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Case Study: Fading Memory
Each of these brightly colored sticky notes represents a piece of information that someone doesn’t want to forget. Although we are all forgetful sometimes, most people do not have trouble remembering things that are important or routine to us, such as our friend’s name or how to get to class. Our brain, the control center of the nervous system and the rest of the body, normally allows us to retain and recall information. But if the brain becomes damaged, a person may need to rely excessively on external reminders — like this wall of sticky notes — rather than being able to trust their own memory. That is if they are able to remember to write things down in the first place.
One person having trouble with their memory is Rosa, who is 68 years old. Rosa has been having difficulty remembering where she has set down objects in her house and forgot about a few doctor’s appointments and lunches she planned with friends. Her family began to notice that she would sometimes not recall recent conversations, requiring them to repeat things to her. Rosa would also sometimes struggle to find the right word in a conversation and would put objects in unusual places, such as the milk in a cabinet instead of the refrigerator. While most people do things like this occasionally, it seemed to Rosa and her family that it was happening to her more often recently.
She also had some other symptoms that were impacting her life, such as having trouble paying her bills on time and managing her budget, which she had previously done well. Rosa ascribed these lapses in memory and mental functioning to the normal effects of aging, but her family was concerned. They noticed that she was also more irritable than usual and would sometimes verbally lash out at them, which was not like her. When she became disoriented on a walk around her neighborhood and a neighbor had to escort her home, her family convinced her to see a doctor.
Besides a complete physical exam and lab tests, Rosa’s doctor interviewed Rosa and her family about her memory, ability to carry out daily tasks, and mood changes. He also administered a variety of tests to assess her memory and cognitive functioning, such as her ability to solve problems and use numbers and language correctly. Finally, he ordered a scan of her brain to investigate whether a tumor or some other observable cause was causing changes in the functioning of her brain.
Based on the results of these tests, Rosa’s doctor came to the conclusion that she most likely has mild Alzheimer’s disease (AD). AD results from abnormal changes in the molecules and cells of the brain, characterized by clumps of proteins called amyloid plaques between brain cells and tangled bundles of protein fibers called neurofibrillary tangles within certain brain cells. The affected brain cells stop functioning properly, lose their connections to other brain cells, and eventually will die. The picture below shows part of a cross-section of a brain from a patient who had severe AD compared to a similar section of a healthy brain. You can see how severely shrunken the brain with AD is, due to the death of many brain cells.
AD is a progressive disease, which means the damage and associated symptoms get worse over time. Clinicians have categorized the progression into three main stages — mild, moderate, and severe AD. Typically, AD cannot be definitively diagnosed until after death when the brain tissue can be directly examined for plaques and tangles. However, based on Rosa’s symptoms and the results of her tests, her doctor thinks she most likely has mild AD, when the brain changes and resulting symptoms are not yet severe.
Although there is currently no cure for AD, and Rosa will eventually get worse, her doctor says that medications and behavioral therapies may improve and prolong her functioning and quality of life over the next few years. He prescribes a medication that improves communication between brain cells, which has been shown to help some people with AD.
As you read this chapter, you will learn much more about how the brain and the rest of the nervous system work, and the multitude of functions they control in the body. By the end of the chapter, you will have enough knowledge about the nervous system to learn more about why AD causes the symptoms that it does, how Rosa’s medication works, and some promising new approaches that may help physicians diagnose and treat AD patients at earlier stages.
Chapter Overview: Nervous System
In this chapter, you will learn about the human nervous system, which includes the brain, spinal cord, and nerves. Specifically, you will learn about:
- The organization of the nervous system, including the central and peripheral nervous systems and their organs and subdivisions.
- The cells of the nervous system — neurons and glia — their parts, and their functions.
- How messages are sent by neurons through the nervous system and to and from the rest of the body.
- How these messages, or nerve impulses, are transmitted by electrical changes within neurons, and through chemical molecules to other cells.
- The structure and functions of different parts of the central nervous system, which includes the brain and spinal cord, and some of the things that can go wrong when they are damaged.
- The structure and functions of the peripheral nervous system, which includes the nerves that carry motor and sensory information to and from the body to control voluntary and involuntary activities.
- The human senses and how visual information, sounds, smells, tastes, touch, and balance are detected by sensory receptor cells and then sent to the brain for interpretation.
- How legal and illegal drugs can have psychoactive effects on the brain-altering mood, perceptions, thinking, and behavior — which can sometimes lead to addiction.
As you read the chapter, think about the following questions:
- Based on Rosa’s symptoms, which parts of her brain may have been affected by Alzheimer’s disease?
- How are messages sent between cells in the nervous system? What molecules are involved in this process? What are the ways in which drugs can alter this process?
- Why can’t Rosa’s brain just grow new cells to replace the ones that have died?
Her name was Marie Stopes, and she was a British author and paleobotanist who lived from 1880 to 1958. She is pictured in Figure 18.11.1 in her lab next to her microscope. Stopes made significant contributions to science and was the first woman on the faculty of the University of Manchester in England. Her primary claim to fame was her work as a family planning pioneer.
Along with her husband, Stopes founded the first birth control clinic in Britain. She also edited a newsletter called Birth Control News, which gave explicit practical advice on how to avoid unwanted pregnancies. In 1918, she published a sex manual titled Married Love. The book was controversial and influential, bringing the subject of contraception into wide public discourse for the first time.
Skull
The skull is the part of the human skeleton that provides a bony framework for the head. It consists of 22 different bones. There are eight bones in the cranium, which encloses the brain, and 14 bones in the face.
Cranium
The cranium forms the entire upper portion of the skull. As shown in Figure 11.3.3, it consists of eight bones: one frontal bone, two parietal bones, two temporal bones, one occipital bone, one sphenoid bone, and one ethmoid bone. The ethmoid bone separates the nasal cavity from the brain. The sphenoid bone is one of several bones, including the frontal bone, that help form the eye sockets. The other bones of the cranium are large and plate-like. They cover and protect the brain. The bottom of the skull has openings for major blood vessels and nerves. A large opening, called the foramen, connects the spinal cord and brain.
Figure 11.3.3 The cranium consists of eight bones that are fused together at their joints.
