scarless repair.

Primitive cells in the walls of these Primitive Mature Interstitial cells tubules develop into mature spermatozoa 30 pills rumalaya forte for sale muscle relaxant and nsaid, aided by spermatozoa spermatozoa neighboring cells called sustentacular (sus-ten-TAK-u- lar) (Sertoli) cells discount rumalaya forte 30pills spasms pelvic area. In males, these traits in- epididymis (ep-ih-DID-ih-mis), which is 6 meters (20 clude a deeper voice, broader shoulders, narrower hips, feet) long and is located on the surface of the testis inside a greater percentage of muscle tissue, and more body the scrotal sac (see Fig. The secretions in semen serve several functions: ◗ Nourish the spermatozoa Head ◗ Transport the spermatozoa Acrosome ◗ Neutralize the acidity of the male urethra and the fe- Neck male vaginal tract ◗ Lubricate the reproductive tract during sexual inter- Nucleus course ◗ Prevent infection with antibacterial enzymes and anti- Midpiece Mitochondria bodies The glands discussed next contribute secretions to the semen (see Fig. The glandular lining produces a thick, yellow, alka- line secretion containing large quantities of simple sugar and other substances that provide nourishment for the sperm. The thin, alkaline prostatic sum enlarges to form the glans penis, which is covered secretion helps neutralize the acidity of the vaginal tract with a loose fold of skin, the prepuce (PRE-puse), com- and enhance the motility of the spermatozoa. It is the end of the foreskin that prostate gland is also supplied with muscular tissue, is removed in a circumcision (sir-kum-SIZH-un), a sur- which, upon signals from the nervous system, contracts gery frequently performed on male babies for religious or to aid in the expulsion of the semen from the body. Experts disagree on the medical value of circumcision with regard to improved cleanliness and Bulbourethral Glands The bulbourethral (bul-bo-u- disease prevention. RE-thral) glands, also called Cowper glands, are a pair of The penis and scrotum together make up the external pea-sized organs located in the pelvic floor just inferior to genitalia of the male. During ejaculation, the involuntary Checkpoint 23-6: What glands, aside from the testis, contribute sphincter at the base of the bladder closes to prevent the secretions to semen? Out of the The Urethra and Penis millions of spermatozoa in an ejaculation, only one, if The male urethra, as discussed in Chapter 22, serves the any, can fertilize an ovum. At the distal end of the penis, the corpus spongio- ◗ Follicle-stimulating hormone (FSH) stimulates the sustentacular (Sertoli) cells and promotes the forma- Dorsal artery tion of spermatozoa. Dorsal veins ◗ Luteinizing hormone (LH) stimulates the interstitial cells between the seminiferous tubules to produce Dorsal nerve testosterone, which is also needed for sperm cell devel- opment. Corpus spongiosum tissue As the blood level of testosterone increases, the hypothal- Skin amus secretes less releasing hormone; as the level of Figure 23-5 Cross-section of the penis. In this procedure, a portion of the ductus deferens on each side is removed, and the cut end is closed to keep spermatozoa from The Effects of Aging on Male reaching the urethra. A man who has had a vasectomy retains the A gradual decrease in the production of testosterone and ability to produce hormones and all other seminal secre- spermatozoa begins as early as 20 years of age and con- tions as well as the ability to perform the sex act, but no tinues throughout life. The proportion of infertility in couples that can be attrib- This turning may occur during descent of the testis or uted to defects involving the male has been estimated later in life, most commonly between the ages of 8 to 18 from 40% to 50%. It requires The tubules of the testes are sensitive to x-rays, infec- emergency surgery to correct the defect, and may involve tions, toxins, and malnutrition, all of which bring about removal the testis (orchiectomy). Such damage may cause a decrease developmental disorder that often affects both glands, so in the numbers of spermatozoa produced, leading to a the other testis must be examined to determine whether condition called oligospermia (ol-ih-go-SPER-me-ah). Adequate numbers of sperm are required to disperse the Hernia (HER-ne-ah), or rupture, refers to the abnor- coating around the ovum so that one sperm can fertilize mal protrusion of an organ or organ part through the wall it. Hernias most often occur where there is a weak area Box 23-1 Clinical Perspectives Treating Erectile Dysfunction: When NO Means YesTreating Erectile Dysfunction: When NO Means Yes pproximately 25 million American men and their partners Physical factors that cause ED prevent these physiological oc- Aare affected by erectile dysfunction (ED), the inability to currences. Although ED is more common in men over Until recently, treatment options for ED, such as penile in- the age of 65, it can occur at any age and can have many causes. It is now known that many Today, drugs that target the physiologic mechanisms that un- cases of ED are caused by physical factors, including cardiovas- derlie erection are giving men who suffer from ED new hope. Sexual arousal stim- cause some relatively minor side effects, including headache, ulates parasympathetic nerves in the penis to release a com- nasal congestion, stomach upset, and blue-tinged vision. Via- pound called nitric oxide (NO), which activates the vascular gra should never be used by men who are taking nitrate drugs smooth muscle enzyme guanylyl cyclase. Because nitrate drugs elevate NO levels, taking alyzes production of cyclic GMP (cGMP), a potent vasodilator them with Viagra, a drug that prolongs the effects of NO, can that increases blood flow into the penis to cause erection. Infections Sexually transmitted infections (STI), formerly known as sexually transmitted diseases (STD) or venereal diseases Epididymis (VD), are spread through sexual contact in both males and females. The infection may travel along the mucous membrane into the prostate gland and the A B epididymis; if both sides are affected and enough scar tis- sue is formed to destroy the tubules, sterility may result. Because syphilis In this region, during development, the testis pushes its spreads quickly in the bloodstream, it is regarded as a sys- way through the muscles and connective tissues of the temic disorder (see Appendix 5, Table 1). The genital ul- abdominal wall, carrying with it the blood vessels and cers caused by syphilis increase the chances of infection other structures that form the spermatic cord. A congenital mal- Phimosis (fi-MO-sis) is a tightness of the foreskin formation in the urinary tract can predispose to epi- (prepuce), so that it cannot be drawn back. While not Sgonorrhea, genital herpes, HIV, and syphilis are some of the 100% effective, condoms greatly reduce the risk of con- most common infectious diseases in the United States, affect- tracting an STI. Women may be diseases are associated with complications such as pelvic in- more infectious as well as more susceptible to certain flammatory disease, epididymitis, infertility, liver failure, neu- STIs during this time.

