Association between angiotensin-converting enzyme (ACE) gene I/D polymorphism with the risk of knee OA: A systematic review, meta-analysis, and meta-regression.

Background: Previous studies have linked genetics to knee osteoarthritis. Angiotensin-converting enzyme (ACE) gene I/D polymorphism may cause OA. However, evidence remains inconsistent. This study examines knee OA risk and ACE gene I/D polymorphism. Methods: We explored Europe PMC, Medline, Scopus, and Cochrane Library using keywords. Three assessment bias factors were assessed using the Newcastle-Ottawa Scale (NOS). Criteria for inclusion: (1) Split the study population into knee OA patients and healthy controls; (2) Analysed the ACE gene I/D polymorphism; (3) Case-control or cross-sectional surveys. Studies with non-knee OA, incomplete data, and no full-text were excluded. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated using random-effect models. Results: A total of 6 case-control studies consist of 1,226 patients with knee OA and 1,145 healthy subjects as controls were included. Our pooled analysis revealed that a significant association between ACE gene I/D polymorphism and risk of knee OA was only seen in the dominant (DD + ID vs. II) [OR 1.69 (95% CI 1.14 - 2.50), p = 0.009, I2 = 72%], and ID vs. II [OR 1.37 (95% CI 1.01- 1.86), p = 0.04, I2 = 43%] genotype models. Other genotype models, including recessive (DD vs. ID + II), alleles (D vs. I), DD vs. ID, and DD vs. II models did not show a significant association with knee OA risk. Further regression analysis revealed that ethnicity and sex may influence those relationships in several genotype models. Conclusions: Dominant and ID vs. II ACE gene I/D polymorphism models increased knee OA risk significantly. More research with larger samples and different ethnic groups is needed to confirm our findings. After ethnicity subgroup analysis, some genetic models in our study showed significant heterogeneities, and most studies are from Asian countries with Asian populations, with little evidence on Arabs.

Dynamic interaction of obesity, age, MCP-1 Level, and ACE-1 gene with the severity of knee osteoarthritis: a cross-sectional study.

The risk factors most strongly associated with knee osteoarthritis (OA) are old age and obesity. However, few studies have evaluated the interaction between aging and obesity in conjunction with inflammatory markers and knee OA severity as part of a complete assessment of knee OA management. Therefore, this study aims to evaluate the interaction between obesity, age, inflammation [including the I/D polymorphism of angiotensin converting enzyme-1 (ACE-1)], and the severity of knee OA. Methods: A total of 80 knee OA patients were included in this cross-sectional study. The severity of knee OA was determined based on the Kellgren-Lawrence system. All patients underwent physical and radiological examination; monocyte chemoattractant protein 1 (MCP-1) markers were measured. The parameters of the ACE-1 gene were examined with sequencing DNA. Results: There was a significant relationship between age and severity of knee OA (P=0.007), with subjects aged greater than or equal to 65 having a 3.56-fold higher risk of developing moderate to severe OA than subjects aged less than 65. There was a significant difference between body weight and knee OA severity (P=0.026), in which subjects weighing greater than or equal to 60 kg had 3.14 times the risk of experiencing severe knee OA. Multivariate regression analysis indicated that age was the strongest independent variable for knee OA severity compared with body weight. MCP-1 levels were significantly higher in mild knee OA than in moderate to severe knee OA. The DD genotype of the ACE-1 gene increases the risk of severe knee OA by four times in subjects aged greater than or equal to 65 compared to subjects aged less than 65. However, the DD genotype of the ACE-1 gene does not increase the risk of severe knee OA in subjects weighing greater than or equal to 60 kg. Conclusion: While obesity and age were found to be associated with the severity of knee OA, age emerged as the independent risk factor for knee OA severity. Furthermore, MCP-1 levels were significantly higher in cases of mild knee OA compared to severe knee OA. It was observed that the DD genotype of the ACE-1 gene increases the risk of severe knee OA in individuals aged 65 years or older.

Congenital talipes equinovarus: A literature review.

Congenital talipes equinovarus (CTEV) is a congenital disability characterized by leg deformities in the cavus, adducts, varus, and equinus. The etiology of CTEV is poorly understood, despite its incidence ranging from 0.76 to 3.49 cases per 1000 live births in Indonesia. CTEV involves the fixation of the foot in the adducts, varus, and equinus with concurrent soft tissue anomalies. Despite advances in treatment, disability often persists. Theoretical models have been proposed for neurological, vascular, connective tissue, bone, and muscular causes; however, the currently available data suggests that mild cases are associated with intrauterine position. CTEV's etiology appears to involve a hereditary component, as its prevalence varies by ethnic group. Genetic factors have been identified in 24-50% of cases, depending on the community studied. Based on a complex segregation analysis, the most plausible inheritance pattern is a single large-effect gene interacting with a polygenic background.