Facial Bones
The 14 facial bones of the skull are located below the frontal bone of the cranium, and they are depicted in Figure 11.3.4. Large bones in the face include the upper jaw bones, or maxillae (singular, maxilla), which form the middle part of the face and the bottom of the two eye sockets. The maxillae are fused together, except for an opening between them for the nose. The lower edge of the maxillae contains sockets for the upper teeth. The lower jaw bone, or mandible, is also large. The top edge of the mandible contains sockets for the lower teeth. The mandible opens and closes to chew food and is controlled by strong muscles. There are two zygomatic (or cheek) bones and two nasal bones. The nasal region also contains seven smaller bones, as indicated in Figure 11.3.4.
Figure 11.3.4 The 14 bones that make up the face are labeled in this drawing of the skull.
Results
Participant characteristics
Between May and August 2016, a total of 762 adult participants, including 378 (43.4% male) AUF participants (AUFs) and 384 (43.0% male) afebrile participants (Controls), were included in this analysis ( Figure 1 ). The median (interquartile range [IQR]) ages of the AUFs and Controls were 38 (25�) and 42 (27�.5) years, respectively.
Flowchart of the enrolment of patients with AUF.
Of the 378 AUFs, 168 patients (44.4%) were farmers, 41 patients (11.1%) performed forest-related activities, and 38 patients (10.1%) had a chronic disease or comorbid condition ( Table 1 ). Patients with AUF usually had high fever and a short course of illness, with a mean peak temperature of 39.2ଌ (95% CI: 39.1�.3) and a median febrile duration of 5 (4𠄶) days. The most common accompanying symptom was headache (81.0%), followed by disappetite (54.5%), muscle pain (44.3%), dizziness (37.5%), cough (30.4%), back pain (28%) and other less frequent symptoms. A small proportion of AUFs also presented some clinical signs, such as rash (4.3%), lymphadenopathy (4.0%), eschar (3.2%), haemorrhage (2.4%), hepatomegaly (0.8%) and splenomegaly (0.5%). Shock, altered mental status, and seizures were not observed in our patients. The overall median (IQR) white blood cell count (WBC) was 6.9 (5𠄹.1) ×� 9 /L, and approximately one-fifth of the patients presented with an abnormal WBC classified as either leukocytosis (WBC >� ×� 9 /L 35 [9.3%] patients) or leukopenia (WBC <𠂔 ×� 9 /L 50 [13.2%] patients). The overall median (IQR) platelet count (PLT) was 176.5 (133�) ×� 9 /L, and one-third of the patients (129 patients 34.1%) exhibited thrombocytopenia (PLT <� ×� 9 /L). The median (IQR) values of the aspartate aminotransferase level (AST) and alanine aminotransferase level (ALT) were 31.5 (23�.5) and 26.5 (15.5�.5) IU/L, respectively. Abnormal aminotransferase levels were observed in 116 (30.7%) patients, which presented either an elevated level of one (elevated AST in 21 cases, elevated ALT in 6 cases) or both of the enzymes (89 cases). Abdominal ultrasound confirmed some cases presenting with hepatomegaly or splenomegaly but did not indicate other abnormal signs. The chest X-ray and urine analysis results did not indicate specific abnormalities in any cases. No patients were excluded because of being human immunodeficiency virus (HIV) positive. No specific aetiological diagnoses were made for any febrile patients during the sampling period.
Table 1.
Notes: ⁑ Clinicians assessed the patients clinically and confirmed by ultrasound.
a Data are missing in 7 cases b data are missing in 2 cases c data are missing in 3 cases d data are missing in 4 cases e data are missing 1 case f data are missing in 86 cases.
Whole blood, plasma, urine and throat swab specimens were collected from all the participants at the time of enrolment in the study. In addition, 260 (68.8%) convalescent-phase plasmas were obtained from patients with AUF who returned to the hospital after discharge. Additionally, eschar swab specimens were collected for aetiology analyses from 10 of 12 AUF patients presenting an eschar.
Infectious disease agents identified
Vector-borne diseases agents and Leptospira
Rickettsial agents, dengue virus and Leptospira were identified in 41 (10.8%), 29 (7.7%) and 18 (4.8%) AUFs, respectively, and in one (0.3%), two (0.5%) and three (0.8%) Controls, respectively (p < .05) ( Table 2 ). Among the rickettsial agents detected in AUFs, O. tsutsugamushi was found in more than half of the cases (21/41 patients 51.2%), and R. typhi (18/41 patients 43.9%) and R. felis (2/41 patients 4.9%) were found in smaller proportions of cases (Table S1). R. felis was also detected in one control. Anaplasma spp., Bartonella spp., Borrelia spp., or C. burnetii were not found. Among the dengue agents observed in AUFs, dengue virus serotype-1 (DEN-1) was found in slightly more than three-quarters of the patients (22/29 patients 75.9%), and DEN-4 (5 patients 17.2%) and DEN-2 (2 patients 6.9%) were detected in smaller proportions of the patients.
Table 2.
Notes: qPCR = real-time polymerase chain reaction, qRT-PCR = real-time reverse-transcription polymerase chain reaction, IFA = indirect immunofluorescence assay, WB = western blot.
a Four cases were positive in both eschar and whole blood specimens.
b One case was positive in only the blood specimen, and one case was positive in only the eschar specimen.
Respiratory viruses and bacteria
At least one pathogen was detected in the throat swabs from 246 AUFs (65.1%) and 195 Controls (50.8%) (p < .001). In most positive cases (59.4% of AUFs and 71.3% of Controls), a single pathogen was detected, whereas several pathogens were detected in the remaining positive cases (Figure S1). Specifically, six viruses and seven bacteria were found in the throat swabs from the AUFs, whereas five viruses and eight bacteria were found in those from the Controls ( Table 3 , Figure 2 ).
Detected pathogens and their frequency in throat swabs from patients with AUF and controls in central Vietnam.
Table 3.
Influenza virus was the most frequently detected virus (79 patients 20.9%) in AUFs and was not found in Controls (p < .001). Similarly, enterovirus was detected in eight (2.1%) patients with AUFs but not in Controls (p < .001), and adenovirus was found in 18 (4.8%) patients with AUFs and four (1.0%) Controls (p < .05). In contrast, other viruses, including parainfluenza virus, respiratory syncytial viruses (RSV) A/B and coronaviruses, were detected in AUFs and Controls at similar frequencies.
