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Clinical evaluation of vertigo.

In attempting to outline the clinical evaluation of these patients with vertigo we have discussed examples which range in order from benign self-limited disease to those requiring emergency surgery or extensive diagnostic evaluation. We sought also to illustrate how the logic of hypothesis testing is generally employed by clinicians in approaching this or other diagnostic problems. The examples were chosen to illustrate the indications for, as well as the limitations of, the various diagnostic modalities--caloric testing, electronystagmography, audiometric testing, roentgenographic and nuclear medicine procedures--which may be employed by the clinician. Most of the skills discussed in our paper, though traditionally accorded to the fields of neurology and otolaryngology, would seem to be fundamental for any general physician, while the problem of vertigo is an example of how common ambulatory problems may require knowledgeable approach to sort self-limited from more serious illnesses as well as to utilize procedures with purpose and efficiency.

Adult

Testing the lipid hypothesis. Clinical trials.

It is generally accepted that we still lack a conclusive answer, to whether lowering of the lipid level will prevent the development or reverse the progression of coronary atherosclerosis. Multiple risk factor intervention trials now have the merit of addressing themselves to probable and practical needs for intervening on several of the major risk factors to obtain the maximum impact on populations at risk.

Cholesterol, Dietary

Testing the TRH hypothesis of pineal function.

In the Syrian hamster gonadal involution may be induced by exposure of the animal to darkness, short photoperiod, or blindness for several weeks. These conditions also influence body metabolism by inducing a substantial decrease in thyroxin concentrations. The role of the pineal gland in these phenomena has been demonstrated by experiments showing that if pinealectomized hamsters are subjected to darkness, short photoperiod, or blindness, their gonads do not involute and plasma thyroxin levels remain normal. Since thyrotrophin releasing hormone (TRH) causes the release of both prolactin and thyrotrophin from the pituitary we can predict on theoretical grounds that TRH mediates both pineal-gonad and pineal-thyroid phenomena. Melatonin may be the pineal hormone regulating hypothalamic TRH levels.

Animals

Inavolisib for PIK3CA-mutated advanced endometrial cancer: a multicentric, phase II, MITO END-4 trial.

BACKGROUND: The phosphatase and tensin homolog-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway is frequently altered in gynecological tumors, notably in endometrial cancer where PIK3CA mutations are found in nearly half of patients. Despite this, evidence of clinical activity of PI3K inhibitors in endometrial cancer is poor and limited. Alpelisib, an oral PI3K alpha-selective inhibitor, showed encouraging preliminary activity in advanced gynecological tumors harboring PIK3CA alterations. Inavolisib is a highly potent and selective PI3K inhibitor. PRIMARY OBJECTIVE(S): The MITO END-4 trial aims to assess the efficacy and safety of inavolisib in patients with endometrial cancer who have received platinum-based chemotherapy and immunotherapy. The primary objective is to determine the anti-tumor activity (assessed by objective response rate) of inavolisib in patients with advanced endometrial cancer with PIK3CA mutated tumors. STUDY HYPOTHESIS: The study tests the hypothesis that inavolisib has superior anti-tumor activity compared to historically available standard therapies in previously treated patients with advanced endometrial cancer harboring a PIK3CA mutation. TRIAL DESIGN: This is a phase II, single-arm, multicenter trial in which advanced endometrial cancer patients whose tumors harbor a pathogenic PIK3CA mutation will receive inavolisib. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients aged 18 years and older with documented evidence of PIK3CA mutated advanced endometrial cancer (endometrioid, serous, clear cell, carcinosarcoma or mixed histology) will be enrolled. Patients have previously received at least 1 platinum-based chemotherapy in any setting (adjuvant or advanced) with or without immune checkpoint inhibitor, alone or in combination. Not more than 4 lines of therapy are allowed. Key exclusion criteria include uterine sarcoma and prior treatment with any PI3K, AKT, or mechanistic target of rapamycin (mTOR) inhibitor. PRIMARY ENDPOINT(S): Objective response rate defined as a complete response or partial response by the Investigator using RECIST v1.1 criteria over the whole treatment period. SAMPLE SIZE: 48 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL: May 2028. TRIAL REGISTRATION: MITO END-4; EU-CT NUMBER: 2025-522981-61-00; NCT07522697.

Endometrial cancer

Hyperkinesis and food additives: testing the Feingold hypothesis.

Teacher ratings, objective classroom and laboratory observational data, attention-concentration, and other psychological measures obtained on 36 school-age, hyperactive boys under experimental and control diet conditions yielded no support for the Feingold hypothesis. Parental ratings revealed positive behavioral changes for the experimental diet; however, they seemed primarily attributable to one diet sequence. Parents' behavioral ratings on ten hyperactive, preschool boys indicated a positive response to the experimental diet; again, laboratory observations showed no diet effect.