Hypothyroidism in Bangladesh: Is Autoimmunity the Next Big Threat?

In many low and middle-income countries, iodine-deficient hypothyroidism leads to complex public health consequences. However, increasing evidence from population-based studies has linked thyroid autoimmunity with excess iodine intake. The iodine supplementation program in Bangladesh was a success story. This cross-sectional study aims to assess the pattern and predictors of autoimmunity among Bangladeshi hypothyroid patients. In this study, 154 consecutive, newly detected, biochemically-confirmed patients with primary hypothyroidism were recruited from the Endocrinology outpatient department of Bangabandhu Sheikh Mujib Medical University and tested for anti-thyroid peroxidase and anti-thyroglobulin antibody levels from October 2015 and November 2016. Patterns of thyroid autoimmunity were assessed via descriptive statistics. Predictors of autoimmunity were assessed with multivariable mixed-effect logistic regression. The mean age of participants was 36.1±11.0 years, and 70.1% were female. The frequency of thyroid autoimmunity in the study subjects was very high, 89.0% were positive for either anti-TPO or anti-Tg antibodies and 48.7% were positive for both. More participants were positive for anti-TPO antibodies (82.5%) than anti-Tg antibodies (55.2%). The risk of autoimmunity was associated with the thyroid's structural abnormalities but not with functional status. Weight gain and hypertension were associated with autoimmunity, whereas diabetes was protective against autoimmunity.

Antithyroid Antibody Status in Non-Pregnant Adult Bangladeshi Patients with Subclinical Hypothyroidism.

Sub clinical hypothyroidism (SCH) is common in clinical practice. Autoimmunity is thought to be the most important cause of SCH. In this cross-sectional study, we investigated 120 SCH patients and 100 healthy controls attending the Endocrinology Outpatient Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from June 2014 to April 2015 for anti-thyroid antibodies (anti-TPO and anti-Tg). Measurement of serum TSH, FT4, anti-TPO, and anti-Tg antibodies were done by using the chemiluminescent sequential immunometric assay. SCH patients had a higher mean age; the frequencies of female subjects, those having family history of thyroid disease or other autoimmune diseases, and goiter were higher in SCH group than in the control group. Forty-five percent (45%) of SCH patients were positive for anti-thyroid antibodies (23.3% for both anti-TPO and anti-Tg, 16.7% for only anti-TPO, and 5% positive for only anti-Tg) in comparison to only 10% anti-thyroid antibody positive controls (none for both antibodies, 8% for only anti-TPO, and 2% positive for only anti-Tg). The SCH subjects in the lower age group, females and with a TSH >10µIU/mL had the higher frequency of thyroid autoimmunity. Female gender, high socioeconomic condition, the presence of other autoimmune diseases, the presence of goiter and TSH >10µIU/mL were associated with higher odds of anti-thyroid antibody positivity in the SCH group, though none were statistically significant. The frequency of anti-thyroid antibody was higher in SCH and was more prevalent among the females, younger patients and those having a goiter, other autoimmune diseases, and TSH >10µIU/mL.

Development of the geniculocortical pathway in rats.

Most cell of the dorsal laterial geniculate nucleus of rats are generated on fetal days 12 to 14. Their axons invade the telencephalon on fetal day 16 and run in the intermediate zone just below the cortical plate, reaching the visual area of fetal day 18. The axons do not invade the cortical plate significantly until close to birth (day 22 of gestation) and reach their zone of terminal distribution between postnatal days 1 and 4. In subsequent days the projection becomes progressively more heavily distrubuted in layers IV and I, and synapses of thalamic origin can be identified in these layers. While cells destined for layers IV cross the intermediate zone at the time that thalamic axons first arrive, this coincidence of growth does not seem to be a factor which determines the specificity of patterns of thalamocortical connections since the cells reach layer IV several days before the axons. It is unclear why the axons should wait several days in the region immediately below the cortical plate before invading; although there is a parallel in previous studies on the development of the chick retinotectal pathway (Crossland et al., '75).

Anatomical connections of the primate pretectal nucleus of the optic tract.