This form of somatosensory feedback allows the encoding of spatiotemporal patterns of vibration in the skin order 30pills rumalaya forte overnight delivery muscle relaxant images. Sandler and colleagues43 are currently looking at the electrophysiological changes that occur during conditional motor learning in owl monkeys using this kind of feedback buy 30 pills rumalaya forte overnight delivery spasms piriformis. After training, the subject could learn to use this source of feedback as a source of information that is supplementary to visual feedback. Availability of this “soma- tosensory” feedback in a BMI could be very advantageous in real life situations where a clear visual perception of the artificial limb is absent. These include the type of brain signals17–19,44 (single unit, multiple unit, or field potentials) that would provide the optimal input for a such a device, and the number of single units (small [8–30]6,7 or substantially larger [hundreds to thousands]9,10) that may be necessary to operate a BMI efficiently for many years. These and other questions were investigated in our recent study in which we showed how macaque monkeys learned to use a BMI to reach and grasp virtual objects with a robot even in the absence of overt arm movement signals. Monkeys were implanted with multiple arrays (96 in monkey 1, and 320 in monkey 2) in several frontal and parietal cortical areas (PMd, M1, supplementary motor area [SMA], S1, and posterior parietal [PP]). In this study we used multiple linear models, similar to the one described in Section 1. Although all these parameters were extracted in real time in each session, only some of them were used to control the BMI, depending on each of the three tasks the monkeys had to solve in a given day. In each recording session, an initial 30-minute period was used for training of these models. During this period, monkeys used a handheld pole either to move a cursor on the screen or to change the cursor size by application of GF to the pole. As the models converged to an optimal performance, their coefficients were fixed and the control of the cursor position (tasks 1 and 3) and/or size (tasks 2 and 3) was obtained directly from the output of the linear models. During the brain control mode, animals initially produced arm movements, but they soon realized that these were not necessary and ceased to produce them for periods of time. Accurate performance was possible because large populations of neurons from multiple cortical areas were sampled, showing that large ensembles are preferable for efficient operation of a BMI. This conclusion is consistent with the notion that motor programming and execution is represented in a highly distributed fashion across frontal and parietal areas, and that each of these areas contains neurons that represent multiple motor parameters. We suggest that, in principle, any of these areas could be used to operate a BMI, provided that a large enough neuronal sample was obtained. This is supported by the analysis of neuron dropping curves9,10 shown in Color Figures 13. Although all cortical areas surveyed contained information about any given motor parameter, for each area different numbers of neurons were required to achieve the same level of prediction. Although a significant sample of M1 neurons consistently provides the best predictions of all motor parameters analyzed, neurons in areas such as SMA, S1, PMd, and PP contribute to BMI performance as well. Another important finding of this study is that accurate real-time prediction of all motor parameters as well as a high level of BMI control can be obtained from multiple-unit signals. This observation is essential because it eliminates the need to develop elaborated real-time spike-sorting algorithms, a major technological chal- lenge, in the design of a future cortical neuroprosthesis for clinical applications. That difference was, however, not critical, as the animals could still maintain high levels of BMI performance in all tasks using multiple-unit activity only. Our experiments demonstrated, for the first time, that monkeys can learn to control a BMI to produce a combination of reaching and grasping movements in * See color insert following page 170. Robot position was translated into cursor position on the screen, and feedback of the gripping force was provided by changing the cursor size. In task 2 the pole was stationary, and the monkey had to grasp a virtual object by developing a particular gripping force instructed by 2 red circles displayed on the screen. The monkey had to move the cursor to the target and then develop a gripping force necessary to grasp a virtual object. From top to bottom, hand position (HPX, HPY) and velocity (HVx, HVy) during execution of task 1, and gripping force (GF) during execution of tasks 2 and 1. Top plots show X-coordinate of the cursor; plots below display EMGs of wrist flexors, wrist extensors, and biceps. The major challenge in task 3 was to predict hand position and gripping force simultaneously using the activity recorded from the same neuronal ensemble. This problem could not be reduced to predicting only hand position as in task 1 or gripping force in task 2, because the animal had to reach for and grasp the target sequentially.