Child

The structuring of interpersonal relations in schizophrenic adolescents: a decentering analysis of Thematic Apperception Test stories.

This study tested the hypothesis that schizophrenics employ more developmentally immature levels of decentering in their structuring of interpersonal relations. A 9-point scale of interpersonal decentering, developed originally by Feffer, was applied to Thematic Appercetion Test stories produced by schizophrenic adolescents and a control group of psychiatrically disturbed patients equivalent in age and intellectual functioning. Results provided convincing support for the hypothesis tested and suggest the theoretical utility of viewing interpersonal deficit in schizophrenia from a cognitive-developmental perspective.

Adolescent

Hemoglobin ontogenesis: test of the gene excision hypothesis.

The gene excision hypothesis of hemoglobin ontogenesis was tested in persons with HbSC disease, with the use of monospecific fluorescent antibodies for the identification of hemoglobins S, C, and F in individual erythrocytes. The results are incompatible with the prediction that only one gamma- or beta-globin gene may be active in any single chromosome and provide further evidence for incomplete repression of gamma-globin genes lying cis to active beta-globin genes.

Fetal Hemoglobin

The moon illusion: a test of the vestibular hypothesis under monocular viewing conditions.

The results of earlier monocular experiments on the moon illusion have been either negative or confounded. To test the role of vestibular function, 24 subjects made forced-choice distance comparisons between stimuli mounted in translucent tubes. The stimulus tube for standard distance could be positioned in three viewing angles (45 degrees up, horizontal, and 45 degrees down). A comparison tube adjustable for distance was mounted horizontally. There was a greater perception of depth in the downward looking condition. The relatively weak effects are discussed in terms of a two-hypothesis explanation of the real-life moon illusion and the poor cues for depth perception in monocular viewing.

Astronomical Phenomena

Effect of combined dopaminergic and GABA-ergic stimulation on ouabain-induced epileptiform activity.

In this study we tested a hypothesis that dopamine and GABA receptor-stimulating agents given together might mutually potentiate their anticonvulsant activities. To test this hypothesis, experiments were performed on free-moving rabbits with epileptiform activity evoked by cortical application of ouabain. After combined treatment with apomorphine and GHBA 3 out of 6 animals displayed no EEG epileptiform activity, and in the remaining 3 rabbits this activity was greatly reduced. A combined pretreatment with apomorphine and GHBA abolished epileptiform EEG activity during the first hour and shortened it during the second hour, but not significantly. Apomorphine given together with amino-oxyacetic acid before ouabain completely abolished the epileptiform activity in 4 out of 6 animals. In the remaining 2 rabbits the latency of ouabain affect was prolonged, the epileptiform activity during the first hour was abolished, and it was markedly decreased during the next 2 hr (significantly from controls or groups receiving apomorphine or amino-oxyacetic acid). Phenytoin was less potent than apomorphine with GHBA or apomorphine given together with AOAA. The animals' behavior was observed.

Aminooxyacetic Acid

Thioredoxin interacting protein promotes invasion in hepatocellular carcinoma.

BACKGROUND: Considerable evidence suggests that oxidative stress plays an essential role in the progression of hepatocellular carcinoma (HCC). While acquired resistance to oxidative stress is the main driver of aggressive cell phenotype, the underlying mechanisms remain unknown. Here, we tested the hypothesis that elevated expression of Thioredoxin-interacting protein (TXNIP) is a main regulator of the aggressive phenotype in HCC. MATERIALS AND METHODS: To test this hypothesis, we measured TXNIP expression levels in 11 HCC cell lines by qPCR and western blotting. In addition, 80 pairs of HCC tissues and matched liver tissues of 73 cases, as well as 11 normal liver tissue samples were examined by immunohistochemistry. Besides, TXNIP expression levels were analyzed by Oncomine Platform in seven independent microarray datasets. Finally, the functional role of TXNIP in HCC was investigated in vitro and in vivo by silencing and overexpression studies. RESULTS: Our results show that TXNIP expression is significantly increased in HCC compared to non-tumor counterparts (p < 0.0001) as well as to normal (p < 0.0001) and cirrhotic (p < 0.0001) liver tissues. Moreover, stable overexpression of TXNIP in HCC cells (i) significantly increases ROS levels, (ii) induces EMT phenotype, (iii) increases motility, invasion and 3D branching tubulogenesis, (iv) decreases apoptosis, and (v) elevates in vivo metastasis in zebrafish embryos. Finally, we identify sinusoidal/stromal and cytoplasmic TXNIP staining patterns as risk factors for intrahepatic vascular invasion (p:0.0400). CONCLUSION: Our results strongly suggest that overexpression of TXNIP has a pivotal role in HCC progression by inducing cell survival, invasion, and metastasis.

EMT

An experimental investigation of the modifiability of the temporal structure of spontaneous speech.