The pretectal nucleus of the optic tract (NOT) plays an essential role in optokinetic nystagmus, the reflexive movements of the eyes to motion of the entire visual scene. To determine how the NOT can influence structures that move the eyes, we injected it with lectin-conjugated horseradish peroxidase and characterized its afferent and efferent connections. The NOT sent its heaviest projection to the caudal half of the ipsilateral dorsal cap of Kooy in the inferior olive. The rostral dorsal cap was free of labeling. The NOT sent lighter, but consistent, projections to other visual and oculomotor-related areas including, from rostral to caudal, the ipsilateral pregeniculate nucleus, the contralateral NOT, the lateral and medial terminal nuclei of the accessory optic system bilaterally, the ipsilateral dorsolateral pontine nucleus, the ipsilateral nucleus prepositus hypoglossi, and the ipsilateral medial vestibular nucleus. The NOT received input from the contralateral NOT, the lateral terminal nuclei bilaterally, and the ipsilateral pregeniculate nucleus. Although our injections involved the pretectal olivary nucleus (PON), there was neither orthograde nor retrograde labeling in the contralateral PON. Our results indicate that the NOT can influence brainstem preoculomotor pathways both directly through the medial vestibular nucleus and nucleus prepositus hypoglossi and indirectly through both climbing and mossy fiber pathways to the cerebellar flocculus. In addition, the NOT communicates strongly with other retino-recipient zones, whose neurons are driven by either horizontal (contralateral NOT) or vertical (medial and lateral terminal nuclei) fullfield image motion.

Transneuronal pathways to the vestibulocerebellum.

The alpha-herpes virus (pseudorabies, PRV) was used to observe central nervous system (CNS) pathways associated with the vestibulocerebellar system. Retrograde transneuronal migration of alpha-herpes virions from specific lobules of the gerbil and rat vestibulo-cerebellar cortex was detected immunohistochemically. Using a time series analysis, progression of infection along polyneuronal cerebellar afferent pathways was examined. Pressure injections of > 20 nanoliters of a 10(8) plaque forming units (pfu) per ml solution of virus were sufficient to initiate an infectious locus which resulted in labeled neurons in the inferior olivary subnuclei, vestibular nuclei, and their afferent cell groups in a progressive temporal fashion and in growing complexity with increasing incubation time. We show that climbing fibers and some other cerebellar afferent fibers transported the virus retrogradely from the cerebellum within 24 hours. One to three days after cerebellar infection discrete cell groups were labeled and appropriate laterality within crossed projections was preserved. Subsequent nuclei labeled with PRV after infection of the flocculus/paraflocculus, or nodulus/uvula, included the following: vestibular (e.g., z) and inferior olivary nuclei (e.g., dorsal cap), accessory oculomotor (e.g., Darkschewitsch n.) and accessory optic related nuclei, (e.g., the nucleus of the optic tract, and the medial terminal nucleus); noradrenergic, raphe, and reticular cell groups (e.g., locus coeruleus, dorsal raphe, raphe pontis, and the lateral reticular tract); other vestibulocerebellum sites, the periaqueductal gray, substantia nigra, hippocampus, thalamus and hypothalamus, amygdala, septal nuclei, and the frontal, cingulate, entorhinal, perirhinal, and insular cortices. However, there were differences in the resulting labeling between infection in either region. Double-labeling experiments revealed that vestibular efferent neurons are located adjacent to, but are not included among, flocculus-projecting supragenual neurons. PRV transport from the vestibular labyrinth and cervical muscles also resulted in CNS infections. Virus propagation in situ provides specific connectivity information based on the functional transport across synapses. The findings support and extend anatomical data regarding vestibulo-olivo-cerebellar pathways.

Asymmetric responses in cortical visually evoked potentials to motion are not derived from eye movements.

PURPOSE: Normal neonates and many adults after abnormal visual development have directional preferences for visual stimulus motions; i.e., they give better responses for optokinetic nystagmus (OKN) and visually evoked potentials (VEPs) in one direction than to those in the opposite direction. The authors tested whether the VEP responses were asymmetrical because of abnormal eye movements. METHODS: VEPs were recorded from the visual cortices of five macaque monkeys: one normal, one neonate, and three reared with alternating monocular occlusion (AMO). They were lightly anesthetized, followed by paralysis to prevent eye movements. They then had "jittered" vertical grating patterns presented in their visual fields. The steady state VEPs were analyzed with discrete Fourier transforms to obtain the amplitudes and phases of the asymmetries. RESULTS: The normal, control monkey had small, insignificant amplitudes of its asymmetrical Fourier component and random phases that were not 180 degrees out of phase across the left and right eyes. The neonatal monkey and the AMO monkeys all had large, significant asymmetries that were approximately 180 degrees out of phase between the left and right eyes. CONCLUSIONS: The neonate and abnormally reared monkeys continued to have asymmetrical responses even after their eyes were paralyzed. Therefore, eye movements cannot be the source of the asymmetrical amplitudes of the VEPs, and the visual cortex is at least one source responsible for asymmetries observed in neonates and adults reared under abnormal visual inputs.