Klebsiella pneumoniae was the most common bacterium found in both groups (109 [28.8%] AUFs and 100 [26.0%] Controls). Haemophilus influenzae (73 [19.3%] AUFs and 61 [15.9%] Controls) and Streptococcus pneumoniae (50 [13.2%] AUFs and 41 [10.7%] Controls) were also commonly detected. Some less common bacteria, including Staphylococcus aureus, Mycoplasma pneumoniae and Moraxella catarrhalis, were also found in a small number of AUFs and Controls. No significant difference in the proportion of bacteria detected in throat swabs was found between AUFs and Controls.
We also investigated the relationship between the occurrence of viruses and bacteria in AUFs, but the correlation test showed no correlation among the detected viruses and bacteria (Table S2).
Multiple pathogen detection
A substantial proportion of pathogen codetection was identified in this study. O. tsutsugamushi was present as the single pathogen in 19 patients and was accompanied by Leptospira in two patients. Influenza virus was the most frequently observed in codetection cases (46/79 58%) with one additional pathogen (K. pneumoniae [n =�], H. influenza [n =𠂖], S. pneumoniae [n =𠂕], Leptospira [n =𠂓], S. aureus [n =𠂑]) or two additional pathogens (H. influenza and K. pneumoniae [n =𠂖], H. influenza and S. pneumoniae [n =𠂕], S. pneumoniae and K. pneumoniae [n =𠂒], coronavirus OC43 and K. pneumoniae [n =𠂑], S. aureus and H. influenza [n =𠂑], S. aureus and K. pneumoniae [n =𠂑]). Adenovirus (n =𠂙), enterovirus (n =𠂒) and coronavirus 229E (n =𠂑) were also observed in combination with other viruses or bacteria. Other codetections included the detection of two or three bacteria in throat swabs, and S. pneumoniae, K. pneumoniae and H. influenza were the most frequently observed bacteria in these cases.
Clinical characteristics of the most frequent causes of AUF
Analyses of the clinical characteristics of patients who presented with single scrub typhus, murine typhus, leptospirosis, dengue fever, influenza and other respiratory viral infections are described in Table 4 . Patients with scrub typhus were more likely to perform forest-related activities (47.4%) and to have eschar (47.4%) and elevated aminotransaminase (AST, ALT) levels than those with other diagnoses (p < .05). Patients with murine typhus had febrile durations (8.5 [6�] days) longer than those of patients with other diagnoses (except those with scrub typhus), and patients with leptospirosis presented a medium course of fever (5.5 [4𠄷] days). Patients with dengue fever exhibited lower WBC and PLT counts than nearly all the patients with other diagnoses (p < .05). Cough was more frequently observed in patients with influenza (63.6%) than in patients with other diagnoses (p < .05). Patients with noninfluenza respiratory viral infection were young, and cough (21.4%) was observed less frequently in these patients than in patients with influenza.
Table 4.
| Characteristics | Scrub typhus (n =�) | Murine typhus (n =�) | Leptospirosis (n =�) | Dengue fever (n =�) | Influenza (n =�) | Nonflu RVI (n =�) |
|---|---|---|---|---|---|---|
| Age (years) a | 47.4 (18.4) ϵ γ | 42.7 (17.3) λ | 35.4 (18.3) | 35.3 (16.1) γ | 43.6 (21.3) ‡ | 28.6 (16.1) ϵ λ ‡ |
| Forest exposure, n (%) | 9 (47.4) α β γ δ ϵ | 0 α | 1 (8.3) β | 3 (11.1) c γ | 0 δ | 1 (7.1) ϵ |
| Fever duration (days) b | 7.5 (5𠄹.5) δ | 8.5 (6�) ζ η θ λ | 5.5 (4𠄷) ζ | 6 (5𠄷) η σ | 5 (4𠄶) δ θ σ | 5 (4𠄶) λ |
| Peak T°(ଌ) a | 39.2 (0.7) | 39.8 (0.8) θ | 39.5 (1.1) | 39.6 (0.7) σ | 39.0 (0.7) θ σ | 39.2 (0.8) |
| Headache, n (%) | 18 (94.8) β γ | 17 (94.4) ζ η | 8 (66.7) β ζ | 18 (64.3) γ η | 26 (78.8) | 11 (78.6) |
| Nausea, n (%) | 1 (5.3) | 3 (16.7) | 3 (25) | 6 (21.4) | 9 (27.3) | 4 (28.6) |
| Vomiting, n (%) | 1 (5.3) | 3 (16.7) | 1 (8.3) | 2 (7.1) | 3 (9.1) | 2 (14.3) |
| Diarrhoea, n (%) | 0 | 2 (11.1) | 2 (16.7) | 3 (10.7) | 5 (15.2) | 1 (7.1) |
| Sore throat, n (%) | 1 (5.3) | 2 (11.1) | 3 (25) | 4 (14.3) | 9 (27.3) | 4 (28.6) |
| Cough, n (%) | 6 (31.6) δ | 5 (27.8) θ | 1 (8.3) π | 3 (10.7) σ | 21 (63.6) δ θ π σ ‡ | 3 (21.4) ‡ |
| Abdominal pain, n (%) | 5 (26.3) | 5 (27.8) | 2 (16.7) | 5 (17.9) | 8 (24.2) | 3 (21.4) |
| Muscle pain, n (%) | 11 (57.9) | 8 (44.4) | 6 (50) | 10 (35.7) | 11 (33.3) | 7 (50) |
| Joint pain, n (%) | 7 (36.8) γ δ ϵ | 5 (27.8) λ | 2 (16.7) | 4 (14.3) γ | 4 (12.1) δ | 0 ϵ λ |
| Rash, n (%) | 1 (5.3) | 3 (16.7) η θ | 1 (8.3) | 0 η | 0 θ | 0 |
| Haemorrhage, n (%) | 0 | 0 | 0 | 2 (7.4) c | 1 (3.0) | 0 |
| Eschar, n (%) | 9 (47.4) α β γ δ ϵ | 0 α | 0 β | 0 γ | 0 δ | 0 ϵ |
| Lymphadenopathy, n (%) | 8 (42.1) γ δ ϵ | 1 (5.6) | 1 (8.3) | 1 (3.6) γ | 0 δ | 0 ϵ |
| WBC (k/µL) b | 8.2 (5.5𠄹.1) γ δ | 6.3 (5.0𠄷.9) η | 7.4 (6.8𠄸.5) μ π | 4.3 (3.0𠄶.2) γ η μ φ | 5.4 (3.8𠄷) δ π ‡ | 8.0 (5.7𠄹.8) φ ‡ |
| PLT (k/µL) b | 140.5 (103.5�) | 133.5 (116.5�) η λ | 165.5 (134.5�.5) μ | 118 (65.5�.5)η μ σ φ | 165 (132�) σ | 199.5 (153�) λ φ |
| AST (IU/L) b | 125 (67�) α β γ δ ϵ | 73.5 (34�) α θ λ | 44 (23�) β | 38 (26�) γ σ | 25 (21�) δ θ σ | 39 (16�) ϵ λ |
| ALT (IU/L) b | 106 (77�) α β γ δ ϵ | 50 (27�) α θ λ | 44 (18�) β | 29 (22�) γ σ | 15 (13�) δ θ σ | 26 (13�) ϵ λ |
Notes: Nonflu RVI = noninfluenza respiratory viral infection.