This study attempted to test the hypothesis that the temporal structure of spontaneous speech is modifiable by reinforcing and punishing pauses, of a certain duration, in an operant conditioning situation. Pause rate was significantly affected by these contingencies: moreover, rate of change was rapid, indicating a "prepared" association between pausing and such contingencies. This study also attempted to test the hypothesis that there is a class of noncognitive pauses in monologue by punishing UPs to determine if UPs can be eliminated without affecting speech content. Although this manipulation did lead to a decline in pause rate, a significant increase in the amount of filled hesitation, particularly in repetition, resulted. This suggests that the overall amount of hesitation is fixed by the cognitive demands of the task but that a speaker is able to adapt to different interactional contexts by varying the category of hesitation used for cognitive planning.

Conditioning, Operant

Suppression of multiplication of avian sarcoma virus by rapid spread of transformation-defective virus of the same subgroup.

We have tested the hypothesis that some transformation-defective (td) viruses grow faster than the avian sarcoma viruses (ASV) from which they are derived, resulting in establishment of interference by the td virus and suppression of the ASV multiplication. Using an ASV of subgroup A (ASV-A) that does not contain td virus and an independently isolated tdASV-A, we performed separate and mixed infections to test this hypothesis. At multiplicities of 1 or less, tdASV alone grew to higher titers and more rapidly than ASV alone. In mixed infections at low multiplicities that allowed spread of progeny virus, when as little as 10% of the virus inoculum was td virus, there was an excess of td virus by 2 days after infection and a decrease in the titer of ASV relative to a control infection with no td virus. In mixed infections at high multiplicities which minimized spread of progeny virus, there was no excess of td virus and the titer of ASV was not decreased relative to the control infection with no td virus. These data support the hypothesis that we proposed and indicate that deletions in the ASV src gene may not be a high-frequency event. We also present data concerning the amounts of unintegrated viral DNA found after the separare and mixed infections. There was no simple correlation between the amounts of unintegrated viral DNA early after infection and the titers of virus produced, indicating perhaps that virus production was determined by integrated viral DNA.

Animals

Test of a novel method for analysis of the efficacy of antihypertensive drugs.

Diastolic blood-pressure data from 42 published studies, representing 23 anti-hypertensive drug regimens and 971 patients, were used to test the hypothesis that there is a linear relation between pretreatment diastolic pressure (P.T.D.P.) and the drug-induced fall in pressure (deltaD.P.), such that the "ideal-response line" relating these variables has a slope=1.0 and intercepts the P.T.D.P. axis at 90 mm Hg. Most of the regimens failed to show ideal behaviour; slopes of the regression lines were usually less than 1.0, and the intercepts were generally not at 90 mm Hg. Low coefficients of determination (r2) and broad 95% confidence intervals for the slopes and intercepts of the regression lines were common. Only 2 of the 23 regimens examined yielded r2 greater than 0.7, whereas 8 of the regimens exhibited r2 less than 0.25. These findings suggest a large interpatient variation in response to a given regimen. The data reported here show that what is thought to be an ideal-response relation for antihypertensive drug regimens is not observed in practice. However, the manner of presenting the data in order to test the hypothesis provides a useful method for assessing the effectiveness and variability of patient-responses to treatment.

Analysis of Variance

Tardive dyskinesia: a clinical test of the supersensitivity hypothesis.

Patients with tardive dyskinesia showed no significant difference in CSF HVA when compared with groups of schizophrenic or depressives. CSF cAMP in the tardive dyskinesia group was significantly lower when compared to schizophrenics but not depressives. These results do not support a dopamine-receptor supersensitivity hypothesis in permanent tardive dyskinesia.

Adult

Frontal decortication in rhesus monkeys: a test of the interference hypothesis.

Four monkeys with dorsolateral frontal ablations and 3 unoperated controls were run on discrimination problems which sequentially presented both relevant and irrelevant visual stimuli prior to the opportunity for a choice response. As previously reported, monkeys with undamaged brains performed significantly better on those problems presenting relevant information first, being unaffected by later occurring irrelevant stimuli. Contrary to the behavior of the normal monkeys, monkeys with lesions of the dorsolateral frontal cortex were severely impaired when irrelevant stimuli were presented after the relevant stimuli had been processed, but before the opportunity to respond had occurred. In other words, the frontal monkeys performed just the opposite of the normals in these procedures, even though the relevant and irrelevant stimuli were manipulated within the usual temporal definitions of the two-choice discrimination trial. These data demonstrate that the presentation of irrelevant stimuli before the choice response can significantly impair frontally decorticated monkeys and that this impairment does not require the use of a long temporal delay preceding the opportunity to respond. For this reason the data were interpreted as rather direct support of the interference hypothesis of frontal dysfunction. On the basis of these and other data discussed, it was concluded that one function of the dorsolated frontal cortex involves the suppression of interfering stimulus events interposed between the information necessary to guide behavior and the behavior itself.

Animals