Visual inputs to cerebellar ventral paraflocculus during ocular following responses.

The activity of cerebellar Purkinje cells was recorded in the ventral paraflocculus (VPFL) of alert monkeys during ocular following responses induced by brief movements of the visual scene. The mossy fiber input evoked 'simple-spikes' which increased their activity during either ipsiversive or downward motion of the visual scene. On the other hand, the 'complex-spikes' evoked by the climbing fiber input increased their activity during either contraversive or upward movement. To further define the sources of the visual input to the VPFL, we recorded single units in the dorsolateral pontine nucleus (DLPN), which is known to project to the VPFL as mossy fibers, and in the pretectal nucleus of the optic tract (NOT), which is known to project to the inferior olive whose neurons project to the cerebellum as climbing fibers. In both areas, most neurons were directionally selective, and responded to the moving visual scene with very short latencies (approximately 40-60 ms). These results suggest that both DLPN and NOT neurons deliver information concerning movements of the visual scene to the VPFL through different pathways.

Prior strabismus protects kitten cortical neurons from the effects of monocular deprivation.

The effects of 8 days of monocular eyelid suture beginning at 45 days of age were compared in normal kittens and in kittens which had been made strabismic by surgery early in life. In both groups of animals, monocular deprivation increased the relative strength of inputs from the non-deprived eye at the cortical level, but this effect was clearly less pronounced in the strabismic animals. The reduced effect of monocular deprivation in strabismic animals was observed mainly in the cortical hemisphere contralateral to the deprived eye.

The anatomical organization of the macaque pregeniculate complex.

Saccade-related activity recorded in the primate pregeniculate nucleus, and its anatomical connections with the pretectal nucleus of the optic tract (NOT) and superior colliculus (SC), suggest that it plays a role in visual-ocular motor integration. To study this role, a clearer understanding of pregeniculate organization is required. Based on its connectivity and neurotransmitter immunocytochemistry, we demonstrate that this nucleus is composed of several subnuclei, suggesting the term, pregeniculate complex (PrGC). The PrGC includes a weakly developed dorsal lamina, rostrally, and a well-developed ventral lamina. The ventral lamina includes the retinorecipient and superior sublayers, rostrally, and the medial division, caudally. A thin lamina of cells lateral to the dorsal lateral geniculate nucleus is contiguous with the PrGC; we term this the lateral division. The PrGC and the lateral division each project to the SC/NOT; the superior sublayer and medial division of the PrGC are connected reciprocally to the SC/NOT. Immunocytochemistry for gamma-aminobutyric acid (GABA) and substance P (SP) further delineate the PrGC subnuclei. The retinorecipient sublayer stains most intensely for GABA and SP. The superior sublayer and medial division also stain strongly for GABA and SP. Essentially all neurons in the lateral division are GABA-positive. The combination of tract tracing and immunocytochemistry demonstrate differences in the connectivity of the PrGC subnuclei and the lateral division with the SC/NOT. This, combined with the differential localization of GABA in the PrGC, provides a basis for further study of its functional role.

An aberrant crossed visual corticotectal pathway in albino rats.

This study investigates the dynamic nature of the developing corticotectal pathway arising in the visual cortex. Special attention is given to the interaction occurring between the corticotectal pathways of each side of the brain and between corticotectal and retinotectal terminations. Normally the visual cortex of rats projects only to the ipsilateral superior colliculus. If one visual cortex is removed at birth, the remaining visual cortex subsequently shows a bilateral projection to the superior colliculus. The aberrant corticotectal pathway is heavier if the cortical ablation is accompanied by eye removal at birth but eye enucleation alone is not a sufficient stimulus for production of a crossed corticotectal projection. The aberrant crossed pathway shows a topographic order which appears to correspond to that of the normal ipsilateral corticotectal pathway. The pathway differs from the aberrant projections from the retina in that lesions done as late as 20 days postnatal still result in an aberrant crossed corticotectal pathway. This is similar to the aberrant crossed cortical projections from sensorimotor cortex. The pathway would appear to arise as a result of lack of competition from corticotectal axons normally present contralaterally or from attraction of denervated corticotectal sites. While denervated retinotectal sites stimulate sprouting of the corticotectal axons once in the deafferented colliculus, they do not stimulate crossing of the corticotectal projection.