α Scrub typhus vs. Non-ST RI, β Scrub typhus vs. Leptospirosis, γ Scrub typhus vs. Dengue fever, δ Scrub typhus vs. Influenza, ϵ Scrub typhus vs. Noninfluenza RVI, ζ Murine typhus vs. Leptospirosis, η Murine typhus vs. Dengue fever, θ Murine typhus vs. Influenza, λ Murine typhus vs. Noninfluenza RVI, μ Leptospirosis vs. Dengue fever, π Leptospirosis vs. Influenza, ς Leptospirosis vs. Noninfluenza RVI, σ Dengue fever vs. Influenza, φ Dengue fever vs. Noninfluenza RVI, and ‡ Influenza vs. Noninfluenza RVI.
a Mean (standard deviation), b median (interquartile range).
c Data are missing in 1 case.
R. felis was detected in two patients, who presented with continuous mild fever, a peak body temperature of 38ଌ�.5ଌ, headache, and normal WBC, PLT, AST and ALT levels. One individual had an eschar with a 5 ×𠂘-mm, painless, centred black crust surrounded by a red halo on the right side of his face ( Figure 3 ). He also had a rash on his face and certain small swollen lymph nodes on his right neck. The remaining patient did not present with eschar, rash or lymphadenopathy.
Eschar on the right face of a patient with Rickettsia felis infection in central Vietnam. Eschar on the right face (a), close-up view of the eschar (b).
Antimicrobial treatment regimens
At least one empiric antibiotic was administered to 188 (49.7%) patients for a course of 5� days. Among these patients, most (152/188 80.9%) received one antibiotic, and the others (36/188 19.2%) received a combination of two or three antibiotics. Among the monotherapy cases, amoxicillin was the most commonly used antibiotic (43/152 28.3%), followed by doxycycline (39/152 25.7%), 2nd/3rd-generation cephalosporin (28/152 18.4%), fluoroquinolones (22/152 14.5%), macrolides (18/152 11.8%), and antimalarial drugs (2/152 1.3%). The most common combination antibiotic therapy was 2nd/3rd-generation cephalosporin and a fluoroquinolone (16/36 44.4%), followed by 2nd/3rd-generation cephalosporin and doxycycline (6/36, 16.7%).
Twenty-nine of 41 (70.7%) patients with a rickettsial infection (16/21 cases of scrub typhus, 12/18 cases of murine typhus, and 1/2 cases of spotted fever caused by R. felis) received anti-rickettsial antibiotics (doxycycline [n =�], azithromycin [n =𠂕], doxycycline and chloramphenicol [n =𠂑]). With the exception of one case of codetection of scrub typhus and leptospirosis, only six of the remaining 17 (35.3%) patients with leptospirosis received the appropriate antibiotics (doxycycline [n =𠂓], amoxicillin [n =𠂒], ceftizoxime [n =𠂑]). All the patients with influenza were not given anti-influenza agents, but approximately half of them (37/79 46.8%) received an antibacterial agent (mainly 2nd/3rd-generation cephalosporin or amoxicillin). None of the patients died, and all the patients who either received an appropriate or inappropriate antibiotic had recovered completely from their illnesses at the time of discharge.
Materials and Methods
Study Population
We conducted a multicenter collaborative study entitled NPC Genes, Environment, and EBV in the Zhaoqing area of Guangdong Province and the Wuzhou and Guiping/Pingnan areas of Guangxi Autonomous Region, China, during 2010 through 2014. A detailed description of the study has been published elsewhere. 38 Briefly, eligible participants were individuals aged 20 to 74 years residing in the study area and were without a history of malignant disease or congenital or acquired immunodeficiency. In total, 3047 patients who had histopathologically confirmed, incident NPC were identified between 2010 and 2013 using a rapid case-ascertainment network of these eligible individuals, 2554 (84%) agreed to participate (cases). In total, 3202 potential controls who were frequency matched on age (within 5 years), sex, and geographic area distribution of the cases were randomly selected from the total population registries covering the study areas. Of the selected individuals, 2648 (83%) consented to participate (controls).
We excluded 1 case and 17 controls who had lost data during the upload process and 6 controls who were outside the eligible age range at the time of the interview. Further data cleaning led to the exclusion of 20 cases and 28 controls who had poor-quality questionnaire data and 7 cases and 6 controls who were missing information on occupational history. To improve the validity of the study, the self-reported occupational exposure data were reviewed by an expert industrial hygienist who was blinded to case-control status. Subsequently, 12 cases and 5 controls were excluded whose occupational data were deemed unreliable by the industrial hygienist, leaving 2514 cases and 2586 controls in the final analysis.
Data Collection
Face-to-face or telephone interviews with study participants were implemented by trained interviewers using a structured electronic questionnaire. Collected information covered demographics body size residential and occupational history history of chronic ear, nose, and respiratory tract conditions family history of NPC and other cancers cigarette smoking alcohol consumption tea consumption dietary habits and use of Chinese herbal medicine. Extensive efforts were made to minimize information bias and ensure the quality of questionnaire data, as described in our previous publication. 38 For instance, logic checks were built into the electronic questionnaire, interviews were audiotaped, and each interviewer was required to interview approximately equal numbers of cases and controls.