Histogenesis of the superior colliculus of the albino rat: a tritiated thymidine study.

The pattern of generation of neurons in the albino rat superior colliculus has been studied in adult and fetal material. Neurons are generated between embryonic days 12 to 17, with rostrolateral colliculus in advance of caudomedial parts. More of the cells contributing to the deeper layers are generated early, while more of the later generated cells are located superficially. The cells of individual laminae are not formed on specific days as in the cortex, nor are the complicated gradients described previously for the chick optic tectum evident. While the largest cells (found deep in the colliculus) are among the first formed and the small marginal cells among the last, there is in general a broad range of cell size being generated at any one time. The observed patterns are consistent with the concept of simultaneous production of several cell types from the ventricular epithelium on any given day. Studies of material at short times after [3H]thymidine injection allow correlation of the time of arrival of cells in their appropriate layer with time of arrival of afferents. In addition they suggest that factors controlling the final placement of cells in the mature nervous system is a very complex process and may involve some form of intercellular recognition.

Orexin-A inputs onto visuomotor cell groups in the monkey brainstem.

Orexin-A, synthesized by neurons of the lateral hypothalamus helps to maintain wakefulness through excitatory projections to nuclei involved in arousal. Obvious changes in eye movements, eyelid position and pupil reactions seen in the transition to sleep led to the investigation of orexin-A projections to visuomotor cell groups to determine whether direct pathways exist that may modify visuomotor behaviors during the sleep-wake cycle. Histological markers were used to define these specific visuomotor cell groups in monkey brainstem sections and combined with orexin-A immunostaining. The dense supply by orexin-A boutons around adjacent neurons in the dorsal raphe nucleus served as a control standard for a strong orexin-A input. The quantitative analysis assessing various functional cell groups of the oculomotor system revealed that almost no input from orexin-A terminals reached motoneurons supplying the singly-innervated muscle fibers of the extraocular muscles in the oculomotor nucleus, the omnipause neurons in the nucleus raphe interpositus and the premotor neurons in the rostral interstitial nucleus of the medial longitudinal fasciculus. In contrast, the motoneurons supplying the multiply-innervated muscle fibers of the extraocular muscles, the motoneurons of the levator palpebrae muscle in the central caudal nucleus, and especially the preganglionic neurons supplying the ciliary ganglion received a strong orexin input. We interpret these results as evidence that orexin-A does modulate pupil size, lid position, and possibly convergence and eye alignment via the motoneurons of multiply-innervated muscle fibres. However orexin-A does not directly modulate premotor pathways for saccades or the singly-innervated muscle fibre motoneurons.

MSTd neurons during ocular following and smooth pursuit perturbation.

MSTd neurons in the behaving monkey were investigated during step-ramp smooth pursuit eye movements (SPEM), short perturbations of the small visual target during ongoing pursuit, and large-field visual stimulation inducing ocular following responses (OFR). Neurons responded with short latencies to visual motion during OFR. In contrast the non-retinal responses during SPEM and perturbations followed the eye movements by 100-150 ms and were in the opposite direction to the OFR response. Often neurons were not modulated by the perturbation. Although, both the OFR and the perturbation response are involuntary eye movements due to visual motion, it seems very unlikely that these MSTd neurons with non-retinal responses are involved in their direct control. Based on these responses, we suggest that our MSTd neurons may code for gaze direction in space based on visual estimates of self-motion and extraretinal estimates of eye-in-head motion.

Enhanced motion sensitivity follows saccadic suppression in the superior temporal sulcus of the macaque cortex.

The responses of neurons in the middle temporal and medial superior temporal areas of macaque cortex are suppressed during saccades compared with saccade-like stimulus movements. We utilized the short-latency ocular following paradigm to show that this saccadic suppression is followed by postsaccadic enhancement of motion responses. The level of enhancement decays with a time constant of 100 ms from saccade end. The speed of ocular following is also enhanced after saccades and decays over a similar time course, suggesting a link between the neural and behavioral effects. There is some evidence that maximum postsaccadic enhancement occurs when cells are stimulated at their optimum speeds. Latencies of motion responses are saccade dependent: 37 ms for saccade-generated motion, 45 ms for motion in the half-second after saccades, and 70 ms with no prior saccades. The finding that saccades alter response latencies may partially explain perceptual time compression during saccades and time dilation after saccades.