With respect to occupational history, the questionnaire (see Supporting Materials) assessed the ages at which individuals started and ended full-time work (>20 hours per week) and all occupations held for ≥1 year, listed from the earliest to the most recent job, including housework. For each job, participants were asked to report their job title, age at the beginning and end of the job, and exposure to any type of occupational dusts, chemical vapors, exhausts/smokes, acids, or alkalis on the job. In particular, the questionnaire listed wood, metals, textiles, leather, cement, asbestos, chalk, coal, soil, incense, and other as types of dust wood preservatives, formaldehyde, organic solvents, pesticides, benzene, dyes, paints, and other as types of chemical vapor diesel, gasoline, coal, firewood, asphalt/tar, nature gas, vehicles, welding, and other as types of exhaust/smoke and sulfuric acid, hydrochloride, nitric acid, concentrated alkali, ammonia, and other as types of acid/alkali. The selection of subtypes of exposures to be evaluated was based on agents associated with deposition or absorption in the nasopharynx that are fairly common in the workplace in southern China.
Statistical Analyses
We compared the distribution of demographics and other potential confounders between NPC cases and controls using χ 2 tests. Multivariate logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for associations between the risk of NPC and occupational exposures. All multivariate models included the frequency matching variables (age, sex, and geographic area [Zhaoqing, Wuzhou, or Guiping/Pingnan]) as well as potential confounders selected based on known or suspected risk factors for NPC that are plausibly related to occupational exposure, ie, educational level (≤6, 7-9, 10-12, or >12 years), current housing type (building [concrete structure], cottage [clay brick structure], or boat), first-degree family history of NPC (yes, no, or unknown), and cigarette smoking (ever or never). Because EBV infection is a strong risk factor for NPC, we also included EBV seropositivity (immunoglobulin A antibodies against viral capsid antigen [VCA-IgA]) as an additional covariate for individuals who had available data.
Duration of occupational exposure was obtained for each participant by totaling the exposure time from each occupation. We used restricted cubic splines to characterize relations between NPC risk and duration of occupational exposure. 39 Linearity of the associations was examined using the Wald χ 2 test. Knots were pre-set at the 5th, 35th, 65th, and 95th percentiles of the distribution of duration on the basis of the sample size of the current study. 40 Because of the nonlinearity trend exhibited for many exposure types, the duration of occupational exposure and the age at first exposure were also categorized by tertiles of the distribution among controls. The unexposed group was used as the reference for comparing subgroups of duration and age at first exposure.
Likelihood ratio tests were conducted to evaluate potential effect modification by sex, age group, education level, current housing type, first-degree family history of NPC, and cigarette smoking. Joint associations were also examined between occupational exposures for example, occupational dust exposures were cross-classified by occupational chemical vapors. An additive interaction was evaluated using the relative excess risk due to interaction. 41
Sensitivity Analyses
To diminish the potential for reverse causality and to assess the robustness of our findings in our primary analysis, we conducted 3 sets of sensitivity analyses with recalculation of the duration of exposure excluding exposures that occurred in the 5 years preceding diagnosis/interview (5-year lag), restricted to individuals aged 30 to 60 years, who are the majority of the workforce (4118 of 5100 individuals 80.7%, or restricted to EBV VCA-IgA–seropositive individuals (557 controls and 2112 cases). Because we performed large numbers of statistical tests, we also calculated P values using the false discovery rate method to correct for multiple comparisons. Because occupational exposure history was assessed retrospectively based on self-report, there was a potential for misclassification bias. To address this issue, we conducted an additional sensitivity analysis with allowance for exposure misclassification under assumptions of various levels of sensitivity and specificity among cases and controls using the SAS macro %sensmac developed by Fox et al. 42
Analyses were performed with SAS version 9.4 (SAS Institute, Inc, Cary, North Carolina). All statistical tests were 2-sided, and a P value < .05 was considered statistically significant.
Ethics
This study was approved by the institutional review boards/ethics review boards at all participating centers. Written or oral informed consent was obtained from all study participants.
Discussion
This is, to our knowledge, the first study that looked at a cohort of stillbirths and compared their characteristics and placental histopathology with two control groups. Fetal growth restriction, and small for gestational age as its proxy, has the strongest association with stillbirth [25]. Our study confirmed a significant relationship between SGA and risk of intrauterine death at term.
Although some risk factors for stillbirth have been identified, the main cause of stillbirth often remains elusive. Previous studies suggest that advanced maternal age is a risk factor for stillbirth [26] but in our study we do not report any significant difference between the groups. Other maternal factors like nulliparity, smoking status, pre-pregnancy BMI and obesity were all statistically significant, confirming data from other studies [25]. Concerning fetal risk factors, stillbirth is strongly related to impaired fetal growth, so both growth restriction and excess growth are risk factors for death during pregnancy [3], therefore obstetrical care should focus on both SGA and LGA pregnancies.
One challenge for our study was that it could only be conducted retrospectively: in fact, if during pregnancy we had noticed any fetuses at risk for adverse outcomes we would have changed the timing of delivery to prevent intrauterine death. In the absence of prospective information about fetal growth, the use of customized percentiles allowed us to determine retrospectively that many of these babies had failed to reach their growth potential. In previous work we have shown, using ROC curves, that customized standards identified a higher percentage of FGR in all cases of fetal death occurring after the 28th week 26% of stillbirths occurring in the third trimester of pregnancy were reclassified as FGR by customized growth curves. [5].
An impaired placenta might become the limiting element of fetal growth. The fetus and the placenta constitute a single morpho-functional unit and must be analyzed in their ensemble. In case of poor fetal-neonatal outcomes, placental histology allows a better understanding of the pathophysiology of adverse outcomes, and provides useful information for medicolegal considerations and for the management of subsequent pregnancies.
In a review of 104 perinatal deaths, placental examination by itself could identify the cause of fetal death in 48% to 51% of cases, and placental findings could explain the cause of death in 69% of stillbirth cases [27]. These findings coincide with other reviews reporting 35% to 88% of stillbirth cases having placental findings causative of death [28]. In this study we focused on stillborn cases with a post-natal diagnosis of abnormally low fetal weight the objective was to analyze placental characteristics, to explore if small for gestational age stillborn fetuses exhibited particular placental lesions. Comparing live-born babies from pregnancy affected by FGR and live-born from low-risk pregnancy with stillbirth, we observed an increased rate of placental lesions in stillborn cases, 14.6% vs 5.1% vs 1.9% in those with growth failure.
Obstructive lesions seem to be the main conditions associated to with low fetal weight in our stillborn cases in fact, they were present in 54.6% of all stillbirths and 58.9% of SGA/stillbirths, while only in 7.5% of live births from low-risk pregnancy and in 23.5% of late FRG livebirths. This finding suggests that these placental abnormalities may play a crucial role. Also the relationship between obstructive lesions and adaptive lesions have a predominant function in the placentas of stillborn and liveborn with growth failure. We found adaptive lesions in more than half of SGA/stillbirths, in 49% of FGR livebirths and also in 35.8% of placentas from low-risk pregnancy. Moreover, our results show that the ratio of obstructive/adaptive lesions, and not the absolute rate of one type of these histological findings, strongly connected to adverse outcome. Chorionic villi adapt their development on the basis of environmental conditions. During chronic hypoxia placental villi could develop a heterogeneous pattern, showing accelerated maturity, small size and focal hypervascularity (chorangiosis) [29].
Unfortunately we still do not know what kind of injury plays a principal role in the placental dysfunction affecting fetal growth. In our study it is clear that obstructive lesions have a predominant role but if the placenta develops adaptive and compensatory mechanisms this can allow the fetus to survive. This hypothesis can be supported by detecting the highest number of obstructive findings in absence of an adequate number of adaptive lesions when we compare AGA stillbirths with AGA live births. Therefore the identification of this placental pattern in cases of abnormal pregnancy outcome could provide valuable information on the etiopathogenesis of the adverse event [30].
In conclusion, our study compares a population of stillbirths with live births after FGR during pregnancy, and healthy fetuses after uneventful pregnancies, analyzing the differences in placental characteristics. We confirm that several cases of stillbirth may occur in pregnancies unexpectedly affected by intrauterine growth restriction and that customized curves are the best method to assess, even retrospectively, whether a fetus has reached its growth potential. We found that placental evaluation can reveal chronic histological signs that might help to understand the pathophysiology leading to the unfavorable outcome.
Description
HCI Models, Theories, and Frameworks provides a thorough pedagological survey of the science of Human-Computer Interaction (HCI). HCI spans many disciplines and professions, including anthropology, cognitive psychology, computer graphics, graphical design, human factors engineering, interaction design, sociology, and software engineering. While many books and courses now address HCI technology and application areas, none has addressed HCI’s multidisciplinary foundations with much scope or depth. This text fills a huge void in the university education and training of HCI students as well as in the lifelong learning and professional development of HCI practitioners. Contributors are leading researchers in the field of HCI. If you teach a second course in HCI, you should consider this book.
This book provides a comprehensive understanding of the HCI concepts and methods in use today, presenting enough comparative detail to make primary sources more accessible. Chapters are formatted to facilitate comparisons among the various HCI models. Each chapter focuses on a different level of scientific analysis or approach, but all in an identical format, facilitating comparison and contrast of the various HCI models. Each approach is described in terms of its roots, motivation, and type of HCI problems it typically addresses. The approach is then compared with its nearest neighbors, illustrated in a paradigmatic application, and analyzed in terms of its future.
This book is essential reading for professionals, educators, and students in HCI who want to gain a better understanding of the theoretical bases of HCI, and who will make use of a good background, refresher, reference to the field and/or index to the literature.
Cardiovascular Physiology, 11th Edition
Gain a foundational understanding of cardiovascular physiology and how the cardiovascular system functions in health and disease. Cardiovascular Physiology, a volume in the Mosby Physiology Series, explains the fundamentals of this complex subject. . view more
Gain a foundational understanding of cardiovascular physiology and how the cardiovascular system functions in health and disease. Cardiovascular Physiology , a volume in the Mosby Physiology Series, explains the fundamentals of this complex subject in a clear and concise manner, while helping you bridge the gap between normal function and disease with pathophysiology content throughout the book.
- Helps you easily master the material in a systems-based curriculum with learning objectives, Clinical Concept boxes, highlighted key words and concepts, chapter summaries, self-study questions, and a comprehensive exam to help prepare for USMLEs.
- Keeps you current with the latest concepts in vascular, molecular, and cellular biology as they apply to cardiovascular function, thanks to molecular commentaries in each chapter.
- Includes clear, 2-color diagrams that simplify complex concepts.
- Features clinical commentaries that show you how to apply what you've learned to real-life clinical situations.
- Enhanced eBook version included with purchase. Your enhanced eBook allows you to access all of the text, figures, and references from the book on a variety of devices.
Complete the Mosby Physiology Series! Systems-based and portable, these titles are ideal for integrated programs.
| ISBN Number | 9780323594844 |
|---|---|
| Main Author | By Achilles J. Pappano, PhD and Withrow Gil Wier, PhD |
| Copyright Year | 2019 |
| Edition Number | 11 |
| Format | Book |
| Trim | 235 x 191 (7 1/2 x 9 1/4) |
| Illustrations | Approx. 230 illustrations (230 in full color) |
| Imprint | Elsevier |
| Page Count | 300 |
| Publication Date | 29 Oct 2018 |
| Stock Status | IN STOCK |
Chapter 1 OVERVIEW OF THE CIRCULATION AND BLOOD
Blood Is Divided into Groups by Antigens Located on Erythrocytes
Chapter 2 EXCITATION: THE CARDIAC ACTION POTENTIAL
Cardiac Action Potentials Consist of Several Phases
The Principal Types of Cardiac Action Potentials Are the Slow and Fast Types
Ionic Basis of the Resting Potential
The Fast Response Depends Mainly on Voltage-Dependent Sodium Channels
Ionic Basis of the Slow Response
Conduction in Cardiac Fibers Depends on Local Circuit Currents
Conduction of the Fast Response
Conduction of the Slow Response
Cardiac Excitability Depends on the Activation and Inactivation of Specific Currents
Chapter 3 AUTOMATICITY: NATURAL EXCITATION OF THE HEART
The Heart Generates Its Own Pacemaking Activity
Ionic Basis of Automaticity
An Impulse Can Travel Around a Reentry Loop
Afterdepolarizations Lead to Triggered Activity
Electrocardiography Displays the Spread of Cardiac Excitation
Dysrhythmias Occur Frequently and Constitute Important Clinical Problems
Altered Sinoatrial Rhythms
Atrioventricular Transmission Blocks
Chapter 4 THE CARDIAC PUMP
The Microscopic and Gross Structures of the Heart
Cardiac Muscle (myocardial) Cell Morphology
Structure of the Heart: Atria, Ventricles, and Valves
The Force of Cardiac Contraction Is Determined by Excitation-Contraction Coupling and the Initial Sarcomere Length of the Myocardial Cells
Excitation-Contraction Coupling Is Mediated by Calcium
Mechanics of Cardiac Muscle
The Sequential Contraction and Relaxation of the Atria and Ventricles Constitute the Cardiac Cycle
Echocardiography Reveals Movement of the Ventricular Walls and of the Valves
The Two Major Heart Sounds Are Produced Mainly by Closure of the Cardiac Valves
The Pressure-Volume Relationships in the Intact Heart
Passive or Diastolic Pressure-Volume Relationship
Active or End-Systolic Pressure-Volume Relationship
Pressure and Volume during the Cardiac Cycle: The P-V Loop
Preload and Afterload during the Cardiac Cycle
The Fick Principle Is Used to Determine Cardiac Output
Metabolism of ATP and its Relation to Mechanical Function
Interrelation between Fatty Acid and Carbohydrate Metabolism
Effects of plasma substrate and insulin levels
Cardiac O 2 Consumption and the Link between Ventricular Function and Cardiac Metabolism
Chapter 5 REGULATION OF THE HEARTBEAT
Heart Rate is Controlled Mainly by the Autonomic Nerves
Higher Centers Also Influence Cardiac Performance
Heart Rate Can Be Regulated via the Baroreceptor Reflex
The Bainbridge Reflex and Atrial Receptors Regulate Heart Rate
Respiration Induces a Common Cardiac Dysrhythmia
Activation of the Chemoreceptor Reflex Affects Heart Rate
Ventricular Receptor Reflexes Play a Minor Role in the Regulation of Heart Rate
Myocardial Performance Is Regulated by Intrinsic Mechanisms
The Frank-Starling Mechanism Is an Important Regulator of Myocardial Contraction Force
Changes in Heart Rate Affect Contractile Force
Myocardial Performance Is Regulated by Nervous and Humoral Factors
Cardiac Performance Is Also Regulated by Hormonal Substances
Chapter 6 HEMODYNAMICS
Velocity of the Bloodstream Depends on Blood Flow and Vascular Area
Blood Flow Depends on the Pressure Gradient
Relationship Between Pressure and Flow Depends on the Characteristics of the Conduits
Resistances in Series and in Parallel
Flow May Be Laminar or Turbulent
Shear Stress on the Vessel Wall
Rheologic Properties of Blood
Chapter 7 THE ARTERIAL SYSTEM
The Hydraulic Filter Converts Pulsatile Flow to Steady Flow
Arterial Elasticity Compensates for the Intermittent Flow Delivered by the Heart
The Arterial Blood Pressure Is Determined by Physical and Physiological Factors
Total Peripheral Resistance and Arterial Diastolic Pressure
The Pressure Curves Change in Arteries at Different Distances from the Heart
Blood Pressure Is Measured by a Sphygmomanometer in Human Patients
Chapter 8 The MICROCIRCULATION AND LYMPHATICS
Arterioles Are the Stopcocks of the Circulation
Capillaries Permit the Exchange of Water, Solutes, and Gases
The Law of Laplace Explains How Capillaries Can Withstand High Intravascular Pressures
The Endothelium Plays an Active Role in Regulating the Microcirculation
The Endothelium is at the Center of Flow-Initiated Mechanotransduction
The Endothelium Plays a Passive Role in Transcapillary Exchange
Diffusion Is the Most Important Means of Water and Solute Transfer Across the Endothelium
Diffusion of Lipid-Insoluble Molecules Is Restricted to the Pores
Lipid-Soluble Molecules Pass Directly Through the Lipid Membranes of the Endothelium and the Pores
Capillary Filtration Is Regulated by the Hydrostatic and Osmotic Forces Across the Endothelium
Balance of Hydrostatic and Osmotic Forces
The Capillary Filtration Coefficient Provides a Method to Estimate the Rate of Fluid Movement Across the Endothelium
Hypoxia-inducible factor(s) and angiogenesis
Pinocytosis Enables Large Molecules to Cross the Endothelium
The Lymphatics Return the Fluid and Solutes That Escape Through the Endothelium to the Circulating Blood
Chapter 9 The PERIPHERAL CIRCULATION AND ITS CONTROL
The Functions of the Heart and Large Blood Vessels
Contraction and Relaxation of Arteriolar Vascular Smooth Muscle Regulate Peripheral Blood Flow
Cytoplasmic Ca ++ Is Regulated to Control Contraction, via MLCK
Contraction Is Controlled by Excitation-Contraction Coupling and/or Pharmacomechanical Coupling
Control of Vascular Tone by Catecholamines
Control of Vascular Contraction by Other Hormones, Other Neurotransmitters, and Autocoids
Intrinsic Control of Peripheral Blood Flow
Autoregulation and the Myogenic Mechanism Tend to Keep Blood Flow Constant
The Endothelium Actively Regulates Blood Flow
Tissue Metabolic Activity Is the Main Factor in the Local Regulation of Blood Flow
Extrinsic Control of Peripheral Blood Flow Is Mediated Mainly by the Sympathetic Nervous System
Impulses That Arise in the Medulla Descend in the Sympathetic Nerves to Increase Vascular Resistance
Sympathetic Nerves Regulate the Contractile State of the Resistance and Capacitance Vessels
The Parasympathetic Nervous System Innervates Blood Vessels Only in the Cranial and Sacral Regions of the Body
Epinephrine and Norepinephrine Are the Main Humoral Factors That Affect Vascular Resistance
The Vascular Reflexes Are Responsible for Rapid Adjustments of Blood Pressure
The Peripheral Chemoreceptors Are Stimulated by Decreases in Blood Oxygen Tension and pH and by Increases in Carbon Dioxide Tension
The Central Chemoreceptors Are Sensitive to Changes in Paco 2
Balance Between Extrinsic and Intrinsic Factors in Regulation of Peripheral Blood Flow
Chapter 10 CONTROL OF CARDIAC OUTPUT: COUPLING OF HEART AND BLOOD VESSELS
Factors Controlling Cardiac Output
The Cardiac Function Curve Relates Central Venous Pressure (Preload) to Cardiac Output
Preload or Filling Pressure of the Heart
Factors That Change the Cardiac Function Curve
The Vascular Function Curve Relates Central Venous Pressure to Cardiac Output
Mathematical Analysis of the Vascular Function Curve
Venous Pressure Depends on Cardiac Output
Cardiac Output and Venous Return Are Closely Associated
The Heart and Vasculature Are Coupled Functionally
The Right Ventricle Regulates Not Only Pulmonary Blood Flow but Also Central Venous Pressure
Heart Rate Has Ambivalent Effects on Cardiac Output
Ancillary Factors Affect the Venous System and Cardiac Output
Muscular Activity and Venous Valves
Chapter 11 CORONARY CIRCULATION
Functional Anatomy of the Coronary Vessels
Coronary Blood Flow Is Regulated by Physical, Neural, and Metabolic Factors
Neural and Neurohumoral Factors
Diminished Coronary Blood Flow Impairs Cardiac Function
Energy Substrate Metabolism During Ischemia
Coronary Collateral Vessels Develop in Response to Impairment of Coronary Blood Flow
Chapter 12 SPECIAL CIRCULATIONS
Skin Blood Flow Is Regulated Mainly by the Sympathetic Nervous System
Ambient Temperature and Body Temperature Play Important Roles in the Regulation of Skin Blood Flow
Skin Color Depends on the Volume and Flow of Blood in the Skin and on the Amount of O 2 Bound to Hemoglobin
Skeletal Muscle Circulation
Regulation of Skeletal Muscle Circulation
Local Factors Predominate in the Regulation of Cerebral Blood Flow
The Pulmonary and Systemic Circulations Are in Series with Each Other
Regulation of the Pulmonary Circulation
The Renal Circulation Affects the Cardiac Output
The Renal Circulation Is Regulated by Intrinsic Mechanisms
The Splanchnic Circulation Provides Blood Flow to the Gastrointestinal Tract, Liver, Spleen, and Pancreas
Changes in the Circulatory System at Birth
Chapter 13 INTERPLAY OF CENTRAL AND PERIPHERAL FACTORS THAT CONTROL THE CIRCULATION
Mild to Moderate Exercise
Limits of Exercise Performance
Physical Training and Conditioning
Hemorrhage Evokes Compensatory and Decompensatory Effects on the Arterial Blood Pressure
The Compensatory Mechanisms Are Neural and Humoral
The Decompensatory Mechanisms Are Mainly Humoral, Cardiac, and Hematologic
Laparoscopic Sleeve Gastrectomy for Morbid Obesity in Patients After Orthotopic Liver Transplant: a Matched Case-Control Study
Obesity is frequently encountered in patients with orthotopic liver transplant (OLT). The role of bariatric surgery is still unclear for this specific population. The aim of this study was to review our experience with laparoscopic sleeve gastrectomy (LSG) after OLT.
Material and Methods
We performed a retrospective case-control study of patients undergoing LSG after OLT from 2010 to 2016. OLT-LSG patients were matched by age, sex, body mass index (BMI), and year to non-OLT patients undergoing LSG. Demographics, operative variables, postoperative events, and long-term weight loss with comorbidity resolution were collected and compared between cases and controls.
Results
Of 303 patients undergoing LSG, 12 (4%) had previous OLT. They were matched to 36 non-OLT patients. No difference was found between groups in the American Society of Anesthesiologists class, mean operative time, or postoperative morbidity. The non-OLT group, however, had a significantly shorter mean hospital stay than the OLT group (1.7 vs 3.1 days P < .001). There were no conversions to open procedures. For patients with long-term follow-up, change in BMI after LSG was similar between the groups, but the non-OLT patients had significantly more excess body weight loss at 2 years (53.7 vs 45.2% P < .001). Similar resolution of comorbid conditions was noted in both groups. LSG caused no changes in dosage of immunosuppressive medications, and no liver complications occurred.
Conclusion
LSG after OLT in appropriately selected patients appears to have similar outcomes to LSG in non-OLT patients.
Case–control study of risk of Parkinson's disease in relation to hypertension, hypercholesterolemia, and diabetes in Japan
This case–control study investigated the associations of a history of hypertension, hypercholesterolemia, and diabetes mellitus with the risk of Parkinson's disease (PD) in Japan. Included were 249 cases within 6 years of onset of PD. Controls were 368 inpatients and outpatients without a neurodegenerative disease. Data on the vascular risk factors and confounders were obtained from a self-administered questionnaire. The vascular risk factors were defined based on drug treatment. Adjustment was made for sex, age, region of residence, pack-years of smoking, years of education, leisure-time exercise, body mass index, dietary intake of energy, cholesterol, vitamin E, alcohol, and coffee and the dietary glycemic index. The proportions of hypertension, hypercholesterolemia, and diabetes mellitus prior to the onset of PD were 23.7%, 9.6%, and 4.0%, respectively, in cases. Hypertension, hypercholesterolemia, and diabetes mellitus were significantly associated with a decreased risk of PD: the adjusted ORs were 0.43 (95% CI: 0.29–0.64), 0.58 (95% CI: 0.33–0.97), and 0.38 (95% CI: 0.17–0.79), respectively. No significant differences were observed in the association of vascular risk factors with the risk of PD between men and women. We found evidence of significant inverse associations of hypertension, hypercholesterolemia, and diabetes mellitus with the risk of PD in Japan. Further well-designed investigations of the association of vascular risk factors with the risk of PD are needed, particularly large-scale prospective studies in Asia.
